Immune system

The immune system is made up of a complex network of cells, chemicals, tissues, organs, and the substances they make that helps your body fight infections and other diseases. The immune system includes white blood cells and organs and tissues of the lymph system, such as the thymus, spleen, tonsils, lymph nodes, lymph vessels, and bone marrow (see Figures 1 and 2 below). The immune system must recognize foreign invaders and abnormal cells (Table 1) and distinguish them from the body’s healthy cells. An underactive or overactive immune system can cause health issues. For example, autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, happen when the body mounts an immune response against its own tissues instead of a foreign invader. In addition, allergies occur when an individual’s immune system reacts to substances in the environment that are tolerated by most people. Underactivity of the immune system or immunodeficiency, can increase your risk of infection. You may be born with an immunodeficiency (known as primary immunodeficiency or inborn errors of immunity), or acquire it from a medical treatment or another disease (known as secondary immunodeficiency). Primary immunodeficiency are a group of more than 450 rare, chronic conditions in which part of the body’s immune system is missing or does not function correctly. Primary immunodeficiencies are caused by hereditary genetic defects and can affect anyone, regardless of age, gender, or ethnicity ¹. Because the most important function of the immune system is to protect against infection, children and adults with primary immunodeficiency commonly experience increased susceptibility to infection. The infections may be in the skin, sinuses, throat, ears, lungs, brain or spinal cord, or in the urinary or intestinal tracts. Increased susceptibility to infection may show up as repeated infections, infections that are unusually hard to cure or unusually severe infections (requires hospitalization or intravenous antibiotics).

The immune system is constantly working to protect your body from infections, injury, cancers and diseases. The immune system recognizes invaders such as bacteria, viruses and fungi as well as abnormal cells. It mounts an immune response to help the body fight the invasion. When harmful microbes (tiny particles) enter and invade your body, the body produces white blood cells to fight the infection. The white blood cells identify the microbe, produce antibodies (immunoglobulins or or gamma-globulins) to fight it, and help other immune responses to occur. They also ‘remember’ the attack. There are five major classes of antibodies (IgG, IgA, IgM, IgD, and IgE). IgG has four different subclasses (IgG1, IgG2, IgG3, IgG4). IgA has two subclasses (IgA1 and IgA2). Antibodies of the IgA class are produced near mucus membranes and find their way into secretions such as tears, intestines, bile, saliva and mucus, where they protect against infection in the respiratory tract and intestines. Antibodies of the IgM class are the first antibodies formed in response to infection. They are important in protection during the early days of an infection. Antibodies of the IgE class are responsible for allergic reactions. IgD is expressed on mature B cells along with IgM and may play some role in helping B cells differentiate into plasma cells. Recently, studies have suggested that IgD may be important in the gut homeostasis by binding to mast cells and basophils to react against pathogenic bacteria in the gut.

Antibodies protect the body against infection in a number of different ways. For example, some microorganisms, such as viruses, must attach to body cells before they can cause an infection, but antibodies bound to the surface of a virus can interfere with the virus’ ability to attach to the host cell. In addition, antibodies attached to the surface of some microorganisms can cause the activation of a group of proteins called the complement system that can directly kill some bacteria. Antibody-coated bacteria are also much easier for neutrophils to ingest and kill than bacteria that are not coated with antibodies. All of these actions of antibodies prevent microorganisms from successfully invading body tissues and causing serious infections.

The immune response is split into two functional divisions: innate and acquired immunity.

Innate immunity is the first line of defense against foreign invaders. Innate immunity involves immediate, nonspecific responses to pathogens.
Acquired immunity also called adaptive immunity, is the second line of defense against foreign invaders. Acquired immunity involves a complex, targeted response to a specific pathogen. Exposure to a pathogen stimulates the production of certain immune cells that mark the pathogen for destruction. Upon first exposure, it takes several days or weeks to develop the acquired immune response, but the involved immune cells “remember” the encounter and respond quickly upon subsequent exposure to the same pathogen.

The components of the innate and acquired immune systems communicate and work together to protect your body from infection and disease (Table 2).

Major organs of the Immune System (Figure 1):

Thymus: The thymus is an organ located in the upper chest where T cells mature. First, lymphocytes (a type of white blood cell) that are destined to become T cells leave the bone marrow and find their way to the thymus where they are then “educated” to become mature T cells.
Liver: The liver is the major organ responsible for producing proteins of the complement system. In addition, it contains large numbers of phagocytic cells (a specific type of white blood cell) that ingest bacteria in the blood as it passes through the liver.
Bone Marrow: The bone marrow is the location where all cells of the immune system begin their development from stem cells.
Tonsils: Tonsils are collections of lymphocytes in the throat.
Lymph Nodes: Lymph nodes are collections of B cells and T cells throughout the body. Cells congregate in lymph nodes to communicate with each other. Lymph nodes can become swollen when they are fighting an infection.
Spleen: The spleen is a collection of B cells, T cells, and monocytes. It serves to filter the blood and provide a site for invaders/germs and cells of the immune system to interact.
Blood: Blood is contained within the circulatory system that carries cells and proteins of the immune system from one part of the body to another.

The cells that are involved in the immune system (Figure 2):

Granulocytes include basophils, eosinophils, and neutrophils. Basophils and eosinophils are important for host defense against parasites. They also are involved in allergic reactions.
Neutrophils (also known as polymorphonuclear cells, PMNs or granulocytes), the most numerous innate immune cell (the most numerous of all the types of white blood cells), patrol for problems by circulating in the bloodstream. Neutrophils or polymorphonuclear leukocytes are found in the bloodstream and can migrate into sites of infection within a matter of minutes. These cells, like the other cells in the immune system, develop from hematopoietic stem cells in the bone marrow. Neutrophils can phagocytose, or ingest, bacteria, degrading them inside special compartments called vesicles. Neutrophils increase in number in the bloodstream during infection and are in large part responsible for the elevated white blood cell count seen with some infections. They are the cells that leave the bloodstream and accumulate in the tissues during the first few hours of an infection and are responsible for the formation of pus. Their major role is to ingest bacteria or fungi and kill them. Their killing strategy relies on ingesting the infecting organisms in specialized pockets within the cell. Neutrophils contain toxic chemicals that fuse with the bacteria-containing pockets to kill the bacteria. Neutrophils have little role in the defense against viruses.
Monocytes, which develop into macrophages, also patrol and respond to problems. Monocytes make up 5 to 10% of the white blood cells. They also line the walls of blood vessels in organs like the liver and spleen where they capture microorganisms in the blood as they pass by. When monocytes leave the bloodstream and enter the tissues, they change shape and size and become macrophages. Macrophages, “big eater” in Greek, are named for their ability to ingest and degrade bacteria. Macrophages are essential for killing fungi and the class of bacteria to which tuberculosis belongs (mycobacteria). Like neutrophils, macrophages ingest microbes and deliver toxic chemicals directly to the foreign invader to kill it. Macrophages live longer than neutrophils and are especially important for slow growing or chronic infections. Macrophages can be influenced by T cells and often collaborate with T cells in killing microorganisms. Macrophages also have important non-immune functions, such as recycling dead cells, like red blood cells, and clearing away cellular debris. These “housekeeping” functions occur without activation of an immune response. Upon activation, monocytes and macrophages coordinate an immune response by notifying other immune cells of the problem.
B cells (B lymphocytes) and often named on lab reports as CD19 or CD20 cells: These lymphocytes arise in the bone marrow from stem cells. When B cells encounter foreign germs (antigens), they respond by maturing into another cell type called plasma cells. Plasma cells are the mature B cells (mature B lymphocytes) that actually produce the antibodies (also known as immunoglobulins or gamma-globulins) and are located in the spleen and lymph nodes throughout the body. B cells can also mature into memory cells, which allows a rapid response if the same infection is encountered again. The long life of plasma cells enables your body to retain immunity to viruses and bacteria that infected you many years ago. For example, once you have been fully immunized with live vaccine strains of measles virus, you will almost never catch it because your body retain the plasma cells and antibodies for many years and these antibodies prevent infection.
T cells sometimes called T lymphocytes and often named in lab reports as CD3 cells, are another type of immune cell. Some T cells directly attack cells infected with viruses, and others act as regulators of the immune system. Each T cell reacts with one specific antigen, just as each antibody molecule reacts with one specific antigen. In fact, T cells have molecules on their surfaces that are similar to antibodies. The variety of different T cells is also so extensive that the body has T cells that can react against virtually any antigen. T cells have different abilities to recognize antigen and are varied in their function. There are killer or cytotoxic T cells (often denoted in lab reports as CD8 T cells), helper T cells (often denoted in lab reports as CD4 T cells), and regulatory T cells. Each has a different role to play in the immune system.
Cytotoxic T cells (CD8+ T cells or Killer T cells): These lymphocytes mature in the thymus and are responsible for killing cells infected with viruses. Killer T cells protect the body from certain bacteria and viruses that have the ability to survive and even reproduce within the body’s own cells. The killer T cell must migrate to the site of infection and directly bind to its target to ensure its destruction. In addition to fighting germs, killer T cells also recognize and respond to foreign tissues in the body, such as a transplanted kidney. When T cells are fighting infections, they grow and divide, making more T cells.
Helper T cells (CD4+ T-cell): Helper T cells assist B cells to produce antibodies and assist killer T cells in their attack on foreign substances.
Regulatory T cells. Regulatory T cells suppress or turn off the T cells when an infection is controlled and they are no longer needed. Regulatory T cells act as the thermostat of the lymphocyte system to keep it turned on just enough—not too much and not too little. Without regulatory T cells, the immune system would keep working even after an infection has been treated. Without regulatory T cells, there is the potential for the body to overreact to the infection.
Plasma cells: These cells develop from B cells (B lymphocytes) and are the cells that make immunoglobulin (antibodies).
Mast cells also are important for defense against parasites. Mast cells are found in tissues and can mediate allergic reactions by releasing inflammatory chemicals like histamine.
Dendritic cells (DC) also known as antigen-presenting cells (APCs), instruct T cells on what to attack. Dendritic cells (DC) also can develop from monocytes. Antigens are molecules from pathogens, host cells, and allergens that may be recognized by adaptive immune cells. APCs like DCs are responsible for processing large molecules into “readable” fragments (antigens) recognized by adaptive B or T cells. However, antigens alone cannot activate T cells. They must be presented with the appropriate major histocompatiblity complex (MHC) expressed on the APC. MHC provides a checkpoint and helps immune cells distinguish between host and foreign cells.
Natural killer (NK) cells have features of both innate and adaptive immunity. They are important for recognizing and killing virus-infected cells or tumor cells. Natural killer (NK) cells are so named because they easily kill cells infected with viruses. They are said to be natural killer cells as they are always ready to fight and do not require the same thymus education that T cells require. NK cells are derived from the bone marrow and are present in relatively low numbers in the bloodstream and in tissues. They are important in defending against viruses and possibly preventing cancer as well. They contain intracellular compartments chemicals called cytotoxic granules, which are filled with proteins that can form holes in the target cell and also cause apoptosis, the process for programmed cell death. NK cells kill virus-infected cells by injecting them with a killer potion of chemicals called cytotoxic granules. It is important to distinguish between apoptosis and other forms of cell death like necrosis. Apoptosis, unlike necrosis, does not release danger signals that can lead to greater immune activation and inflammation. Through apoptosis, immune cells can discreetly remove infected cells and limit bystander damage. NK cells are particularly important in the defense against herpes viruses. This family of viruses includes the traditional cold sore form of herpes (herpes simplex) as well as Epstein-Barr virus (the cause of infectious mononucleosis or mono) and the varicella virus (the cause of chickenpox and shingles). Recently, researchers have shown in mouse models that NK cells, like adaptive cells, can be retained as memory cells and respond to subsequent infections by the same pathogen.

The immune system relies on an adequate supply of nutrients for its baseline functions as well as for ramping up its activity when necessary ², ³, ⁴, ⁵, ⁶, ⁷. It is well established that malnutrition (protein-energy malnutrition and obesity) and deficiencies in one or more micronutrients (vitamins and nutritionally essential minerals) diminish immune function. In most instances, correcting the nutrient deficiency restores the affected immune functions. At a minimum, getting the recommended dietary allowance (RDA) for vitamin C and vitamin D is necessary for the immune system to function properly; there is some evidence that intakes above the current RDA (recommended dietary allowance) for these vitamins may be of further benefit ⁸. Because supplementation with iron can have unwanted side effects in those with preexisting infections, especially malaria, routine iron supplementation should be accompanied by malaria detection and treatment strategies ⁸. The long-chain Omega-3 Polyunsaturated Fatty Acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have potent anti-inflammatory effects, especially in individuals with chronic or acute inflammation ⁸. Increasing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) consumption increases the EPA and DHA content of immune cell membranes, mainly by displacing the long-chain Omega-6 Polyunsaturated Fatty Acids (PUFA) arachidonic acid and becoming the substrate for the enzymes that synthesize eicosanoids. EPA and DHA also give rise to anti-inflammatory compounds that “turn off” the inflammatory response. In chronic inflammatory states (e.g., rheumatoid arthritis, atherosclerosis), eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) supplements have been shown to reduce symptoms of rheumatoid arthritis and the risk of cardiac events. However, the dose of EPA plus DHA that is optimal for immune function in healthy individuals is not yet established. Ingestion of at least 500 mg/day of EPA plus DHA is recommended by the International Society for the Study of Fatty Acids and Lipids ⁹ and the American Heart Association recommends eating one to two servings of seafood per week to reduce your risk of some heart problems, especially if you consume the seafood in place of less healthy foods ¹⁰. For people with heart disease, the American Heart Association recommends consuming about 1 g per day EPA plus DHA, preferably from oily fish, but supplements are an option under the guidance of a health care provider ¹¹. The AHA does not recommend omega-3 supplements for people who do not have a high risk of cardiovascular disease ¹². The Linus Pauling Institute recommends that generally healthy adults eat fish twice weekly, which provides approximately 500 mg/day of EPA plus DHA; for those who do not regularly consume fish, consider taking a two-gram fish oil supplement several times a week in consultation with a physician ⁸. Higher daily intakes may be recommended for the treatment of specific disorders.

