What is globulin

Globulin is a collective term for all the proteins other than albumin in your blood. Albumin makes up about 60% of the total protein. The remaining 40% of proteins in the blood plasma are referred to as globulins. Globulins are comprised of hundreds of different types. Globulins include enzymes, antibodies, hormones, carrier proteins, and numerous other types of proteins. Globulins proteins are larger than albumin and are divided into Alpha, Beta and Gamma globulins (immune globulins). A protein electrophoresis test can be used to quantify the different groups of globulin proteins (see Table 1 below). An immunofixation electrophoresis test can measure the different types of immune globulins (immunoglobulins) (e.g., IgG, IgM, IgA) as can a quantitative immunoglobulins test.

Two classes of proteins are found in your blood, albumin and globulin. Both globulin and albumin are plasma proteins that help maintain the colloidal osmotic pressure of blood at about 25 mmHg ¹. In adults the reticuloendothelial cells of the liver are in charge of plasma protein synthesis. The bone marrow, degenerating blood cells, and general body tissue cells along with the spleen also contribute to the formation of plasma proteins. Immune globulins also known as immunoglobulins or gamma globulins, are special proteins produced by your body in response to foreign substances including bacteria and viruses; there are five structurally distinct classes of immunoglobulins produced by plasma cells (B lymphocytes) in the bone marrow and other lymphoid tissue that bind to and neutralize foreign substances (antigens). The five major kinds of immunoglobulins are A, D, E, G and M. Certain immunological disorders like congenital or acquired primary immune deficiency, where the body can’t produce antibodies (immune globulins) or other conditions such as the adverse effects seen in cancer treatments, resulting in harm to the bodies antibodies, benefit greatly from immunoglobulin infusions. Immunoglobulins also play a major role in passive immunization. Antidotes to diseases such as chickenpox, rabies, hepatitis, and tetanus are the initial treatment after suspected exposure, to limit disease progression. Such specific immunoglobulins are derived when patients who have been previously affected by a disease, for example, chickenpox donates plasma. This plasma contains high amounts of circulating antibodies against chickenpox that can be collected and stored after fractionation for use as post-exposure vaccines for varicella.

In adult humans, albumin is the most abundant plasma protein with a concentration ranging from 35 to 50 g/L ². Albumin represents 60% of the total protein content of blood plasma, with globulins making up most of the rest. Albumin is exclusively synthesized by the liver, initially a pre-proalbumin and then proalbumin, which in the Golgi apparatus is converted to albumin, which is the final form secreted by the hepatocyte and it has a half-life of 21 days. The synthetic rate is about 10 to 15 grams per day and then secreted into the circulation of which around 40% remains in circulation with a fraction moving from the intravascular to the interstitial space ³. With the exception of the immune globulins and some complement proteins, most of the globulins are also produced in the liver.

Factors that stimulate albumin synthesis include the action of hormones such as insulin and growth hormone. Albumin production may be inhibited by pro-inflammatory mediators such as interleukin-6 (IL-6), interleukin-1 (IL-1) and tumor necrosis factor ⁴. In fetal life, alpha-fetoprotein (AFP) produced by the liver and yolk sac is the most abundant plasma protein. Alpha-fetoprotein (AFP) is thought to be the fetal counterpart of albumin, and both are transcribed by genes located close together on chromosome 4. Approximately 100 variant forms of albumin have been described ⁵.

Albumin has several physiological roles. One of the most important is to maintain the osmotic pressure pressure within the vascular compartments preventing leaking of fluids into the extravascular spaces. It accounts for around 80% of the colloid osmotic pressure. Additionally, albumin functions as a low-affinity, high-capacity carrier of several different endogenous and exogenous compounds acting as a depot and a carrier for these compounds. Binding of compounds to albumin may reduce their toxicity such as in the case of unconjugated bilirubin in the neonate and drugs. Also, albumin binds at least 40% of the circulating calcium and is a transporter of hormones such as thyroxine, cortisol, testosterone, among others. Albumin also is the main carrier for fatty acids and has significant anti-oxidant properties. Albumin is also involved with maintaining acid-base balance as it acts as a plasma buffer. Albumin is used as a marker of nutritional status and disease severity in particular in chronic and critically ill patients ⁵. Renal and gut loss of albumin may account for around 6% and 10% respectively of albumin loss in healthy individuals.

The level of total protein in your blood is normally a relatively stable value, reflecting a balance in loss of old protein molecules and production of new protein molecules.