Table 1. The Immune System responds to Foreign Invaders and Abnormal Cells

Foreign Invaders	Abnormal Cells
Viruses	Cancer cells
Bacteria
Parasites
Mold
Allergens

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Table 2. Functional Divisions and Components of the Immune Response

Innate Immunity (general response to a pathogen)			Acquired Immunity (specific response to a pathogen)
Barriers	Cells	Humoral Factors	Cells	Humoral Factors
Physical: skin, mucous membranes	Phagocytes: engulf and destroy	Eicosanoids: Eicosanoids are compounds made from 20-carbon long-chain polyunsaturated fatty acids (PUFA); the term ‘eicosanoid’ includes many compounds that can either cause, prevent or regulate inflammation	T lymphocytes: detect specific pathogens, secrete cytokines, and coordinate an immune response	Antibodies: specialized proteins that mark a pathogen for destruction
Chemical: acidic environment of the stomach	Mast cells: cause inflammation & symptoms of allergy	Cytokines: Cytokines are proteins made by white blood cells. Cytokines regulate inflammation. They play important roles in your body’s normal immune responses and in the immune system’s ability to respond to cancer.	B lymphocytes: produce antibodies against a specific pathogen
Biological: gut microbiota	Natural killer (NK) cells: release toxic chemicals	Complement proteins: attach to and destroy bacteria; some cause inflammation		Complement proteins: attach to and destroy pathogens marked by antibodies

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Figure 1. Immune system

Figure 2. Cells of the immune system

Footnote: The cells of the immune system originate in the bone marrow from pluripotent hematopoietic stem cells. Pluripotent hematopoietic stem cells give rise to a common lymphoid progenitor, which gives rise to all of the major lymphoid cell types (T‐cells, B‐cells, and Natural killer [NK] cells) or a common myeloid progenitor, which gives rise to all of the major myeloid cell types (neutrophils, eosinophils, basophils, dendritic cells (DCs), mast cells, and monocytes/macrophages) as well as the erythrocytes and megakaryocytes (which generate platelets).

Figure 3. Factors that influence the immune response

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Figure 4. Vitamins and minerals for immune system

Footnotes: Vitamins and minerals have key roles at every stage of the immune response ¹³. This schematic summarizes important components and processes that are involved in different aspects of the innate and adaptive immune responses. The circles highlight those micronutrients that are known to affect these responses. The significant overlap between micronutrients and processes indicates the importance of multiple micronutrients in supporting proper function of the immune system.

Abbreviations: APCs = antigen-presenting cells; C3 = complement component 3; CRP = C-reactive protein; Cu = copper; Fe = iron; IFNs = interferons; Igs = immunoglobulins; ILs = interleukins; GI = gastrointestinal; GM-CSF = granulocyte-macrophage colony stimulating factor; MAC = membrane attack complex; MCP-1 = monocyte chemoattractant protein-1; Mg = magnesium; MHCs = major histocompatibility complexes; NK = natural killer; NO = nitric oxide; ROS = reactive oxygen species; Se = selenium; TLRs = toll-like receptors; TNF = tumor-necrosis factors; Zn = zinc

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How does the immune system work?

The immune system involves many parts of your body. Each part plays a role in recognizing foreign microbes, communicating with other parts of your body, and working to fight the infection. Parts of the immune system are:

Skin – The skin is usually the first line of defense against microbes. Skin cells produce and secrete important antimicrobial proteins, and immune cells can be found in specific layers of skin.
Bone marrow – helps produce immune cells. The bone marrow contains stems cells that can develop into a variety of cell types. The common myeloid progenitor stem cell in the bone marrow is the precursor to innate immune cells—neutrophils, eosinophils, basophils, mast cells, monocytes, dendritic cells, and macrophages—that are important first-line responders to infection. The common lymphoid progenitor stem cell leads to adaptive immune cells—B cells and T cells—that are responsible for mounting responses to specific microbes based on previous encounters (immunological memory). Natural killer (NK) cells also are derived from the common lymphoid progenitor and share features of both innate and adaptive immune cells, as they provide immediate defenses like innate cells but also may be retained as memory cells like adaptive cells. B, T, and NK cells also are called lymphocytes.
Bloodstream: Immune cells constantly circulate throughout the bloodstream, patrolling for problems. When blood tests are used to monitor white blood cells, another term for immune cells, a snapshot of the immune system is taken. If a cell type is either scarce or overabundant in the bloodstream, this may reflect a problem.
The thymus, a small gland in your upper chest where some immune T cells mature.
Lymphatic system is a network of of tiny vessels which allows immune cells to travel between tissues and the bloodstream. The lymphatic system contains lymphocytes (white blood cells; mostly T cells and B cells), which try to recognize any bacteria, viruses or other foreign substances in the body and fight them. They are carried in a milky fluid called lymph. Immune cells are carried through the lymphatic system and converge in lymph nodes, which are found throughout the body.
Lymph nodes, small lumps in the groin, armpit, around the neck and elsewhere that help the lymphatic system to communicate. Lymph nodes are a communication hub where immune cells sample information brought in from the body. They can become swollen when the body mounts an immune response. For instance, if adaptive immune cells in the lymph node recognize pieces of a microbe brought in from a distant area, they will activate, replicate, and leave the lymph node to circulate and address the pathogen. Thus, doctors may check patients for swollen lymph nodes, which may indicate an active immune response.
The spleen is an organ under the ribs behind the stomach on the left that processes information from the blood. While it is not directly connected to the lymphatic system, it is important for processing information from the bloodstream. Immune cells are enriched in specific areas of the spleen, and upon recognizing blood-borne pathogens, they will activate and respond accordingly.
Mucous membranes, like the lining of the inside of your mouth are prime entry points for pathogens, and specialized immune hubs are strategically located in mucosal tissues like the respiratory tract and gut. For instance, Peyer’s patches are important areas in the small intestine where immune cells can access samples from the gastrointestinal tract.

Immune organs

The organ systems involved in the immune response are primarily lymphoid organs which include, spleen, thymus, bone marrow, lymph nodes, tonsils, and liver. The lymphoid organ system classifies according to the following ¹⁴:

Primary lymphoid organs (thymus and bone marrow), where T and B cells first express antigen receptors and become mature functionally.
Secondary lymphoid organs like the spleen, tonsils, lymph nodes, the cutaneous and mucosal immune system; this is where B and T lymphocytes recognize foreign antigens and develop appropriate immune responses.

All immune cells originate in the bone marrow, deriving from hematopoietic stem cells, but an important set of immune cells (T lymphocytes) undergo maturation in an organ known as the thymus. The thymus and bone marrow are known as primary lymphoid tissues. T lymphocytes mature in the thymus, where these cells reach a stage of functional competence while B lymphocytes mature in the bone marrow the site of generation of all circulating blood cells. Excessive release of cytokines stimulated by these organisms can cause tissue damage, such as endotoxin shock syndrome.

Secondary lymphoid tissues, namely the lymph nodes, spleen and mucosa-associated lymphoid tissues (MALT) are important sites for generating adaptive immune responses and contain the lymphocytes (key adaptive cells). The lymphatic system is a system of vessels draining fluid (derived from blood plasma) from body tissues. Lymph nodes, that house lymphocytes, are positioned along draining lymph vessels, and monitor the lymph for signs of infection. MALT tissues are important in mucosal immune responses, and reflect the particular importance of the gut and airways in immune defence. The spleen essentially serves as a ‘lymph node’ for the blood.

Immune cells communication

Immune cells communicate in a number of ways, either by cell-to-cell contact or through secreted signaling molecules. Receptors and ligands are fundamental for cellular communication.

Receptors are protein structures that may be expressed on the surface of a cell or in intracellular compartments. The molecules that activate receptors are called ligands, which may be free-floating or membrane-bound.
Ligand-receptor interaction leads to a series of events inside the cell involving networks of intracellular molecules that relay the message. By altering the expression and density of various receptors and ligands, immune cells can dispatch specific instructions tailored to the situation at hand.

Cytokines are small proteins with diverse functions. In immunity, there are several categories of cytokines important for immune cell growth, activation, and function.

Colony-stimulating factors are essential for cell development and differentiation.
Interferons (IFNs) are necessary for immune-cell activation. Type I interferons mediate antiviral immune responses, and type II interferon is important for antibacterial responses.
Interleukins (ILs), which come in over 30 varieties, provide context-specific instructions, with activating or inhibitory responses.
Chemokines are made in specific locations of the body or at a site of infection to attract immune cells. Different chemokines will recruit different immune cells to the site needed.
Tumor necrosis factor (TNF) family of cytokines stimulates immune-cell proliferation and activation. They are critical for activating inflammatory responses, and as such, TNF blockers are used to treat a variety of disorders, including some autoimmune diseases.

Toll-like receptors (TLRs) are expressed on innate immune cells, like macrophages and dendritic cells. They are located on the cell surface or in intracellular compartments because microbes may be found in the body or inside infected cells. TLRs recognize general microbial patterns, and they are essential for innate immune-cell activation and inflammatory responses.

B-cell receptors (BCRs) and T-cell receptors (TCRs) are expressed on adaptive immune cells. They are both found on the cell surface, but BCRs also are secreted as antibodies to neutralize pathogens. The genes for BCRs and TCRs are randomly rearranged at specific cell-maturation stages, resulting in unique receptors that may potentially recognize anything. Random generation of receptors allows the immune system to respond to unforeseen problems. They also explain why memory B or T cells are highly specific and, upon re-encountering their specific pathogen, can immediately induce a neutralizing immune response.

Major histocompatibility complex (MHC) or human leukocyte antigen (HLA), proteins serve two general roles.

Major histocompatibility complex (MHC) proteins function as carriers to present antigens on cell surfaces. MHC class I proteins are essential for presenting viral antigens and are expressed by nearly all cell types, except red blood cells. Any cell infected by a virus has the ability to signal the problem through MHC class I proteins. In response, CD8+ T cells (also called CTLs) will recognize and kill infected cells. MHC class II proteins are generally only expressed by antigen-presenting cells like dendritic cells and macrophages. MHC class II proteins are important for presenting antigens to CD4+ T cells. MHC class II antigens are varied and include both pathogen- and host-derived molecules.

MHC proteins also signal whether a cell is a host cell or a foreign cell. They are very diverse, and every person has a unique set of MHC proteins inherited from his or her parents. As such, there are similarities in MHC proteins between family members. Immune cells use MHC to determine whether or not a cell is friendly. In organ transplantation, the MHC or HLA proteins of donors and recipients are matched to lower the risk of transplant rejection, which occurs when the recipient’s immune system attacks the donor tissue or organ. In stem cell or bone marrow transplantation, improper MHC or HLA matching can result in graft-versus-host disease, which occurs when the donor cells attack the recipient’s body.

Complement refers to a unique process that clears away pathogens or dying cells and also activates immune cells. Complement consists of a series of proteins found in the blood that form a membrane-attack complex. Complement proteins are only activated by enzymes when a problem, like an infection, occurs. Activated complement proteins stick to a pathogen, recruiting and activating additional complement proteins, which assemble in a specific order to form a round pore or hole. Complement literally punches small holes into the pathogen, creating leaks that lead to cell death. Complement proteins also serve as signaling molecules that alert immune cells and recruit them to the problem area.

Best vitamins for immune system

Through experimental research and studies of people with immune deficiencies, a number of vitamins (A, B6, B12, folate, C, D and E) and trace elements (zinc, copper, selenium, iron) have been demonstrated to have key roles in supporting the human immune system and reducing risk of infections ¹⁵. Other essential nutrients including other vitamins and trace elements, amino acids and fatty acids are also important in this regard. All of the nutrients named above have roles in supporting antibacterial and antiviral defences but zinc and selenium seem to be particularly important for the latter.

Table 3. Vitamins and minerals that affect the immune system

Name	What It Does	Where to Get It	About Supplements
Vitamin A (Retinol) and beta-carotene	Keeps skin, lungs, and stomach healthy. Role in barrier function: Promotes differentiation of epithelial tissue; promotes gut homing of B- and T cells; promotes intestinal immunoglobulin A cells; promotes epithelial integrity Role in cellular aspects of innate immunity: Regulates number and function of NK cells; supports phagocytic and oxidative burst activity of macrophages Role in B-cell mediated immunity: Supports function of B cells; required for immunoglobulin A production Role in T-cell mediated immunity: Regulates development and differentiation of Th1 and Th2 cells; promotes conversion of naive T cells to regulatory T cells; regulates IL-2, IFN-γ and TNF production	liver, whole eggs, milk, dark green, yellow, orange, and red vegetables and fruit (like spinach, pumpkin, green peppers, squash, carrots, papaya, and mangoes). Also found in orange and yellow sweet potatoes	It’s best to get vitamin A from food. Vitamin A supplements are toxic in high doses. Supplements of beta-carotene (the form of vitamin A in fruits and vegetables) have been shown to increase cancer risk in smokers.
Vitamin B-group Thiamin (Vitamin B1), Riboflavin (Vitamin B2), Vitamin B6, Folate (Vitamin B9), Vitamin B12	Keeps the immune and nervous system healthy. Vitamin B6 Role in barrier function: Promotes gut homing of T cells Role in cellular aspects of innate immunity: Supports NK-cell activity Role in B-cell mediated immunity: Supports antibody production Role in T-cell mediated immunity: Promotes T-cell differentiation, proliferation and function, especially Th1 cells; regulates (promotes) IL-2 production Folate (Vitamin B9) Role in barrier function: Survival factor for regulatory T cells in the small intestine Role in cellular aspects of innate immunity: Supports NK-cell activity Role in B-cell mediated immunity: Supports antibody production Role in T-cell mediated immunity: Promotes proliferation of T cells and the Th1-cell response Vitamin B12 Role in barrier function: Important co-factor for gut microbiota Role in cellular aspects of innate immunity: Supports NK-cell activity Role in B-cell mediated immunity: Required for antibody production Role in T-cell mediated immunity: Promotes T-cell differentiation, proliferation and function, especially cytotoxic T cells; controls ratio of T-helper to cytotoxic T cells	white beans, potatoes, meat, fish, chicken, watermelon, grains, nuts, avocados, broccoli, and green leafy vegetables
Vitamin C	Helps protect the body from infection and aids in recovery. Role in barrier function: Promotes collagen synthesis; promotes keratinocyte differentiation; protects against oxidative damage; promotes wound healing; promotes complement Role in cellular aspects of innate immunity: Supports function of neutrophils, monocytes and macrophages including phagocytosis; supports NK-cell activity Role in B-cell mediated immunity: Promotes antibody production Role in T-cell mediated immunity: Promotes production, differentiation and proliferation of T cells especially cytotoxic T cells; regulates IFN-γ production	citrus fruits (like oranges, grapefruit, and lemons), tomatoes, and potatoes
Vitamin D	Important for developing and maintaining healthy bones and teeth. Role in barrier function: Promotes production of antimicrobial proteins (cathelicidin, β-defensin); promotes gut tight junctions (via E-cadherin, connexion 43); promotes homing of T cells to the skin Role in cellular aspects of innate immunity: Promotes differentiation of monocytes to macrophages; promotes macrophage phagocytosis and oxidative burst Role in B-cell mediated immunity: Can decrease antibody production Role in T-cell mediated immunity: Promotes antigen processing but can inhibit antigen presentation; can inhibit T-cell proliferation, Th1-cell function and cytotoxic T-cell function; Promotes the development of regulatory T cells; inhibits differentiation and maturation of dendritic cells; regulates IFN-γ production	fortified milk, fatty fish, sunlight
Vitamin E	Protects cells and helps fight off infection. Role in barrier function: Protects against oxidative damage Role in cellular aspects of innate immunity: Supports NK-cell activity Role in B-cell mediated immunity: Supports antibody production Role in T-cell mediated immunity: Promotes interaction between dendritic cells and T cells; promotes T-cell proliferation and function, especially Th1 cells; regulates (promotes) IL-2 production	green leafy vegetables, vegetable oils, avocados, almonds	Limit to 400 IU per day.
Iron	Not having enough iron can cause anemia. Role in barrier function: Essential for growth and differentiation of epithelial tissue Role in cellular aspects of innate immunity: Promotes bacterial killing by neutrophils; regulates balance of M1 and M2 macrophages; supports NK-cell activity Role in T-cell mediated immunity: Regulates differentiation and proliferation of T cells; regulates IFN-γ production	green leafy vegetables, whole grain breads and pastas, dried fruit, beans, red meat, chicken, liver, fish, and eggs	Limit to 45 mg per day unless otherwise instructed by your doctor. Iron may be a problem for people with HIV because it can increase the activity of some bacteria. Supplements that do not contain iron may be better.
Copper	Copper is a cofactor for several enzymes (known as “cuproenzymes”) involved in energy production, iron metabolism, neuropeptide activation, connective tissue synthesis, and neurotransmitter synthesis. Copper is also involved in many physiologic processes, such as angiogenesis; neurohormone homeostasis; and regulation of gene expression, brain development, pigmentation, and immune system functioning. In addition, defense against oxidative damage depends mainly on the copper-containing superoxide dismutases. Role in cellular aspects of innate immunity: Promotes neutrophil, monocyte and macrophage phagocytosis; supports NK-cell activity Role in T-cell mediated immunity: Regulates differentiation and proliferation of T cells; regulates (promotes) IL-2 production	beef liver, shellfish, seeds and nuts, organ meats, wheat-bran cereals, whole-grain products, and chocolate Tap water and other beverages can also be sources of copper, although the amount of copper in these liquids varies by source (ranging from 0.0005 mg/L to 1 mg/L)	Limit to 900 mcg per day.
Magnesium	Important for the immune system. Cofactor of enzymes of nucleic acid metabolism and stabilizes structure of nucleic acids; Increased numbers of monocytes ¹⁶; Increased NK-cell activity ¹⁶; Decreased oxidative stress after strenuous exercise ¹⁶; After exercises, increases granulocyte count and post-exercise lymphopenia ¹⁷; Decreased levels of cytokines such as IL-6 ¹⁸ Decreased inflammation ¹⁸ Increased T-cell ratios ¹⁶ Involved in DNA replication and repair. Reduces oxidative damage to the DNA of peripheral blood lymphocytes in athletes and sedentary young men ¹⁹; Roles in antigen binding to macrophages ¹⁸; Regulates leukocyte activation ¹⁸; Reduces leukocyte activation ²⁰; Involved in the regulation of apoptosis ¹⁹	green leafy vegetables, such as spinach, legumes, nuts, seeds, and whole grains, are good sources of magnesium	Limit 420 mg (male) and 320 mg (female) per day.
Selenium	Important for the immune system. Role in cellular aspects of innate immunity: Supports NK-cell activity Role in B-cell mediated immunity: Supports antibody production Role in T-cell mediated immunity: Regulates differentiation and proliferation of T cells; regulates (promotes) IFN-γ production	whole grains, meat, fish, poultry, eggs, peanut butter, and nuts	Limit to 400 mcg per day.
Zinc	Important for the immune system. Role in barrier function: Maintains integrity of the skin and mucosal membranes; promotes complement activity Role in cellular aspects of innate immunity: Supports monocyte and macrophage phagocytosis; supports NK-cell activity Role in B-cell mediated immunity: Supports antibody production particularly immunoglobulin G (Ig G) Role in T-cell mediated immunity: Promotes Th1-cell response; Promotes proliferation of cytotoxic T cells; promotes development of regulatory T cells; regulates (promotes) IL-2 and IFN-γ production; reduces development of Th9 and Th17 cells	meat, fish, poultry, beans, peanuts, and milk and dairy products	Limit to 40 mg per day.

Abbreviations: IFN = Interferon; IL= interleukin; NK = natural killer; Th = T-helper; TNF = tumor necrosis factor

[Source ²¹, ⁵ ]

Table 4. Important dietary sources of nutrients that support the immune system

Nutrient	Good dietary sources
Vitamin A (or equivalents)	Milk and cheese, eggs, liver, oily fish, fortified cereals, dark orange or green vegetables (eg, carrots, sweet potatoes, pumpkin, squash, kale, spinach, broccoli), orange fruits (eg, apricots, peaches, papaya, mango, cantaloupe melon), tomato juice
Vitamin B6	Fish, poultry, meat, eggs, whole grain cereals, fortified cereals, many vegetables (especially green leafy) and fruits, soya beans, tofu, yeast extract
Vitamin B12	Fish, meat, some shellfish, milk and cheese, eggs, fortified breakfast cereals, yeast extract
Folate (Vitamin B9)	Broccoli, brussels sprouts, green leafy vegetables (spinach, kale, cabbage), peas, chick peas, fortified cereals
Vitamin C	Oranges and orange juice, red and green peppers, strawberries, blackcurrants, kiwi, broccoli, brussels sprouts, potatoes
Vitamin D	Oily fish, liver, eggs, fortified foods (spreads and some breakfast cereals)
Vitamin E	Many vegetable oils, nuts and seeds, wheat germ (in cereals)
Zinc	Shellfish, meat, cheese, some grains and seeds, cereals, seeded or wholegrain breads
Selenium	Fish, shellfish, meat, eggs, some nuts especially brazil nuts
Iron	Meat, liver, beans, nuts, dried fruit (eg, apricots), wholegrains (eg, brown rice), fortified cereals, most dark green leafy vegetables (spinach, kale)
Copper	Shellfish, nuts, liver, some vegetables
Magnesium	Green leafy vegetables, such as spinach, legumes, nuts, seeds, and whole grains
Essential amino acids	Meat, poultry, fish, eggs, milk and cheese, soya, nuts and seeds, pulses
Essential fatty acids	Many seeds, nuts and vegetable oils
Long chain omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA])	Oily fish

Table 5. Results of multiple scientific studies (meta-analyses) on micronutrients and respiratory infections

Micronutrient	Sample size	Main findings	Stated conclusion in abstract	Reference
Vitamin A	47 randomized controlled trials (1 223 856 children)	Vitamin A did not affect incidence of, or mortality from, respiratory disease; Note: vitamin A decreased all cause mortality and mortality from diarrhea and decreased incidence of diarrhea and measles	Vitamin A supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children.	Imdad et al ²²
Vitamin A	15 randomized controlled trials (3021 children)	Vitamin A did not affect mortality of children with pneumonia. Vitamin A decreased pneumonia morbidity, increased the clinical response rate, shortened clearance time of signs and shortened length of hospital stay.	Vitamin A supplementation helps to relieve clinical symptoms and signs (of pneumonia) and shorten the length of hospital stay.	Hu et al ²³
Vitamin C	3 prophylactic trials (2335 participants) two therapeutic trials (197 patients)	All three trials found vitamin C decreased the incidence of pneumonia. One trial found vitamin C decreased severity and mortality from pneumonia; the other trial found vitamin C shortened duration of pneumonia.		Hemila and Louhiala ²⁴
Vitamin C	29 prophylactic randomized controlled trials investigating incidence (11 306 participants) 31 prophylactic randomized controlled trials investigating duration (9745 episodes)	Vitamin C did not affect incidence of the common cold in the general population (24 randomized controlled trials) but decreased incidence in people under heavy short-term physical stress (5 randomized controlled trials). Vitamin C shortened duration of common cold in all studies (31 randomized controlled trials), in adults (13 randomized controlled trials) and in children (10 randomized controlled trials) and decreased severity of colds.		Hemila and Chalker ²⁵
Vitamin D	11 randomized controlled trials (5660 participants)	Vitamin D decreased the risk of respiratory tract infections.	Vitamin D has a positive effect against respiratory tract infections and dosing once daily seems most effective.	Bergman et al ²⁶
Vitamin D	25 randomized controlled trials (11 321 participants)	Vitamin D decreased the risk of acute respiratory tract infection, effects greater in those with low starting status	Vitamin D supplementation was safe and it protected against respiratory tract infection.	Martineau et al ²⁷
Vitamin D	24 studies; 14 included in meta-analysis of risk of acute respiratory tract infections and 5 in the meta-analysis of severity	Serum vitamin D was inversely associated with risk and severity of acute respiratory tract infections.	There is an inverse non-linear association between 25-hydroxyvitamin D concentration and acute respiratory tract infection.	Pham et al ²⁸
Vitamin D	8 observational studies (20 966 participants)	Participants with vitamin D deficiency had increased risk of community-acquired pneumonia.	There is an association between vitamin D deficiency and increased risk of community-acquired pneumonia.	Zhou et al ²⁹
Zinc, copper and iron	13 studies in Chinese children	Children with recurrent respiratory tract infection had lower hair levels of zinc, copper and iron.	The deficiency of zinc, copper and iron may be a contributing factor for the susceptibility of recurrent respiratory tract infection in Chinese children.	Mao et al ³⁰
Zinc	7 randomized controlled trials (575 participants)	Zinc shortened duration of common cold.		Hemila ³¹
Zinc	17 randomized controlled trials (2121 adults and children)	Zinc decreased duration of common cold symptoms overall and in adults but not in children.	Oral zinc formulations may shorten the duration of symptoms of the common cold.	Science et al ³²
Zinc	6 randomized controlled trials (5193 children)	Zinc decreased incidence of pneumonia. Zinc decreased prevalence of pneumonia.	Zinc supplementation in children is associated with a reduction in the incidence and prevalence of pneumonia.	Lassi et al ³³
Zinc	6 randomized controlled trials (2216 adults with severe pneumonia)	Zinc given as an adjunct therapy decreased mortality. No effect of zinc on treatment failure or antibiotic treatment.	Zinc given as an adjunct to the treatment of severe pneumonia is effective in reducing mortality.	Wang and Song ³⁴

List of foods containing Vitamins and Minerals that Affect the Immune System

Vitamin A

Vitamin A is name of a group of fat-soluble vitamin (retinoids, including retinol, retinal, and retinyl esters) ³⁵, ³⁶, ³⁷, that is naturally present in many foods.

Vitamin A is important for normal vision, gene expression, the immune system, embryonic development, growth, and reproduction. Vitamin A also helps the heart, lungs, kidneys, and other organs work properly ³⁸.

There are two different types of vitamin A ³⁹.

The first type, preformed vitamin A (retinol and its esterified form, retinyl ester), is found in meat (especially liver), poultry, fish, and dairy products.
The second type, provitamin A carotenoids (beta-carotene, alpha-carotene and beta-cryptoxanthin), is found in fruits, vegetables, and other plant-based products (oily fruits and red palm oil). The most common type of provitamin A carotenoids in foods and dietary supplements is beta-carotene (β-carotene). The body converts these plant pigments into vitamin A.

There are a number of reviews of the role of vitamin A and its metabolites (eg, 9-cis-retinoic acid) in immunity and in host susceptibility to infection ⁴⁰. Vitamin A is important for normal differentiation of epithelial tissue and for immune cell maturation and function. Thus, vitamin A deficiency is associated with impaired barrier function, altered immune responses and increased susceptibility to a range of infections. Vitamin A-deficient mice show breakdown of the gut barrier and impaired mucus secretion (due to loss of mucus-producing goblet cells), both of which would facilitate entry of pathogens. Many aspects of innate immunity, in addition to barrier function, are modulated by vitamin A and its metabolites. Vitamin A controls neutrophil maturation and in vitamin A deficiency blood neutrophil numbers are increased, but they have impaired phagocytic function. Therefore, the ability of neutrophils to ingest and kill bacteria is impaired. Vitamin A also supports phagocytic activity and oxidative burst of macrophages, so promoting bacterial killing. Natural killer cell activity is diminished by vitamin A deficiency, which would impair antiviral defences. The impact of vitamin A on acquired immunity is less clear and may depend on the exact setting and the vitamin A metabolite involved. Vitamin A controls dendritic cell and CD4+ T lymphocyte maturation and its deficiency alters the balance between T helper 1 and T helper 2 lymphocytes. Studies in experimental model systems indicate that the vitamin A metabolite 9-cis retinoic acid enhances T helper 1 responses. Retinoic acid promotes movement (homing) of T lymphocytes to the gut-associated lymphoid tissue. Interestingly, some gut-associated immune cells are able to synthesise retinoic acid. Retinoic acid is required for CD8+ T lymphocyte survival and proliferation and for normal functioning of B lymphocytes including antibody generation. Thus, vitamin A deficiency can impair the response to vaccination, as discussed elsewhere ⁴¹. In support of this, vitamin A-deficient Indonesian children provided with vitamin A showed a higher antibody response to tetanus vaccination than seen in vitamin A-deficient children ⁴². Vitamin A deficiency predisposes to respiratory infections, diarrhoea and severe measles. Systematic reviews and meta-analyses of trials in children with vitamin A report reduced all-cause mortality ²², reduced incidence, morbidity and mortality from measles ²² and from infant diarrhoea ²² and improved symptoms in acute pneumonia ²³.

You can get recommended amounts of vitamin A by eating a variety of foods, including the following:

Beef liver and other organ meats (but these foods are also high in cholesterol, so limit the amount you eat).
Some types of fish, such as salmon.
Green leafy vegetables and other green, orange, and yellow vegetables, such as broccoli, carrots, and squash.
Fruits, including cantaloupe, apricots, and mangos.
Dairy products, which are among the major sources of vitamin A for Americans.
Fortified breakfast cereals.