Total protein may decrease in conditions:

• Where production of albumin or globulin proteins is impaired, such as malnutrition or severe liver disease
• That accelerate the breakdown or loss of protein, such as kidney disease (nephrotic syndrome)
• That increase/expand plasma volume (diluting the blood), such as congestive heart failure

Total protein may increase with conditions that cause:

• Abnormally high production of protein (e.g., inflammatory disorders, multiple myeloma)
• Dehydration

Some laboratories report total protein, albumin, and the calculated ratio of albumin to globulins, termed the albumin globulin ratio. The albumin globulin ratio is calculated from measured total protein, measured albumin, and calculated globulin (total protein – albumin).

Normally, there is a little more albumin than globulins, giving a normal albumin globulin ratio ratio of slightly over 1. The albumin globulin ratio may change whenever the proportions of albumin and other proteins shift (increase or decrease) in relationship to each other. Because disease states affect the relative amounts of albumin and globulin, the albumin globulin ratio may provide a clue as to the cause of the change in protein levels.

• A low albumin globulin ratio may reflect overproduction of globulins, such as seen in multiple myeloma or autoimmune diseases, or underproduction of albumin, such as may occur with cirrhosis, or selective loss of albumin from the circulation, as may occur with kidney disease (nephrotic syndrome).
• A high albumin globulin ratio suggests underproduction of immune globulins as may be seen in some genetic deficiencies and in some leukemias.

Total protein and albumin tests may be ordered in a variety of settings to help diagnose disease, to monitor changes in health status, and as a screen that may indicate the need for various follow-up tests.

Total protein may also be ordered to provide general information about a person’s nutritional status, such as when someone has undergone a recent, unexplained weight loss. Total protein can be ordered along with several other tests to provide information when someone has symptoms that suggest a liver, kidney, or bone marrow disorder, or to investigate the cause of abnormal pooling of fluid in tissue (edema). Sometimes conditions are detected with routine testing before symptoms appear. If total protein is abnormal, further testing must be performed to identify which specific protein is abnormally low or high so that a specific diagnosis can be made. Some examples of follow-up tests include protein electrophoresis and quantitative immunoglobulins.

• A low total protein level can suggest a liver disorder, a kidney disorder, or a disorder in which protein is not digested or absorbed properly. Low levels may be seen in severe malnutrition and with conditions that cause malabsorption, such as celiac disease or inflammatory bowel disease (IBD). Drugs that may decrease protein levels include estrogens and oral contraceptives.
• A high total protein level may be seen with chronic inflammation or infections such as viral hepatitis or HIV. It also may be associated with bone marrow disorders such as multiple myeloma.
• With a low total protein that is due to plasma expansion (dilution of the blood), the albumin globulin ratio will typically be normal because both albumin and globulin will be diluted to the same extent.

Following an abnormal total protein result and depending on the suspected cause, more specific tests are typically performed to make an accurate diagnosis. Some examples include liver enzyme tests, renal panel, serum protein electrophoresis, or tests for celiac disease or inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).

Will a high protein diet raise my total protein level?

No, increasing your intake of protein will not increase your total protein test result.

Is there something I can do to alter my immune globulin levels?

In most cases, immune globulins do not respond to lifestyle changes. If you are taking a drug that is decreasing one or more of your immunoglobulins, then you and your healthcare practitioner may decide to alter your medications. It is very important, however, NOT to discontinue or change your medication dosage without consulting with your healthcare provider.

Infants gradually lose protection from infections as the levels of IgG they receive through the placenta from their mothers decrease after birth. Greater protection can be provided for babies through breastfeeding since breast milk contains IgA, which protects against infections.

My newborn had an immune globulin test. Why?

Sometimes an IgM test is used to determine whether a newborn acquired an infection before birth (congenital). IgM may be produced by a developing baby (fetus) in response to infection. Due to the size of IgM antibodies, they cannot pass through the placenta from mother to baby during pregnancy. Thus, any IgM antibodies present in a newborn’s blood are not from the mother but were produced by the baby. This indicates that an infection began during pregnancy.

What is transient hypogammaglobulinemia of infancy?

Infants with otherwise normal immune systems may have temporarily decreased IgG levels when production is delayed. Protection from infections is lost as concentrations of the mother’s IgG in the baby’s blood decrease over several months. The level of IgG remains at low concentrations until the baby’s IgM and IgG production ramps up. This creates a period of time during which the baby is at an increased risk for recurrent infections.

However, infants who are breastfed acquire IgA from breast milk. The IgA in breast milk can be protective against infections, particularly in the time between the decrease of mother’s antibodies and the production of the baby’s own antibodies.

Are there symptoms associated with decreased immune globulins?