Table 4 suggests many dietary sources of vitamin A. The foods from animal sources contain primarily preformed vitamin A, the plant-based foods have provitamin A, and the foods with a mixture of ingredients from animals and plants contain both preformed vitamin A and provitamin A.

sources of vitamin A

Table 6. Selected Food Sources of Vitamin A

Food	mcg RAE per serving	IU per serving	Percent DV*
Sweet potato, baked in skin, 1 whole	1,403	28,058	561
Beef liver, pan fried, 3 ounces	6,582	22,175	444
Spinach, frozen, boiled, ½ cup	573	11,458	229
Carrots, raw, ½ cup	459	9,189	184
Pumpkin pie, commercially prepared, 1 piece	488	3,743	249
Cantaloupe, raw, ½ cup	135	2,706	54
Peppers, sweet, red, raw, ½ cup	117	2,332	47
Mangos, raw, 1 whole	112	2,240	45
Black-eyed peas (cowpeas), boiled, 1 cup	66	1,305	26
Apricots, dried, sulfured, 10 halves	63	1,261	25
Broccoli, boiled, ½ cup	60	1,208	24
Ice cream, French vanilla, soft serve, 1 cup	278	1,014	20
Cheese, ricotta, part skim, 1 cup	263	945	19
Tomato juice, canned, ¾ cup	42	821	16
Herring, Atlantic, pickled, 3 ounces	219	731	15
Ready-to-eat cereal, fortified with 10% of the DV for vitamin A, ¾–1 cup (more heavily fortified cereals might provide more of the DV)	127–149	500	10
Milk, fat-free or skim, with added vitamin A and vitamin D, 1 cup	149	500	10
Baked beans, canned, plain or vegetarian, 1 cup	13	274	5
Egg, hard boiled, 1 large	75	260	5
Summer squash, all varieties, boiled, ½ cup	10	191	4
Salmon, sockeye, cooked, 3 ounces	59	176	4
Yogurt, plain, low fat, 1 cup	32	116	2
Pistachio nuts, dry roasted, 1 ounce	4	73	1
Tuna, light, canned in oil, drained solids, 3 ounces	20	65	1
Chicken, breast meat and skin, roasted, ½ breast	5	18	0

Footnote: *DV = Daily Value. DVs were developed by the FDA to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin A is 5,000 IU for adults and children age 4 and older. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

[Source ⁴³]

Beta Carotene

Beta-carotene is a red-orange pigment found in plants and fruits, especially carrots and colorful vegetables. It is the yellow/orange pigment that gives vegetables and fruits their rich colors.

Carotene is an orange photosynthetic pigment important for photosynthesis. It is responsible for the orange color of the carrot and many other fruits and vegetables. It contributes to photosynthesis by transmitting the light energy it absorbs to chlorophyll. Chemically, carotene is a terpene. It is the dimer of retinol (vitamin A) and comes in two primary forms: alpha- and beta-carotene. Gamma-, delta- and epsilon-carotene also exist. Carotene can be stored in the liver and converted to vitamin A as needed.

Beta-carotene in itself is not an essential nutrient, but vitamin A is.

Beta-carotene is a carotenoid that is a precursor of vitamin A and the human body converts beta-carotene into vitamin A (retinol). We need vitamin A for healthy skin and mucus membranes, our immune system, and good eye health and vision.

Beta-carotene, like all carotenoids, is an antioxidant. An antioxidant is a substance that inhibits the oxidation of other molecules; it protects the body from free radicals.

Free radicals damage cells through oxidation. Eventually, the damage caused by free radicals can cause several chronic illnesses.

Several studies have shown that antioxidants through diet help people’s immune systems, protect against free radicals, and lower the risk of developing cancer and heart disease.

Some studies have suggested that those who consume at least four daily servings of beta-carotene rich fruits and/or vegetables have a lower risk of developing cancer or heart disease.

Beta-carotene may also slow down cognitive decline. Men who have been taking beta-carotene supplements for 15 or more years are considerably less likely to experience cognitive decline than other males, researchers from Harvard Medical School reported in Archives of Internal Medicine.

B-group vitamins

There is a recent comprehensive review of B vitamins and immunity ⁴⁴. B vitamins are involved in intestinal immune regulation, thus contributing to gut barrier function. Folic acid (vitamin B9) deficiency in animals causes thymus and spleen atrophy, and decreases circulating T lymphocyte numbers. Spleen lymphocyte proliferation is also reduced but the phagocytic and bactericidal capacity of neutrophils appears unchanged. In contrast, vitamin B12 deficiency decreases phagocytic and bacterial killing capacity of neutrophils, while vitamin B6 deficiency causes thymus and spleen atrophy, low blood T lymphocyte numbers and impaired lymphocyte proliferation and T lymphocyte-mediated immune responses. Vitamins B6 and B12 and folate all support the activity of natural killer cells and CD8+ cytotoxic T lymphocytes, effects which would be important in antiviral defence. Patients with vitamin B12 deficiency had low blood numbers of CD8+ T lymphocytes and low natural killer cell activity ⁴⁵. In a study in healthy older humans ⁴⁶, a vitamin B6-deficient diet for 21 days resulted in a decreased percentage and total number of circulating lymphocytes, and a decrease in T and B lymphocyte proliferation and IL-2 production. Repletion over 21 days using vitamin B6 at levels below those recommended did not return immune function to starting values, while repletion at the recommended intake (22.5 µg/kg body weight per day, which would be 1.575 mg/day in a 70 kg individual) did ⁴⁶. Providing excess vitamin B6 (33.75 µg/kg body weight per day, which would be 2.362 mg/day in a 70 kg individual) for 4 days caused a further increase in lymphocyte proliferation and IL-2 production.

Thiamin (Vitamin B1)

Thiamin (or thiamine) is one of the water-soluble B vitamins. It is also known as vitamin B1. Thiamin is naturally present in some foods, added to some food products, and available as a dietary supplement. This vitamin plays a critical role in energy metabolism and, therefore, in the growth, development, and function of cells ⁴⁷.

Thiamin (also called vitamin B1) helps turn the food you eat into the energy you need. Thiamin is important for the growth, development, and function of the cells in your body.

Table 7. Selected Food Sources of Thiamine (vitamin B1)

Food	Milligrams (mg) per serving	Percent DV*
Breakfast cereals, fortified with 100% of the DV for thiamin, 1 serving	1.5	100
Rice, white, long grain, enriched, parboiled, ½ cup	1.4	73
Egg noodles, enriched, cooked, 1 cup	0.5	33
Pork chop, bone-in, broiled, 3 ounces	0.4	27
Trout, cooked, dry heat, 3 ounces	0.4	27
Black beans, boiled, ½ cup	0.4	27
English muffin, plain, enriched, 1 muffin	0.3	20
Mussels, blue, cooked, moist heat, 3 ounces	0.3	20
Tuna, Bluefin, cooked, dry heat, 3 ounces	0.2	13
Macaroni, whole wheat, cooked, 1 cup	0.2	13
Acorn squash, cubed, baked, ½ cup	0.2	13
Rice, brown, long grain, not enriched, cooked, ½ cup	0.1	7
Bread, whole wheat, 1 slice	0.1	7
Orange juice, prepared from concentrate, 1 cup	0.1	7
Sunflower seeds, toasted, 1 ounce	0.1	7
Beef steak, bottom round, trimmed of fat, braised, 3 ounces	0.1	7
Yogurt, plain, low fat, 1 cup	0.1	7
Oatmeal, regular and quick, unenriched, cooked with water, ½ cup	0.1	7
Corn, yellow, boiled, 1 medium ear	0.1	7
Milk, 2%, 1 cup	0.1	7
Barley, pearled, cooked, 1 cup	0.1	7
Cheddar cheese, 1½ ounces	0	0
Chicken, meat and skin, roasted, 3 ounces	0	0
Apple, sliced, 1 cup	0	0

[Source ⁴⁸]

Vitamin B2 (Riboflavin)

Riboflavin also called vitamin B2 is one of the B vitamins, which are all water soluble and it’s important for the growth, development, and function of the cells in your body. It also helps turn the food you eat into the energy you need.

More than 90% of dietary riboflavin is in the form of flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN); the remaining 10% is comprised of the free form and glycosides or esters ⁴⁹, ⁵⁰. Most riboflavin is absorbed in the proximal small intestine ⁵¹. The body absorbs little riboflavin from single doses beyond 27 mg and stores only small amounts of riboflavin in the liver, heart, and kidneys. When excess amounts are consumed, they are either not absorbed or the small amount that is absorbed is excreted in urine ⁵⁰.

Bacteria in the large intestine produce free riboflavin that can be absorbed by the large intestine in amounts that depend on the diet. More riboflavin is produced after ingestion of vegetable-based than meat-based foods ⁴⁹.

Riboflavin is yellow and naturally fluorescent when exposed to ultraviolet light ⁵². Moreover, ultraviolet and visible light can rapidly inactivate riboflavin and its derivatives. Because of this sensitivity, lengthy light therapy to treat jaundice in newborns or skin disorders can lead to riboflavin deficiency. The risk of riboflavin loss from exposure to light is the reason why milk is not typically stored in glass containers ⁵⁰, ⁵³.

Table 8. Selected Food Sources of Riboflavin (vitamin B2)

Food	Milligrams (mg) per serving	Percent DV*
Beef liver, pan fried, 3 ounces	2.9	171
Breakfast cereals, fortified with 100% of the DV for riboflavin, 1 serving	1.7	100
Oats, instant, fortified, cooked with water, 1 cup	1.1	65
Yogurt, plain, fat free, 1 cup	0.6	35
Milk, 2% fat, 1 cup	0.5	29
Beef, tenderloin steak, boneless, trimmed of fat, grilled, 3 ounces	0.4	24
Clams, mixed species, cooked, moist heat, 3 ounces	0.4	24
Mushrooms, portabella, sliced, grilled, ½ cup	0.3	18
Almonds, dry roasted, 1 ounce	0.3	18
Cheese, Swiss, 3 ounces	0.3	18
Rotisserie chicken, breast meat only, 3 ounces	0.2	12
Egg, whole, scrambled, 1 large	0.2	12
Quinoa, cooked, 1 cup	0.2	12
Bagel, plain, enriched, 1 medium (3½”–4” diameter)	0.2	12
Salmon, pink, canned, 3 ounces	0.2	12
Spinach, raw, 1 cup	0.1	6
Apple, with skin, 1 large	0.1	6
Kidney beans, canned, 1 cup	0.1	6
Macaroni, elbow shaped, whole wheat, cooked, 1 cup	0.1	6
Bread, whole wheat, 1 slice	0.1	6
Cod, Atlantic, cooked, dry heat, 3 ounces	0.1	6
Sunflower seeds, toasted, 1 ounce	0.1	6
Tomatoes, crushed, canned, ½ cup	0.1	6
Rice, white, enriched, long grain, cooked, ½ cup	0.1	6
Rice, brown, long grain, cooked, ½ cup	0	0

[Source ⁴⁸]

Vitamin B6 (Pyridoxine)

Vitamin B6 includes a group of closely related compounds: pyridoxine, pyridoxal, and pyridoxamine. Substantial proportions of the naturally occurring pyridoxine in fruits, vegetables, and grains exist in glycosylated forms that exhibit reduced bioavailability ⁵⁴. The body needs vitamin B6 for more than 100 enzyme reactions involved in metabolism. They are metabolized in the body to pyridoxal phosphate, which acts as a coenzyme in many important reactions in blood, CNS, and skin metabolism. Vitamin B6 is important in heme and nucleic acid biosynthesis and in lipid, carbohydrate, and amino acid metabolism. Vitamin B6 is also involved in brain development during pregnancy and infancy as well as immune function.

Vitamin B6 in coenzyme forms performs a wide variety of functions in the body and is extremely versatile, with involvement in more than 100 enzyme reactions, mostly concerned with protein metabolism. Both pyridoxal 5’ phosphate and pyridoxamine 5’ phosphate are involved in amino acid metabolism, and pyridoxal 5’ phosphate is also involved in the metabolism of one-carbon units, carbohydrates, and lipids ⁵⁴. Vitamin B6 also plays a role in cognitive development through the biosynthesis of neurotransmitters and in maintaining normal levels of homocysteine, an amino acid in the blood ⁵⁴. Vitamin B6 is involved in gluconeogenesis and glycogenolysis, immune function (for example, it promotes lymphocyte and interleukin-2 production), and hemoglobin formation ⁵⁴.

The human body absorbs vitamin B6 in the jejunum. Phosphorylated forms of the vitamin are dephosphorylated, and the pool of free vitamin B6 is absorbed by passive diffusion ⁵⁵.

Table 9. Selected Food Sources of Vitamin B6 (Pyridoxine)

Food	Milligrams (mg) per serving	Percent DV*
Chickpeas, canned, 1 cup	1.1	55
Beef liver, pan fried, 3 ounces	0.9	45
Tuna, yellowfin, fresh, cooked, 3 ounces	0.9	45
Salmon, sockeye, cooked, 3 ounces	0.6	30
Chicken breast, roasted, 3 ounces	0.5	25
Breakfast cereals, fortified with 25% of the DV for vitamin B6	0.5	25
Potatoes, boiled, 1 cup	0.4	20
Turkey, meat only, roasted, 3 ounces	0.4	20
Banana, 1 medium	0.4	20
Marinara (spaghetti) sauce, ready to serve, 1 cup	0.4	20
Ground beef, patty, 85% lean, broiled, 3 ounces	0.3	15
Waffles, plain, ready to heat, toasted, 1 waffle	0.3	15
Bulgur, cooked, 1 cup	0.2	10
Cottage cheese, 1% low-fat, 1 cup	0.2	10
Squash, winter, baked, ½ cup	0.2	10
Rice, white, long-grain, enriched, cooked, 1 cup	0.1	5
Nuts, mixed, dry-roasted, 1 ounce	0.1	5
Raisins, seedless, ½ cup	0.1	5
Onions, chopped, ½ cup	0.1	5
Spinach, frozen, chopped, boiled, ½ cup	0.1	5
Tofu, raw, firm, prepared with calcium sulfate, ½ cup	0.1	5
Watermelon, raw, 1 cup	0.1	5

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin B6 is 2 mg for adults and children age 4 and older. However, the FDA does not require food labels to list vitamin B6 content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

[Source ⁴⁸]

Vitamin B12 (Cyanocobalamin)

Vitamin B12 is also known as Cyanocobalamin is a nutrient that helps keep the body’s nerve and blood cells healthy and helps make DNA, the genetic material in all cells. Vitamin B12 also helps prevent a type of anemia called megaloblastic anemia that makes people tired and weak.

Vitamin B12 is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement and a prescription medication. Vitamin B12 exists in several forms and contains the mineral cobalt ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, so compounds with vitamin B12 activity are collectively called “cobalamins”. Methylcobalamin and 5-deoxyadenosylcobalamin are the forms of vitamin B12 that are active in human metabolism ⁶⁰.

Two steps are required for the body to absorb vitamin B12 from food.

First, food-bound vitamin B12 is released in the stomach’s acid environment (hydrochloric acid and and gastric protease in the stomach separate vitamin B12 from the protein to which vitamin B12 is attached in food) and is bound to R protein (haptocorrin) ⁶⁰. When synthetic vitamin B12 is added to fortified foods and dietary supplements, it is already in free form and thus, does not require this separation step.
Second, pancreatic enzymes cleave this B12 complex (B12-R protein) in the small intestine. After cleavage, intrinsic factor (a protein made by the stomach), secreted by parietal cells in the gastric mucosa, binds with the free vitamin B12. Intrinsic factor is required for absorption of vitamin B12, which takes place in the terminal ileum ⁶⁰, ⁶¹. Approximately 56% of a 1 mcg oral dose of vitamin B12 is absorbed, but absorption decreases drastically when the capacity of intrinsic factor is exceeded (at 1–2 mcg of vitamin B12) ⁶². Some people have pernicious anemia, a condition where they cannot make intrinsic factor. As a result, they have trouble absorbing vitamin B12 from all foods and dietary supplements.

Several food sources of vitamin B12 are listed in Table 10.

Table 10. Selected Food Sources of Vitamin B12

Food	Micrograms (mcg) per serving	Percent DV*
Clams, cooked, 3 ounces	84.1	1402
Liver, beef, cooked, 3 ounces	70.7	1178
Breakfast cereals, fortified with 100% of the DV for vitamin B12, 1 serving	6	100
Trout, rainbow, wild, cooked, 3 ounces	5.4	90
Salmon, sockeye, cooked, 3 ounces	4.8	80
Trout, rainbow, farmed, cooked, 3 ounces	3.5	58
Tuna fish, light, canned in water, 3 ounces	2.5	42
Cheeseburger, double patty and bun, 1 sandwich	2.1	35
Haddock, cooked, 3 ounces	1.8	30
Breakfast cereals, fortified with 25% of the DV for vitamin B12, 1 serving	1.5	25
Beef, top sirloin, broiled, 3 ounces	1.4	23
Milk, low-fat, 1 cup	1.2	18
Yogurt, fruit, low-fat, 8 ounces	1.1	18
Cheese, Swiss, 1 ounce	0.9	15
Beef taco, 1 soft taco	0.9	15
Ham, cured, roasted, 3 ounces	0.6	10
Egg, whole, hard boiled, 1 large	0.6	10
Chicken, breast meat, roasted, 3 ounces	0.3	5

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers determine the level of various nutrients in a standard serving of food in relation to their approximate requirement for it. The DV for vitamin B12 is 6.0 mcg. However, the FDA does not require food labels to list vitamin B12 content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

[Source ⁴⁸]

Folate (Vitamin B9)

Folate is also known vitamin B9 (Folacin, Folic Acid, Pteroylglutamic acid) that is naturally present in many foods. Folic Acid is a form of folate that is manufactured and used in dietary supplements and fortified foods ⁶³. Everyone needs folic acid. Our bodies need folate to make DNA and other genetic material. Folate is also needed for the body’s cells to divide.

Folic acid and folate also help your body make healthy new red blood cells. Red blood cells carry oxygen to all the parts of your body. If your body does not make enough red blood cells, you can develop anemia. Anemia happens when your blood cannot carry enough oxygen to your body, which makes you pale, tired, or weak. Also, if you do not get enough folic acid, you could develop a type of anemia called folate-deficiency anemia ⁶⁴.

Folate-deficiency anemia is most common during pregnancy. Other causes of folate-deficiency anemia include alcoholism and certain medicines to treat seizures, anxiety, or arthritis.

In women and pregnant mothers, folic acid is very important because it can help prevent some major birth defects of the baby’s brain and spine (anencephaly and spina bifida) ⁶⁵.

Every woman needs folic acid every day, whether she’s planning to get pregnant or not, for the healthy new cells the body makes daily. Think about the skin, hair, and nails. These – and other parts of the body – make new cells each day.

Centers for Disease Control and Prevention (CDC) urges women to take 400 mcg of folic acid every day, starting at least one month before getting pregnant and while she is pregnant, to help prevent major birth defects of the baby’s brain and spine.

Folate is naturally present in many foods and food companies add folic acid to other foods, including bread, cereal, and pasta. You can get recommended amounts by eating a variety of foods, including the following:

Leafy Green Vegetables (especially asparagus, Brussels sprouts, and dark green leafy vegetables such as spinach and mustard greens).
Fruits and fruit juices (especially oranges and orange juice).
Nuts, beans, and peas (such as peanuts, black-eyed peas, and kidney beans).
Grains (including whole grains; fortified cold cereals; enriched flour products such as bread, bagels, cornmeal, and pasta; and rice).
Folic acid is added to many grain-based products, enriched breads, cereals and corn masa flour (used to make corn tortillas and tamales, for example). To find out whether folic acid has been added to a food, check the product label.

Beef liver is high in folate but is also high in cholesterol, so limit the amount you eat. Only small amounts of folate are found in other animal foods like meats, poultry, seafood, eggs, and dairy products.

Table 11. Selected Food Sources of Folate and Folic Acid

Food	mcg DFE per serving	Percent DV*
Beef liver, braised, 3 ounces	215	54
Spinach, boiled, ½ cup	131	33
Black-eyed peas (cowpeas), boiled, ½ cup	105	26
Breakfast cereals, fortified with 25% of the DV†	100	25
Rice, white, medium-grain, cooked, ½ cup†	90	23
Asparagus, boiled, 4 spears	89	22
Spaghetti, cooked, enriched, ½ cup†	83	21
Brussels sprouts, frozen, boiled, ½ cup	78	20
Lettuce, romaine, shredded, 1 cup	64	16
Avocado, raw, sliced, ½ cup	59	15
Spinach, raw, 1 cup	58	15
Broccoli, chopped, frozen, cooked, ½ cup	52	13
Mustard greens, chopped, frozen, boiled, ½ cup	52	13
Green peas, frozen, boiled, ½ cup	47	12
Kidney beans, canned, ½ cup	46	12
Bread, white, 1 slice†	43	11
Peanuts, dry roasted, 1 ounce	41	10
Wheat germ, 2 tablespoons	40	10
Tomato juice, canned, ¾ cup	36	9
Crab, Dungeness, 3 ounces	36	9
Orange juice, ¾ cup	35	9
Turnip greens, frozen, boiled, ½ cup	32	8
Orange, fresh, 1 small	29	7
Papaya, raw, cubed, ½ cup	27	7
Banana, 1 medium	24	6
Yeast, baker’s, ¼ teaspoon	23	6
Egg, whole, hard-boiled, 1 large	22	6
Vegetarian baked beans, canned, ½ cup	15	4
Cantaloupe, raw, 1 wedge	14	4
Fish, halibut, cooked, 3 ounces	12	3
Milk, 1% fat, 1 cup	12	3
Ground beef, 85% lean, cooked, 3 ounces	7	2
Chicken breast, roasted, ½ breast	3	1

Footnote: * DV = Daily Value. The FDA developed DVs to help consumers compare the nutrient contents of products within the context of a total diet. The DV for folate is 400 mcg for adults and children aged 4 and older. However, the FDA does not require food labels to list folate content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

† Fortified with folic acid as part of the folate fortification program.

[Source ⁴⁸]

Vitamin C

Vitamin C also known as ascorbic acid or ascorbate, is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement. Vitamin C is synthesized from D-glucose or D-galactose by many plants and animals. However, humans lack the enzyme L-gulonolactone oxidase required for ascorbic acid synthesis and must obtain vitamin C through food or supplements ⁶⁶, ⁶⁷. Vitamin C is found in many fruits and vegetables, including citrus fruits, tomatoes, potatoes, red and green peppers, kiwifruit, broccoli, strawberries, brussels sprouts, and cantaloupe. In the body, vitamin C acts as an antioxidant, helping to protect cells from the damage caused by free radicals. Free radicals are compounds formed when our bodies convert the food we eat into energy. People are also exposed to free radicals in the environment from cigarette smoke, air pollution, and ultraviolet light from the sun.

The Recommended Dietary Allowance (RDA; average daily level of intake sufficient to meet the nutrient requirement of 97–98% healthy individuals) for vitamin C ranges from 15 to 115 mg for infants and children (depending on age) and from 75 to 120 mg for nonsmoking adults; people who smoke need 35 mg more per day ⁶⁸. The intestinal absorption of vitamin C is regulated by at least one specific dose-dependent, active transporter ⁶⁹. Cells accumulate vitamin C via a second specific transport protein. In vitro studies have found that oxidized vitamin C, or dehydroascorbic acid, enters cells via some facilitated glucose transporters and is then reduced internally to ascorbic acid. The physiologic importance of dehydroascorbic acid uptake and its contribution to overall vitamin C economy is unknown.

Vitamin C plays a role in collagen, carnitine, hormone, and amino acid formation. It is essential for wound healing and facilitates recovery from burns. Vitamin C is also an antioxidant, supports immune function, and facilitates the absorption of iron ⁷⁰. Vitamin C also plays an important role in both innate and adaptive immunity, probably because of its antioxidant effects, antimicrobial and antiviral actions, and effects on immune system modulators ⁷¹. Vitamin C helps maintain epithelial integrity, enhance the differentiation and proliferation of B cells and T cells, enhance phagocytosis, normalize cytokine production, and decrease histamine levels ⁷². Vitamin C might also inhibit viral replication ⁷³.

Vitamin C deficiency impairs immune function and increases susceptibility to infections ⁷². Some research suggests that supplemental vitamin C enhances immune function ⁷⁴, but its effects might vary depending on an individual’s vitamin C status ⁷⁵.

Vitamin C deficiency is uncommon in the United States, affecting only about 7% of individuals aged 6 years and older ⁷⁶. People who smoke and those whose diets include a limited variety of foods (such as some older adults and people with alcohol or drug use disorders) are more likely than others to obtain insufficient amounts of vitamin C ⁷⁴.

High-Dose vitamin C, when taken by intravenous (IV) infusion, vitamin C can reach much higher levels in the blood than when it is taken by mouth. Studies suggest that these higher levels of vitamin C may cause the death of cancer cells in the laboratory. Surveys of healthcare practitioners at United States complementary and alternative medicine conferences in recent years have shown that high-dose IV vitamin C is frequently given to patients as a treatment for infections, fatigue, and cancers, including breast cancer ⁷⁷.

There are reviews of the role of vitamin C in immunity and in host susceptibility to infection ⁷⁸. Vitamin C is required for collagen biosynthesis and is vital for maintaining epithelial integrity. Vitamin C also has roles in several aspects of immunity, including leucocyte migration to sites of infection, phagocytosis and bacterial killing, natural killer cell activity, T lymphocyte function (especially of CD8+ cytotoxic T lymphocytes) and antibody production. Jacob et al ⁷⁹ showed that a vitamin C-deficient diet in healthy young adult humans decreased mononuclear cell vitamin C content by 50% and decreased the T lymphocyte-mediated immune responses to recall antigens. Vitamin C deficiency in animal models increases susceptibility to a variety of infections ⁷⁸. People deficient in vitamin C are susceptible to severe respiratory infections such as pneumonia. A meta-analysis ²⁴ reported a significant reduction in the risk of pneumonia with vitamin C supplementation, particularly in individuals with low dietary intakes. Vitamin C supplementation has also been shown to decrease the duration and severity of upper respiratory tract infections, such as the common cold, especially in people under enhanced physical stress ²⁵.

Vitamin C is required for the biosynthesis of collagen, L-carnitine, and certain neurotransmitters; vitamin C is also involved in protein metabolism ⁶⁷, ⁸⁰. Collagen is an essential component of connective tissue, which plays a vital role in wound healing. Vitamin C is also an important physiological antioxidant ⁸¹ and has been shown to regenerate other antioxidants within the body, including alpha-tocopherol (vitamin E) ⁸². Ongoing research is examining whether vitamin C, by limiting the damaging effects of free radicals through its antioxidant activity, might help prevent or delay the development of certain cancers, cardiovascular disease, and other diseases in which oxidative stress plays a causal role. In addition to its biosynthetic and antioxidant functions, vitamin C plays an important role in immune function ⁸² and improves the absorption of nonheme iron ⁸³, the form of iron present in plant-based foods. Insufficient vitamin C intake causes scurvy, which is characterized by fatigue or lassitude, widespread connective tissue weakness, and capillary fragility ⁶⁷, ⁸⁰, ⁸², ⁸⁴, ⁸⁵, ⁸⁶, ⁸⁷.

Table 12. Selected Food Sources of Vitamin C

Food	Milligrams (mg) per serving	Percent (%) DV*
Red pepper, sweet, raw, ½ cup	95	158
Orange juice, ¾ cup	93	155
Orange, 1 medium	70	117
Grapefruit juice, ¾ cup	70	117
Kiwifruit, 1 medium	64	107
Green pepper, sweet, raw, ½ cup	60	100
Broccoli, cooked, ½ cup	51	85
Strawberries, fresh, sliced, ½ cup	49	82
Brussels sprouts, cooked, ½ cup	48	80
Grapefruit, ½ medium	39	65
Broccoli, raw, ½ cup	39	65
Tomato juice, ¾ cup	33	55
Cantaloupe, ½ cup	29	48
Cabbage, cooked, ½ cup	28	47
Cauliflower, raw, ½ cup	26	43
Potato, baked, 1 medium	17	28
Tomato, raw, 1 medium	17	28
Spinach, cooked, ½ cup	9	15
Green peas, frozen, cooked, ½ cup	8	13

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin C is 60 mg for adults and children aged 4 and older. The FDA requires all food labels to list the percent DV for vitamin C. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

[Source ⁴⁸]

Vitamin D

Vitamin D is a fat-soluble vitamin that is naturally present in very few foods, added to others, and available as a dietary supplement. It is also produced endogenously when ultraviolet rays from sunlight strike the skin and trigger vitamin D synthesis. Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylations in the body for activation ⁸⁸. The first occurs in the liver and converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known as calcidiol. The second occurs primarily in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as calcitriol ⁸⁹.

Vitamin D is a nutrient found in some foods that is needed for health and to maintain strong bones. It does so by helping the body absorb calcium (one of bone’s main building blocks) from food and supplements. People who get too little vitamin D may develop soft, thin, and brittle bones, a condition known as rickets in children and osteomalacia in adults.

Vitamin D is important to the body in many other ways as well. Muscles need it to move, for example, nerves need it to carry messages between the brain and every body part, and the immune system needs vitamin D to fight off invading bacteria and viruses. Together with calcium, vitamin D also helps protect older adults from osteoporosis. Vitamin D is found in cells throughout the body.

Vitamin D promotes calcium absorption in the gut and maintains adequate serum calcium and phosphate concentrations to enable normal mineralization of bone and to prevent hypocalcemic tetany. It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts ⁸⁹, ⁹⁰. Without sufficient vitamin D, bones can become thin, brittle, or misshapen. Vitamin D sufficiency prevents rickets in children and osteomalacia in adults ⁸⁹. Together with calcium, vitamin D also helps protect older adults from osteoporosis.

Vitamin D has other roles in the body, including modulation of cell growth, neuromuscular and immune function, and reduction of inflammation ⁸⁹, ⁹¹, ⁹². Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D ⁸⁹. Many cells have vitamin D receptors, and some convert 25(OH)D to 1,25(OH)2D.