Not specific ones. Unexplained recurrent infections, multiple infections, or opportunistic infections, with or without chronic diarrhea, may indicate a need to check a person’s immune status. A positive family history of an immunodeficiency may also require follow up. A thorough physical examination and a careful medical history can be critical to a diagnosis.

In addition to the blood sample for immune globulin test, I was instructed to collect a urine sample. Why?

You may have been directed to give a urine sample to check for the presence of protein in your urine and/or to determine the amount and type of protein present in your urine. Your healthcare practitioner may suspect that, based on your medical history, signs and symptoms and/or other test results, you have a condition associated with abnormal or excessive immunoglobulin production. In such cases, a quantitative immunoglobulin test is often performed along with tests such as serum and urine protein electrophoresis to help establish a diagnosis.

What are Bence Jones proteins?

They are free immune globulin light chains that are found in the urine.

What is Tamm-Horsfell protein?

The term Tamm-Horsfell refers to a glycoprotein that is a normal component of urine. It is more commonly called uromodulin. It is produced by the kidney and is the most abundant protein in normal urine.

Globulin function

Globulin proteins are important building blocks of all cells and tissues. Globulin proteins form the structural part of most organs and make up enzymes and hormones that regulate body functions. Body fluids contain many different globulin proteins that serve diverse functions, such as transport of nutrients, removal of toxins, control of metabolic processes, and defense against invaders. Protein electrophoresis is a method for separating globulin proteins based on their size and electrical charge.

When globulin proteins in body fluids are separated by electrophoresis, they form a characteristic pattern of bands of different widths and intensities, reflecting the mixture of globulin proteins present. This pattern is divided into four fractions, called Alpha 1 globulin, Alpha 2 globulin, Beta globulin, and Gamma globulin (immune globulin). In some cases, the beta fraction is further divided into Beta 1 and Beta 2.

Certain conditions or diseases may be associated with decreases or increases in various serum proteins, as reflected below.

Table 1. Major plasma proteins and their functions listed according to their electrophoretic group

GROUP	PROTEIN	FUNCTION
Albumin	Albumin	Main plasma protein; reduces tissue water accumulation, transports many substances
Alpha1-globulin	Alpha1-Antitrypsin	Inactivates trypsin and other proteolytic enzymes, reduces damage from inflammation
	Orosomucoid (Alpha-1-acidic glycoprotein)	Immune response modifier, binds acidic drugs such as lidocaine
	High Density Lipoprotein (HDL)	Reverse transport of cholesterol (“good cholesterol”)
Alpha2-globulin	Alpha2-Macroglobulin	Binds to and inactivates enzymes, preventing tissue damage
	Haptoglobin	Hemoglobin-binding protein
	Ceruloplasmin	Copper-containing enzyme, involved in normal iron metabolism
Beta-globulin	Transferrin	Iron transport and delivery to cells
	Low Density Lipoprotein (LDL)	Cholesterol delivery to tissue
	Complement component 3	Helps regulate inflammatory response to foreign substances
Gamma-globulin (immune globulin)	IgA	Immunoglobulin involved in secretions
	IgG	Major immunoglobulin; long term immunity
	IgM	Initial response immunoglobulin
	C-reactive protein	Inflammatory response mediator
	Fibrinogen	Coagulation factor (found only in plasma, not serum)

Immune globulins

Immunoglobulins (gamma globulins) play a key role in your body’s immune system. Immune globulins are proteins produced by specific immune cells called plasma cells in response to bacteria, viruses, and other microorganisms as well as exposures to other substances that are recognized by the body as “non-self” harmful antigens.

The first time a person is infected or otherwise exposed to a foreign substance (antigen), their immune system recognizes the microorganism or substance as “non-self” and stimulates plasma cells to produce specific immunoglobulin(s), also called antibodies, that can bind to and neutralize the threat. With subsequent exposures, the immune system “remembers” the antigen that was encountered, which allows for the rapid production of more antibodies and, in the case of microorganisms, helps prevent re-infection.

There are five classes of immune globulins (immunoglobulins) and several subclasses. Each class represents a group of antibodies and has a slightly different role.