There are a number of reviews of the role of vitamin D and its metabolites in immunity and in host susceptibility to infection ⁹³. The active form of vitamin D (1,25-dihydroxyvitamin D3) is referred to here as vitamin D. Vitamin D receptors have been identified in most immune cells and some cells of the immune system can synthesise the active form of vitamin D from its precursor, suggesting that vitamin D is likely to have important immunoregulatory properties. Vitamin D enhances epithelial integrity and induces antimicrobial peptide (eg, cathelicidin) synthesis in epithelial cells and macrophages, directly enhancing host defence ⁹⁴. However, the effects of vitamin D on the cellular components of immunity are rather complex. Vitamin D promotes differentiation of monocytes to macrophages and increases phagocytosis, superoxide production and bacterial killing by innate immune cells. It also promotes antigen processing by dendritic cells although antigen presentation may be impaired. Vitamin D is also reported to inhibit T-cell proliferation and production of cytokines by T helper 1 lymphocytes and of antibodies by B lymphocytes, highlighting the paradoxical nature of its effects. Effects on T helper 2 responses are not clear and vitamin D seems to increase number of regulatory T lymphocytes. Vitamin D seems to have little impact on CD8+ T lymphocytes. A systematic review and meta-analysis of the influence of vitamin D status on influenza vaccination (nine studies involving 2367 individuals) found lower seroprotection rates to influenza A virus subtype H3N2 and to influenza B virus in those who were vitamin D deficient ⁹⁵. Berry et al ⁹⁶ described an inverse linear relationship between vitamin D levels and respiratory tract infections in a cross-sectional study of 6789 British adults. In agreement with this, data from the US Third National Health and Nutrition Examination Survey which included 18 883 adults showed an independent inverse association between serum 25(OH)-vitamin D and recent upper respiratory tract infection ⁹⁷. Other studies also report that individuals with low vitamin D status have a higher risk of viral respiratory tract infections ⁹⁸. Supplementation of Japanese schoolchildren with vitamin D for 4 months during winter decreased the risk of influenza by about 40% ⁹⁹. Meta-analyses have concluded that vitamin D supplementation can reduce the risk of respiratory tract infections ²⁹, ²⁸.

Table 13. Selected Food Sources of Vitamin D

Food	IUs per serving*	Percent DV**
Cod liver oil, 1 tablespoon	1360	340
Swordfish, cooked, 3 ounces	566	142
Salmon (sockeye), cooked, 3 ounces	447	112
Tuna fish, canned in water, drained, 3 ounces	154	39
Orange juice fortified with vitamin D, 1 cup (check product labels, as amount of added vitamin D varies)	137	34
Milk, nonfat, reduced fat, and whole, vitamin D-fortified, 1 cup	115-124	29-31
Yogurt, fortified with 20% of the DV for vitamin D, 6 ounces (more heavily fortified yogurts provide more of the DV)	80	20
Margarine, fortified, 1 tablespoon	60	15
Sardines, canned in oil, drained, 2 sardines	46	12
Liver, beef, cooked, 3 ounces	42	11
Egg, 1 large (vitamin D is found in yolk)	41	10
Ready-to-eat cereal, fortified with 10% of the DV for vitamin D, 0.75-1 cup (more heavily fortified cereals might provide more of the DV)	40	10
Cheese, Swiss, 1 ounce	6	2

Footnotes: * IUs = International Units. ** DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient contents among products within the context of a total daily diet. The DV for vitamin D is currently set at 400 IU for adults and children age 4 and older. Food labels, however, are not required to list vitamin D content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

[Source ⁴⁸]

Vitamin E

Naturally occurring vitamin E exists in eight chemical forms (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) that have varying levels of biological activity ¹⁰⁰. Alpha- (or α-) tocopherol is the only form that is recognized to meet human requirements, but beta-, gamma-, and delta-tocopherols, 4 tocotrienols, and several stereoisomers may also have important biologic activity. These compounds act as antioxidants, which prevent lipid peroxidation of polyunsaturated fatty acids in cellular membranes ¹⁰¹.

Serum concentrations of vitamin E (alpha-tocopherol) depend on the liver, which takes up the nutrient after the various forms are absorbed from the small intestine.

Vitamin E is a fat-soluble antioxidant that stops the production of reactive oxygen species formed when fat undergoes oxidation. Scientists are investigating whether, by limiting free-radical production and possibly through other mechanisms, vitamin E might help prevent or delay the chronic diseases associated with free radicals.

Antioxidants protect cells from the damaging effects of free radicals, which are molecules that contain an unshared electron. Free radicals damage cells and might contribute to the development of cardiovascular disease and cancer ¹⁰². Unshared electrons are highly energetic and react rapidly with oxygen to form reactive oxygen species. The body forms reactive oxygen species endogenously when it converts food to energy, and antioxidants might protect cells from the damaging effects of reactive oxygen species. The body is also exposed to free radicals from environmental exposures, such as cigarette smoke, air pollution, and ultraviolet radiation from the sun. Reactive oxygen species are part of signaling mechanisms among cells.

The body also needs vitamin E to boost its immune system so that it can fight off invading bacteria and viruses. It helps to widen blood vessels and keep blood from clotting within them.

In addition to its activities as an antioxidant, vitamin E is involved in immune function and, as shown primarily by in vitro studies of cells, cell signaling, regulation of gene expression, and other metabolic processes ¹⁰⁰. Alpha-tocopherol inhibits the activity of protein kinase C, an enzyme involved in cell proliferation and differentiation in smooth muscle cells, platelets, and monocytes ¹⁰³. Vitamin-E–replete endothelial cells lining the interior surface of blood vessels are better able to resist blood-cell components adhering to this surface. Vitamin E also increases the expression of two enzymes that suppress arachidonic acid metabolism, thereby increasing the release of prostacyclin from the endothelium, which, in turn, dilates blood vessels and inhibits platelet aggregation ¹⁰³.

There are a number of reviews of the role of vitamin E in immunity and host susceptibility to infection ¹⁰⁴. In laboratory animals, vitamin E deficiency decreases lymphocyte proliferation, natural killer cell activity, specific antibody production following vaccination and phagocytosis by neutrophils. Vitamin E deficiency also increases susceptibility of animals to infectious pathogens. Vitamin E supplementation of the diet of laboratory animals enhances antibody production, lymphocyte proliferation, T helper 1-type cytokine production, natural killer cell activity and macrophage phagocytosis. Vitamin E promotes interaction between dendritic cells and CD4+ T lymphocytes. There is a positive association between plasma vitamin E and cell-mediated immune responses, and a negative association has been demonstrated between plasma vitamin E and the risk of infections in healthy adults over 60 years of age ¹⁰⁵. There appears to be particular benefit of vitamin E supplementation for the elderly ¹⁰⁶. Studies by Meydani et al ¹⁰⁷ demonstrated that vitamin E supplementation at high doses, one study used 800 mg/day ¹⁰⁸ and the other used doses of 60, 200 and 800 mg/day ¹⁰⁷ enhanced T helper 1 cell-mediated immunity (lymphocyte proliferation, IL-2 production) and improved vaccination responses, including to hepatitis B virus. Supplementation of older adults with vitamin E (200 mg/day) improved neutrophil chemotaxis and phagocytosis, natural killer cell activity and mitogen-induced lymphocyte proliferation ¹⁰⁶. Secondary analysis of data from the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study identified that daily vitamin E supplements for 5 to 8 years reduced the incidence of hospital treated, community-acquired pneumonia in smokers ¹⁰⁹. One study reported that vitamin E supplementation (200 IU/day~135 mg/day) for 1 year decreased risk of upper respiratory tract infections in the elderly ¹¹⁰, but another study did not see an effect of supplemental vitamin E (200 mg/day) on the incidence, duration or severity of respiratory infections in an elderly population ¹¹¹.

Table 14. Selected Food Sources of Vitamin E (Alpha-Tocopherol)

Food	Milligrams (mg) per serving	Percent DV*
Wheat germ oil, 1 tablespoon	20.3	100
Sunflower seeds, dry roasted, 1 ounce	7.4	37
Almonds, dry roasted, 1 ounce	6.8	34
Sunflower oil, 1 tablespoon	5.6	28
Safflower oil, 1 tablespoon	4.6	25
Hazelnuts, dry roasted, 1 ounce	4.3	22
Peanut butter, 2 tablespoons	2.9	15
Peanuts, dry roasted, 1 ounce	2.2	11
Corn oil, 1 tablespoon	1.9	10
Spinach, boiled, ½ cup	1.9	10
Broccoli, chopped, boiled, ½ cup	1.2	6
Soybean oil, 1 tablespoon	1.1	6
Kiwifruit, 1 medium	1.1	6
Mango, sliced, ½ cup	0.7	4
Tomato, raw, 1 medium	0.7	4
Spinach, raw, 1 cup	0.6	3

Footnote: *DV = Daily Value. DVs were developed by the FDA to help consumers compare the nutrient content of different foods within the context of a total diet. The DV for vitamin E is 30 IU (approximately 20 mg of natural alpha-tocopherol) for adults and children age 4 and older. However, the FDA does not require food labels to list vitamin E content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

[Source ⁴⁸]

Iron

Iron is a mineral that our bodies need for many functions. In the human body, iron is present in all cells and has several vital functions — as a carrier of oxygen to the tissues from the lungs in the form of hemoglobin (Hb), as a facilitator of oxygen use and storage in the muscles as myoglobin, as a transport medium for electrons within the cells in the form of cytochromes, and as an integral part of enzyme reactions in various tissues. Too little iron can interfere with these vital functions and lead to morbidity and mortality ¹¹², ¹¹³.

In adults, the recommended dietary allowance of iron is 8 to 11 mg per day for men and 8 to 18 mg for women in whom higher levels are recommended during pregnancy (27 mg per day) ¹¹⁴. Iron is poorly absorbed and body and tissue iron stores are controlled largely by modifying rates of absorption. Adequate amounts of iron are found in most Western diets, with highest levels found in red meats and moderate levels in fish, poultry, green vegetables, cereals and grains (some of which are fortified with iron).

Your body needs the right amount of iron. If you have too little iron, you may develop iron deficiency anemia. Iron deficiency is usually due to loss of iron, predominantly as a result of blood loss in the gastrointestinal tract or from menstruation and is rarely due to deficiency in intake or an inability to absorb enough iron from foods. People at higher risk of having too little iron are young children and women who are pregnant or have periods.

There are a number of reviews of the role of iron in immunity and host susceptibility to infection ¹¹⁵. Iron deficiency induces thymus atrophy, reducing output of naive T lymphocytes, and has multiple effects on immune function in humans. The effects are wide ranging and include impairment of respiratory burst and bacterial killing, natural killer cell activity, T lymphocyte proliferation and production of T helper 1 cytokines. T lymphocyte proliferation was lower by 50% to 60% in iron-deficient than in iron-replete housebound older Canadian women ¹¹⁶. These observations would suggest a clear case for iron deficiency increasing susceptibility to infection. However, the relationship between iron deficiency and susceptibility to infection remains complex ¹¹⁷. Evidence suggests that infections caused by organisms that spend part of their life-cycle intracellularly, such as plasmodia and mycobacteria, may actually be enhanced by iron. In the tropics, in children of all ages, iron at doses above a particular threshold has been associated with increased risk of malaria and other infections, including pneumonia. Thus, iron intervention in malaria-endemic areas is not advised, particularly high doses in the young, those with compromised immunity and during the peak malaria transmission season. There are different explanations for the detrimental effects of iron administration on infections. First, iron overload causes impairment of immune function ¹¹⁸. Second, excess iron favors damaging inflammation. Third, micro-organisms require iron and providing it may favor the growth of the pathogen. Perhaps for the latter reasons several host immune mechanisms have developed for withholding iron from a pathogen ¹¹⁵. In a recent study giving iron (50 mg on each of 4 days a week) to iron-deficient school children in South Africa increased the risk of respiratory infections ¹¹⁹; coadministration of omega-3 fatty acids (500 mg on each of 4 days a week) mitigated the effect of iron. Meta-analysis of studies in Chinese children showed that those with recurrent respiratory tract infection were more likely to have low hair iron ³⁰.

What foods provide iron?

Iron is found naturally in many foods and is added to some fortified food products. You can get recommended amounts of iron by eating a variety of foods, including the following:

Lean meat, seafood, and poultry.
Iron-fortified breakfast cereals and breads.
White beans, lentils, spinach, kidney beans, and peas.
Nuts and some dried fruits, such as raisins.

Iron in food comes in two forms: heme iron and nonheme iron. Nonheme iron is found in plant foods and iron-fortified food products. Meat, seafood, and poultry have both heme and nonheme iron.

Heme iron has higher bioavailability than nonheme iron, and other dietary components have less effect on the bioavailability of heme than nonheme iron ¹²⁰. The bioavailability of iron is approximately 14% to 18% from mixed diets that include substantial amounts of meat, seafood, and vitamin C (ascorbic acid, which enhances the bioavailability of nonheme iron) and 5% to 12% from vegetarian diets ¹²¹. In addition to ascorbic acid, meat, poultry, and seafood can enhance nonheme iron absorption, whereas phytate (present in grains and beans) and certain polyphenols in some non-animal foods (such as cereals and legumes) have the opposite effect ¹²². Unlike other inhibitors of iron absorption, calcium might reduce the bioavailability of both nonheme and heme iron. However, the effects of enhancers and inhibitors of iron absorption are attenuated by a typical mixed western diet, so they have little effect on most people’s iron status.

Several food sources of iron are listed in Table 15. Some plant-based foods that are good sources of iron, such as spinach, have low iron bioavailability because they contain iron-absorption inhibitors, such as polyphenols ¹²³.

Your body absorbs iron from plant sources better when you eat it with meat, poultry, seafood, and foods that contain vitamin C, like citrus fruits, strawberries, sweet peppers, tomatoes, and broccoli.

Table 15. Selected Food Sources of Iron

Food	Milligrams per serving	Percent DV*
Breakfast cereals, fortified with 100% of the DV for iron, 1 serving	18	100
Oysters, eastern, cooked with moist heat, 3 ounces	8	44
White beans, canned, 1 cup	8	44
Chocolate, dark, 45%–69% cacao solids, 3 ounces	7	39
Beef liver, pan fried, 3 ounces	5	28
Lentils, boiled and drained, ½ cup	3	17
Spinach, boiled and drained, ½ cup	3	17
Tofu, firm, ½ cup	3	17
Kidney beans, canned, ½ cup	2	11
Sardines, Atlantic, canned in oil, drained solids with bone, 3 ounces	2	11
Chickpeas, boiled and drained, ½ cup	2	11
Tomatoes, canned, stewed, ½ cup	2	11
Beef, braised bottom round, trimmed to 1/8” fat, 3 ounces	2	11
Potato, baked, flesh and skin, 1 medium potato	2	11
Cashew nuts, oil roasted, 1 ounce (18 nuts)	2	11
Green peas, boiled, ½ cup	1	6
Chicken, roasted, meat and skin, 3 ounces	1	6
Rice, white, long grain, enriched, parboiled, drained, ½ cup	1	6
Bread, whole wheat, 1 slice	1	6
Bread, white, 1 slice	1	6
Raisins, seedless, ¼ cup	1	6
Spaghetti, whole wheat, cooked, 1 cup	1	6
Tuna, light, canned in water, 3 ounces	1	6
Turkey, roasted, breast meat and skin, 3 ounces	1	6
Nuts, pistachio, dry roasted, 1 ounce (49 nuts)	1	6
Broccoli, boiled and drained, ½ cup	1	6
Egg, hard boiled, 1 large	1	6
Rice, brown, long or medium grain, cooked, 1 cup	1	6
Cheese, cheddar, 1.5 ounces	0	0
Cantaloupe, diced, ½ cup	0	0
Mushrooms, white, sliced and stir-fried, ½ cup	0	0
Cheese, cottage, 2% milk fat, ½ cup	0	0
Milk, 1 cup	0	0

[Source ⁴⁸]

Copper

Copper is an essential mineral that you need to stay healthy. Your body uses copper to carry out many important functions, including making energy, connective tissues, and blood vessels. Copper also helps maintain the nervous, pigmentation, and immune systems, and activates genes. Your body also needs copper for brain development ¹²⁴. In addition, defense against oxidative damage depends mainly on the copper-containing superoxide dismutases ¹²⁵. Copper is a cofactor for several enzymes known as “cuproenzymes” involved in energy production, iron metabolism, neuropeptide activation, connective tissue synthesis, and neurotransmitter synthesis ¹²⁴. One abundant cuproenzyme is ceruloplasmin, which plays a role in iron metabolism and carries more than 95% of the total copper in healthy human plasma ¹²⁶.

There are a number of reviews of the role of copper in immunity and host susceptibility to infection ¹²⁷. Copper itself has antimicrobial properties. Copper supports neutrophil, monocyte and macrophage function and natural killer cell activity. It promotes T lymphocyte responses such as proliferation and IL-2 production. Copper deficiency in animals impairs a range of immune functions and increases susceptibility to bacterial and parasitic challenges. Human studies show that subjects on a low copper diet have decreased lymphocyte proliferation and IL-2 production, with copper administration reversing these effects ¹²⁸. Children with Menke’s syndrome, a rare congenital disease with complete absence of the circulating copper-carrying protein caeruloplasmin, show immune impairments and have increased bacterial infections, diarrhea and pneumonia ¹²⁹. Meta-analysis of studies in Chinese children showed that those with recurrent respiratory tract infection were more likely to have low hair copper ³⁰.

A wide variety of plant and animal foods contain copper, and the average human diet provides approximately 1,400 mcg/day for men and 1,100 mcg/day for women that is primarily absorbed in the upper small intestine ¹³⁰. Almost two-thirds of the body’s copper is located in the skeleton and muscle ¹²⁴.

Only small amounts of copper are typically stored in the body, and the average adult has a total body content of 50–120 mg copper ¹²⁴. Most copper is excreted in bile, and a small amount is excreted in urine. Total fecal losses of copper of biliary origin and nonabsorbed dietary copper are about 1 mg/day ¹²⁴. Copper levels in the body are homeostatically maintained by copper absorption from the intestine and copper release by the liver into bile to provide protection from copper deficiency and toxicity ¹³¹.

Copper status is not routinely assessed in clinical practice, and no biomarkers that accurately and reliably assess copper status have been identified ¹³². Human studies typically measure copper and cuproenzyme activity in plasma and blood cells because individuals with known copper deficiency often have low blood levels of copper and ceruloplasmin ¹³². However, plasma ceruloplasmin and copper levels can be influenced by other factors, such as estrogen status, pregnancy, infection, inflammation, and some cancers ¹³². Normal serum concentrations are 10–25 mcmol/L (63.5–158.9 mcg/dL) for copper and 180–400 mg/L for ceruloplasmin ¹³³.

The amount of copper you need each day depends on your age. Typical diets in the United States meet or exceed the copper recommended dietary allowance (RDA), which is the average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals. Mean dietary intakes of copper from foods range from 800 to 1,000 mcg per day for children aged 2–19 ¹³⁴. In adults aged 20 and older, average daily intakes of copper from food are 1,400 mcg for men and 1,100 mcg for women. Total intakes from supplements and foods are 900 to 1,100 mcg/day for children and 1,400 to 1,700 mcg/day for adults aged 20 and over.

Copper deficiency is uncommon in humans ¹³². Based on studies in animals and humans, the effects of copper deficiency include anemia, hypopigmentation, hypercholesterolemia, connective tissue disorders, osteoporosis and other bone defects, abnormal lipid metabolism, ataxia, and increased risk of infection ¹³⁵.

Copper is available in dietary supplements containing only copper, in supplements containing copper in combination with other ingredients, and in many multivitamin/multimineral products ¹³⁶. These supplements contain many different forms of copper, including cupric oxide, cupric sulfate, copper amino acid chelates, and copper gluconate. To date, no studies have compared the bioavailability of copper from these and other forms ¹³⁷. The amount of copper in dietary supplements typically ranges from a few micrograms to 15 mg (about 17 times the daily value [DV] for copper) ¹³⁶.

Table 16. Selected Food Sources of Copper

Food	Micrograms (mcg) per serving	Percent DV*
Beef, liver, pan fried (3 ounces)	12400	1378
Oysters, eastern, wild, cooked, 3 ounces	4850	539
Baking chocolate, unsweetened, 1 ounce	938	104
Potatoes, cooked, flesh and skin, 1 medium potato	675	75
Mushrooms, shiitake, cooked, cut pieces, ½ cup	650	72
Cashew nuts, dry roasted, 1 ounce	629	70
Crab, Dungeness, cooked, 3 ounces	624	69
Sunflower seed kernels, toasted, ¼ cup	615	68
Turkey, giblets, simmered, 3 ounces	588	65
Chocolate, dark, 70%-85% cacao solids, 1 ounce	501	56
Tofu, raw, firm, ½ cup	476	53
Chickpeas, mature sees, ½ cup	289	32
Millet, cooked, 1 cup	280	31
Salmon, Atlantic, wild, cooked, 3 ounces	273	30
Pasta, whole wheat, cooked, 1 cup (not packed)	263	29
Avocado, raw, ½ cup	219	24
Figs, dried, ½ cup	214	24
Spinach, boiled, drained, ½ cup	157	17
Asparagus, cooked, drained, ½ cup	149	17
Seseame seeds, ¼ cup	147	16
Turkey, ground, cooked, 3 ounces	128	14
Cereals, Cream of Wheat, cooked with water, stove-top, 1 cup	104	12
Tomatoes, raw, chopped, ½ cup	53	6
Yogurt, Greek, plain, lowfat, 7-ounce container	42	5
Milk, nonfat, 1 cup	27	3
Apples, raw, with skin, ½ cup slices	17	2

Footnote: *DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for copper is 0.9 mg (900 mcg) for adults and children age 4 years and older [13]. The FDA does not require food labels to list copper content unless copper has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

[Source ⁴⁸]

Selenium

Selenium is a trace element that is naturally present in many foods, added to others, and available as a dietary supplement. Selenium, which is nutritionally essential for humans, is a constituent of more than two dozen selenoproteins that play critical roles in reproduction, thyroid hormone metabolism, DNA synthesis, and protection from oxidative damage and infection ¹³⁸.

Selenium exists in two forms:

inorganic (selenate and selenite) and
organic (selenomethionine and selenocysteine) ¹³⁹.

Both forms can be good dietary sources of selenium ¹⁴⁰. Soils contain inorganic selenites and selenates that plants accumulate and convert to organic forms, mostly selenocysteine and selenomethionine and their methylated derivatives.

Selenium is found naturally in many foods. The amount of selenium in plant foods depends on the amount of selenium in the soil where they were grown. The amount of selenium in animal products depends on the selenium content of the foods that the animals ate. You can get recommended amounts of selenium by eating a variety of foods, including the following:

Seafood
Meat, poultry, eggs, and dairy products
Breads, cereals, and other grain products.

Selenium is important for reproduction, thyroid gland function, DNA production, and protecting the body from damage caused by free radicals and from infection ¹⁴¹, ¹⁴². Selenium is incorporated into selenoproteins that have a wide range of pleiotropic effects, ranging from antioxidant and anti-inflammatory effects to the production of active thyroid hormone ¹⁴³. In the past 10 years, the discovery of disease-associated polymorphisms in selenoprotein genes has drawn attention to the relevance of selenoproteins to health. Low selenium status has been associated with increased risk of mortality, poor immune function, and cognitive decline. Higher selenium status or selenium supplementation has antiviral effects, is essential for successful male and female reproduction, and reduces the risk of autoimmune thyroid disease. Prospective studies have generally shown some benefit of higher selenium status on the risk of prostate, lung, colorectal, and bladder cancers, but findings from trials have been mixed, which probably emphasises the fact that supplementation will confer benefit only if intake of a nutrient is inadequate. Supplementation of people who already have adequate intake with additional selenium might increase their risk of type-2 diabetes. The crucial factor that needs to be emphasised with regard to the health effects of selenium is the inextricable U-shaped link with status; whereas additional selenium intake may benefit people with low status, those with adequate-to-high status might be affected adversely and should not take selenium supplements.

There are a number of reviews of the role of selenium in immunity and host susceptibility to infection ¹⁴⁴. Selenium deficiency in laboratory animals adversely affects several components of both innate and acquired immunity, including T and B lymphocyte function including antibody production and increases susceptibility to infections. Lower selenium concentrations in humans have been linked with diminished natural killer cell activity and increased mycobacterial disease. Selenium deficiency was shown to permit mutations of coxsackievirus, polio virus and murine influenza virus increasing virulence ¹⁴⁵. These latter observations suggest that poor selenium status could result in the emergence of more pathogenic strains of virus, thereby increasing the risks and burdens associated with viral infection. Selenium supplementation (100 to 300 µg/day depending on the study) has been shown to improve various aspects of immune function in humans ¹⁴⁶, including in the elderly ¹⁴⁷. Selenium supplementation (50 or 100 µg/day) in adults in the UK with low selenium status improved some aspects of their immune response to a poliovirus vaccine ¹⁴⁸.

Table 17. Selected Food Sources of Selenium

Food	Micrograms (mcg) per serving	Percent DV*
Brazil nuts, 1 ounce (6–8 nuts)	544	777
Tuna, yellowfin, cooked, dry heat, 3 ounces	92	131
Halibut, cooked, dry heat, 3 ounces	47	67
Sardines, canned in oil, drained solids with bone, 3 ounces	45	64
Ham, roasted, 3 ounces	42	60
Shrimp, canned, 3 ounces	40	57
Macaroni, enriched, cooked, 1 cup	37	53
Beef steak, bottom round, roasted, 3 ounces	33	47
Turkey, boneless, roasted, 3 ounces	31	44
Beef liver, pan fried, 3 ounces	28	40
Chicken, light meat, roasted, 3 ounces	22	31
Cottage cheese, 1% milkfat, 1 cup	20	29
Rice, brown, long-grain, cooked, 1 cup	19	27
Beef, ground, 25% fat, broiled, 3 ounces	18	26
Egg, hard-boiled, 1 large	15	21
Puffed wheat ready-to-eat cereal, fortified, 1 cup	15	21
Bread, whole-wheat, 1 slice	13	19
Baked beans, canned, plain or vegetarian, 1 cup	13	19
Oatmeal, regular and quick, unenriched, cooked with water, 1 cup	13	19
Spinach, frozen, boiled, 1 cup	11	16
Milk, 1% fat, 1 cup	8	11
Yogurt, plain, low fat, 1 cup	8	11
Lentils, boiled, 1 cup	6	9
Bread, white, 1 slice	6	9
Spaghetti sauce, marinara, 1 cup	4	6
Cashew nuts, dry roasted, 1 ounce	3	4
Corn flakes, 1 cup	2	3
Green peas, frozen, boiled, 1 cup	2	3
Bananas, sliced, 1 cup	2	3
Potato, baked, flesh and skin, 1 potato	1	1
Peaches, canned in water, solids and liquids, 1 cup	1	1
Carrots, raw, 1 cup	0	0
Lettuce, iceberg, raw, 1 cup	0	0

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for selenium is 70 mcg for adults and children aged 4 and older. Foods providing 20% or more of the DV are considered to be high sources of a nutrient. The U.S. Department of Agriculture’s (USDA’s) Nutrient Database Web site ¹⁴⁹ lists the nutrient content of many foods and provides a comprehensive list of foods containing selenium arranged by nutrient content and by food name.

[Source ⁴⁸]

Zinc

Zinc is involved in numerous aspects of cellular metabolism. It is required for the catalytic activity of approximately 100 enzymes, including many nicotinamide adenine dinucleotide (NADH) dehydrogenases, RNA and DNA polymerases, and DNA transcription factors as well as alkaline phosphatase, superoxide dismutase, and carbonic anhydrase ¹⁵⁰, ¹⁵¹ and it plays a role in immune function ¹⁵², ¹⁵³, protein synthesis ¹⁵³, wound healing ¹⁵⁴, DNA synthesis ¹⁵¹, ¹⁵³ and cell division ¹⁵³. Zinc also supports normal growth and development during pregnancy, childhood, and adolescence ¹⁵⁵, ¹⁵⁶, ¹⁵⁷ and is required for proper sense of taste and smell ¹⁵⁸. A daily intake of zinc is required to maintain a steady state because the body has no specialized zinc storage system ¹⁵⁹.

Most Americans get enough zinc from the foods they eat.

There are a number of reviews of the role of zinc in immunity and host susceptibility to infection ¹⁶⁰. Of note, Read et al ¹⁶¹ have recently provided a very insightful evaluation of the role of zinc in antiviral immunity. Zinc inhibits the RNA polymerase required by RNA viruses, like coronaviruses, to replicate ¹⁶², suggesting that zinc may play a key role in host defence against RNA viruses. In vitro replication of influenza virus was inhibited by the zinc ionophore pyrrolidine dithiocarbamate ¹⁶³ and there are indications that zinc might inhibit replication of SARS-associated coronavirus (SARS-CoV) in vitro ¹⁶⁴. In addition, as discussed by Read et al ¹⁶¹, the zinc-binding metallothioneins seem to play an important role in antiviral defence ¹⁶⁵. Zinc deficiency has a marked impact on bone marrow, decreasing the number immune precursor cells, with reduced output of naive B lymphocytes and causes thymic atrophy, reducing output of naive T lymphocytes. Therefore, zinc is important in maintaining T and B lymphocyte numbers. Zinc deficiency impairs many aspects of innate immunity, including phagocytosis, respiratory burst and natural killer cell activity. Zinc also supports the release of neutrophil extracellular traps that capture microbes ¹⁶⁶. There are also marked effects of zinc deficiency on acquired immunity. Circulating CD4+ T lymphocyte numbers and function (eg, IL-2 and IFN-γ production) are decreased and there is a disturbance in favour of T helper 2 cells. Likewise, B lymphocyte numbers and antibody production are decreased in zinc deficiency. Zinc supports proliferation of CD8+ cytotoxic T lymphocytes, key cells in antiviral defence. Many of the in vitro immune effects of zinc are prevented by zinc chelation ¹⁶⁷. Moderate or mild zinc deficiency or experimental zinc deficiency in humans result in decreased natural killer cell activity, T lymphocyte proliferation, IL-2 production and cell-mediated immune responses which can all be corrected by zinc repletion ¹⁶⁸. In patients with zinc deficiency related to sickle cell disease, natural killer cell activity is decreased, but can be returned to normal by zinc supplementation ¹⁶⁹. Patients with the zinc malabsorption syndrome acrodermatitis enteropathica display severe immune impairments ¹⁷⁰ and increased susceptibility to bacterial, viral and fungal infections. Zinc supplementation (30 mg/day) increased T lymphocyte proliferation in elderly care home residents in the USA, an effect mainly due to an increase in numbers of T lymphocytes ¹⁷¹. The wide ranging impact of zinc deficiency on immune components is an important contributor to the increased susceptibility to infections, especially lower respiratory tract infection and diarrhoea, seen in zinc deficiency. Correcting zinc deficiency lowers the likelihood of diarrhea and of respiratory and skin infections, although some studies fail to show benefit of zinc supplementation in respiratory disease ¹⁷². Meta-analysis of studies in Chinese children showed that those with recurrent respiratory tract infection were more likely to have low hair zinc ³⁰. Recent systematic reviews and meta-analyses of trials with zinc report shorter duration of common cold in adults ³¹, reduced incidence and prevalence of pneumonia in children ³³ and reduced mortality when given to adults with severe pneumonia ³⁴.

Table 18. Selected Food Sources of Zinc

Food	Milligrams (mg) per serving	Percent DV*
Oysters, cooked, breaded and fried, 3 ounces	74	493
Beef chuck roast, braised, 3 ounces	7	47
Crab, Alaska king, cooked, 3 ounces	6.5	43
Beef patty, broiled, 3 ounces	5.3	35
Breakfast cereal, fortified with 25% of the DV for zinc, ¾ cup serving	3.8	25
Lobster, cooked, 3 ounces	3.4	23
Pork chop, loin, cooked, 3 ounces	2.9	19
Baked beans, canned, plain or vegetarian, ½ cup	2.9	19
Chicken, dark meat, cooked, 3 ounces	2.4	16
Yogurt, fruit, low fat, 8 ounces	1.7	11
Cashews, dry roasted, 1 ounce	1.6	11
Chickpeas, cooked, ½ cup	1.3	9
Cheese, Swiss, 1 ounce	1.2	8
Oatmeal, instant, plain, prepared with water, 1 packet	1.1	7
Milk, low-fat or non fat, 1 cup	1	7
Almonds, dry roasted, 1 ounce	0.9	6
Kidney beans, cooked, ½ cup	0.9	6
Chicken breast, roasted, skin removed, ½ breast	0.9	6
Cheese, cheddar or mozzarella, 1 ounce	0.9	6
Peas, green, frozen, cooked, ½ cup	0.5	3
Flounder or sole, cooked, 3 ounces	0.3	2

Footnote: * DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient contents of products within the context of a total diet. The DV for zinc is 15 mg for adults and children age 4 and older. Food labels, however, are not required to list zinc content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

[Source ⁴⁸ ]

Magnesium

Magnesium (Mg) is an abundant mineral in your body that your body needs to stay healthy and is naturally present in many foods, added to other food products, available as a dietary supplement, and present in some medicines (such as antacids and laxatives) ¹⁷³. Magnesium is important for many processes in your body, including regulating muscle and nerve function, energy production, blood sugar levels, and blood pressure and making protein, bone, and DNA. Magnesium is a cofactor in more than 300 enzyme systems that regulate diverse biochemical reactions in the body, including protein synthesis, muscle and nerve function, blood glucose control, and blood pressure regulation ¹⁷⁴, ¹⁷⁵, ¹⁷⁶, ¹⁷⁷, ¹⁷⁸. Low magnesium levels (hypomagnesemia) don’t cause symptoms in the short term. However, chronically low magnesium levels can increase your risk of high blood pressure, heart disease, type 2 diabetes and osteoporosis ¹⁷⁹.

Magnesium is required for energy production, oxidative phosphorylation, and glycolysis ¹⁸⁰. It contributes to the structural development of bone and is required for the synthesis of DNA, RNA, and the antioxidant glutathione. Magnesium also plays a role in the active transport of calcium and potassium ions across cell membranes, a process that is important to nerve impulse conduction, muscle contraction, and normal heart rhythm ¹⁷⁶. Many people don’t get enough magnesium in their diets. However, before you reach for a supplement, though, you should know that just a few servings of magnesium-rich foods a day can meet your need for this important nutrient.

An adult body contains approximately 25 g magnesium, with 50% to 60% present in the bones and most of the rest in soft tissues ¹⁸¹. Less than 1% of total magnesium is in blood serum, and these levels are kept under tight control through its absorption, reservoir, and excretion process by various organs such as the gut, bone, and kidney ¹⁸². Besides these organs, several hormones, namely vitamin D, parathyroid hormone, and estrogen, are involved in the regulation of normal level of magnesium ¹⁸³. Normal serum magnesium concentrations range between 0.75 and 0.95 millimoles (mmol)/L ¹⁷⁴, ¹⁸⁴. Hypomagnesemia is defined as a serum magnesium level less than 0.75 mmol/L ¹⁸⁵. Magnesium homeostasis is largely controlled by the kidney, which typically excretes about 120 mg magnesium into the urine each day ¹⁷⁵. Urinary excretion is reduced when magnesium status is low ¹⁷⁴. Hypomagnesemia is characterized by tetany (involuntary contraction of muscles), convulsion (seizures), and cardiac arrhythmia ¹⁸⁶. Clinical and preclinical studies revealed that the magnesium level is found to be low in various pathological conditions such as migraine, diabetes, osteoporosis, asthma, preeclampsia, cardiovascular diseases and its correction is an important treatment strategy for these conditions ¹⁸⁷, ¹⁸⁸, ¹⁸⁹, ¹⁹⁰, ¹⁹¹.

The diets of many people in the United States provide less than the recommended amounts of magnesium. Men older than 70 and teenage girls and boys are most likely to have low intakes of magnesium. When the amount of magnesium people get from food and dietary supplements is combined, however, total intakes of magnesium are generally above recommended amounts.

Assessing magnesium status is difficult because most magnesium is inside cells or in bone ¹⁷⁶. The most commonly used and readily available method for assessing magnesium status is measurement of serum magnesium concentration, even though serum levels have little correlation with total body magnesium levels or concentrations in specific tissues ¹⁸⁵. Other methods for assessing magnesium status include measuring magnesium concentrations in erythrocytes, saliva, and urine; measuring ionized magnesium concentrations in blood, plasma, or serum; and conducting a magnesium-loading (or “tolerance”) test. No single method is considered satisfactory ¹⁹². Some experts ¹⁸¹ but not others ¹⁷⁶ consider the tolerance test (in which urinary magnesium is measured after parenteral infusion of a dose of magnesium) to be the best method to assess magnesium status in adults. To comprehensively evaluate magnesium status, both laboratory tests and a clinical assessment might be required ¹⁸⁵.

Magnesium is important in acquired immunity via regulating lymphocyte growth ¹⁹³. An in vitro study (test tube study) carried out in chicken B cell line DT40 revealed that the removal of magnesium channel, TRPM7, results in cell death and can be partially corrected by magnesium supplementation ¹⁹⁴. Mutation in a magnesium transporter, MagT1, is reported in patients with X-linked immunodeficiency diseases, Epstein–Barr virus infection, and neoplasia ¹⁹⁵. Low CD4+ T cells and defective activation of T-lymphocytes are due to the decreased magnesium influx, which fails to activate PLCγ1 ¹⁹⁶. The importance of magnesium for CD4+ activation is also evident from reported studies conducted in asthma patients ¹⁹⁷. However, further studies are essential to conclude the effect of magnesium on T cell signaling.

Magnesium has an important role in synthesizing and releasing immune cells and other associated processes like cell adhesion and phagocytosis ¹⁹⁸. Magnesium acts as a natural calcium antagonist, the molecular basis for inflammatory response could be the result of modulation of intracellular calcium concentration ¹⁹⁹. Besides, magnesium acts as a cofactor for the synthesis of immunoglobulin, CI 3 convertase, antibody-dependent cytolysis, macrophage responses to lymphocyte, IgM lymphocyte binding, T helper B cell adherence, substance P binding with lymphoblast, and binding of antigen to macrophage ²⁰⁰, ²⁰¹. Magnesium deficiency affects various immune functions like the decline in NK cell level, monocytes and T cell ratio, increased oxidative stress after strenuous exercise, and elevated cytokine IL-6 level and inflammatory events. Deficiency of magnesium may be prone to recurrent bacterial and fungal infection ²⁰². Many studies have demonstrated that in humans, a moderate or subclinical magnesium deficiency can induce chronic low-grade inflammation or exacerbate inflammatory stress caused by other factors ²⁰³. This low-grade inflammation increases the secretion of pro-inflammatory cytokines, which stimulate the resorption of bone by the induction of the differentiation of osteoclasts from their precursors ²⁰⁴. The ability of magnesium to decrease the inflammatory response and oxidative stress, as well as improving lung inflammation, possibly by inhibiting IL-6 pathway, NF-κB pathway, and L-type calcium channels ²⁰⁵, has raised the hypothesis of a possible magnesium supplementation in the prevention and treatment of COVID-19 patients, as suggested in the recent papers by Tang et al ²⁰⁶ and Iotti ²⁰⁷. Based Tang et al ²⁰⁸ basic and clinical research study, it is evident that magnesium effectively treats respiratory diseases like asthma and pneumonia because of its anti-inflammatory, antioxidant, and smooth muscle relaxant properties. A substantial decrease in the need for oxygen or intensive treatment assistance is reported in elderly COVID-19 patients upon the intake of vitamin D, magnesium, and vitamin B12 in combination ²⁰⁹. Iran’s clinical trial registry ²¹⁰ confirmed that magnesium sulphate inhalation is effective in improving respiratory symptoms such as shortness of breath, cough and oxygen saturation in COVID-19 patients.

Magnesium deficient animal model exhibits inflammation as the first noticeable change with elevated levels of pro-inflammatory mediators like TNFα with declined anti-inflammatory cytokine levels ²¹¹, ²⁰¹. The activation of immune cells like monocyte, macrophages, and polymorphonuclear cells are involved in the release of inflammatory mediators like cytokine, free radical and eicosanoids ²⁰¹. Administration of magnesium reduces leukocyte activation and oxidative damage to peripheral blood lymphocyte DNA in athletes and sedentary young men ¹⁹. Thus, magnesium is an important factor for optimum immune cell functioning by regulating the proliferation and function of lymphocytes ¹⁹⁸. In vitro studies also prove the role of magnesium in reducing leukocyte activation through its calcium antagonistic action ²⁰⁰. Magnesium deficiency results in the stress condition that activate the sympathetic system and hypothalamic-pituitary axis causes fat accumulation and release of neuropeptides; results in the immune response followed by inflammatory cascades ²¹².

Magnesium can inhibit cytokine storm and hyper oxidative stress in COVID-19 patients through various mechanisms such as its antioxidant, immune-modulatory, and anti-inflammatory activities ²¹³.

Table 19. Magnesium Rich Foods

Food	Milligrams (mg) per serving	Percent Daily Value (DV)*
Almonds, dry roasted, 1 ounce	80	20
Spinach, boiled, ½ cup	78	20
Cashews, dry roasted, 1 ounce	74	19
Peanuts, oil roasted, ¼ cup	63	16
Cereal, shredded wheat, 2 large biscuits	61	15
Soymilk, plain or vanilla, 1 cup	61	15
Black beans, cooked, ½ cup	60	15
Edamame, shelled, cooked, ½ cup	50	13
Peanut butter, smooth, 2 tablespoons	49	12
Bread, whole wheat, 2 slices	46	12
Avocado, cubed, 1 cup	44	11
Potato, baked with skin, 3.5 ounces	43	11
Rice, brown, cooked, ½ cup	42	11
Yogurt, plain, low fat, 8 ounces	42	11
Breakfast cereals, fortified with 10% of the DV for magnesium	40	10
Oatmeal, instant, 1 packet	36	9
Kidney beans, canned, ½ cup	35	9
Banana, 1 medium	32	8
Salmon, Atlantic, farmed, cooked, 3 ounces	26	7
Milk, 1 cup	24–27	6–7
Halibut, cooked, 3 ounces	24	6
Raisins, ½ cup	23	6
Chicken breast, roasted, 3 ounces	22	6
Beef, ground, 90% lean, pan broiled, 3 ounces	20	5
Broccoli, chopped and cooked, ½ cup	12	3
Rice, white, cooked, ½ cup	10	3
Apple, 1 medium	9	2
Carrot, raw, 1 medium	7	2

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for magnesium is 400 mg for adults and children aged 4 and older. However, the FDA does not require food labels to list magnesium content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

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Vitamins for immune system

Immune system

How does the immune system work?

Immune organs

Immune cells communication

Best vitamins for immune system

Table 3. Vitamins and minerals that affect the immune system

Table 4. Important dietary sources of nutrients that support the immune system

Table 5. Results of multiple scientific studies (meta-analyses) on micronutrients and respiratory infections

List of foods containing Vitamins and Minerals that Affect the Immune System

Vitamin A

Table 6. Selected Food Sources of Vitamin A

Beta Carotene

B-group vitamins

Thiamin (Vitamin B1)

Table 7. Selected Food Sources of Thiamine (vitamin B1)

Vitamin B2 (Riboflavin)

Table 8. Selected Food Sources of Riboflavin (vitamin B2)

Vitamin B6 (Pyridoxine)

Table 9. Selected Food Sources of Vitamin B6 (Pyridoxine)

Vitamin B12 (Cyanocobalamin)

Table 10. Selected Food Sources of Vitamin B12

Folate (Vitamin B9)

Table 11. Selected Food Sources of Folate and Folic Acid

Vitamin C

Table 12. Selected Food Sources of Vitamin C

Vitamin D

Table 13. Selected Food Sources of Vitamin D

Vitamin E

Table 14. Selected Food Sources of Vitamin E (Alpha-Tocopherol)

Iron

Table 15. Selected Food Sources of Iron

Copper

Table 16. Selected Food Sources of Copper

Selenium

Table 17. Selected Food Sources of Selenium

Zinc

Table 18. Selected Food Sources of Zinc

Magnesium

Table 19. Magnesium Rich Foods