Classes of immune globulins include:

• Immunoglobulin M (IgM) – IgM antibodies are produced as a body’s first response to a new infection or to a new “non-self” antigen, providing short-term protection. They increase for several weeks and then decline as IgG production begins.
• Immunoglobulin G (IgG) – About 70-80% of the immunoglobulins in the blood are IgG. Specific IgG antibodies are produced during an initial infection or other antigen exposure, rising a few weeks after it begins, then decreasing and stabilizing. The body retains a catalog of IgG antibodies that can be rapidly reproduced whenever exposed to the same antigen. IgG antibodies form the basis of long-term protection against microorganisms. In those with a normal immune system, sufficient IgG is produced to prevent re-infection. Vaccinations use this process to prevent initial infections and add to the catalog of IgG antibodies, by exposing a person to a weakened, live microorganism or to an antigen that stimulates recognition of the microorganism. IgG is the only immunoglobulin that can pass through the placenta. The mother’s IgG antibodies provide protection to the fetus during pregnancy and to the baby during its first few months of life. There are four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4.
• Immunoglobulin A (IgA) – IgA comprises about 15% of the total immunoglobulins in the blood but is also found in saliva, tears, respiratory and gastric secretions, and breast milk. IgA provides protection against infection in mucosal areas of the body such as the respiratory tract (sinus and lungs) and the gastrointestinal tract (stomach and intestines). When passed from mother to baby during breast-feeding, it helps protect the infant’s gastrointestinal tract. Significant amounts of IgA are not produced by a baby until after 6 months of age so any IgA present in a baby’s blood before then is from the mother’s milk. There are two IgA subclasses: IgA1 and IgA2.
• Immunoglobulin D (IgD) – the role of IgD is not completely understood and IgD is not routinely measured.
• Immunoglobulin E (IgE) – IgE is associated with allergies, allergic diseases, and with parasitic infections. It is almost always measured as part of an allergy testing blood panel but typically is not included as part of a quantitative immunoglobulins test.

Immunoglobulins testing measures the total amount of each primary immunoglobulin class, IgA, IgM, and IgG, without distinguishing between subclasses. Separate testing can be performed to measure immunoglobulin subclasses and/or to detect and measure specific antibodies.

A variety of conditions can cause an increase (hypergammaglobulinemia) or decrease (hypogammaglobulinemia) in the production of immune globulins (immunoglobulins). Some cause an excess or deficiency of all classes of immune globulins (immunoglobulins) while others affect only one class. Some of the conditions are passed from one generation to the next (inherited) and others are acquired.

Globulin blood test

Some globulin proteins can be measured directly using specific tests for the protein of interest. The tests are most valuable in instances where a specific protein is associated with a disease or condition. The specific protein tests may be ordered to provide information to the healthcare practitioner when particular signs and symptoms are present that suggest one of these diseases or conditions. A few examples of proteins associated with specific conditions are C-reactive protein (inflammation), fibrinogen (clotting disorders), ferritin (iron deficiency), and ceruloplasmin (Wilson disease).

A test for immune globulins (Igs) is used to detect an excess or deficiency in the three major classes of immunoglobulins (IgG, IgA, and IgM). It gives important information about the health of an individual’s immune system and is used to help diagnose various conditions and diseases that affect the levels of one or more of these immune globulin (Ig) classes.

• Immune globulins test is ordered when a person has symptoms of an immunoglobulin deficiency such as recurrent infections, especially of the respiratory tract (sinus, lungs) or digestive system (stomach, intestines), and/or chronic diarrhea.
• Immunoglobulins testing may also be ordered when a person has signs of chronic inflammation or chronic infection and when a healthcare practitioner suspects excess or abnormal immunoglobulin production. The test may be ordered periodically to monitor the course of a person’s condition.
• Immune globulins test may also be performed on cerebrospinal fluid (CSF) whenever a healthcare practitioner suspects that a condition affecting the central nervous system may be associated with excess immunoglobulin production.

In general, immune globulin disorders can be classified as:

Immunoglobulin excess

• Polyclonal—an Ig excess in any or all immunoglobulin classes from many different immune (plasma) cells
• Monoclonal—the excess immunoglobulins are from the clones of one plasma cell

Immunoglobulin deficiency

• Secondary (acquired)—the most common Ig deficiencies are caused by an underlying condition or contributing factor
• Primary (inherited)—these are rare disorders in which the body is not able to produce one or more classes of immunoglobulins

Immune globulins test may be ordered along with others, such as a serum and/or urine protein electrophoresis, to help diagnose and monitor conditions associated with abnormal or excessive immunoglobulin production. When this is the case, a urine sample may be collected in addition to blood.

If an excessive amount of one of the immunoglobulin types is present, further testing by immunofixation can be done to determine if the immunoglobulin comes from clones of an abnormal plasma cell (monoclonal gammopathy). Monoclonal gammopathies are seen with multiple myeloma, a malignancy of plasma cells. Serum free light chain testing may also be performed.

Protein electrophoresis

Protein electrophoresis may be ordered as a follow up to abnormal findings on other laboratory tests or as an initial test in evaluating a person’s symptoms. Once a disease or condition has been diagnosed, electrophoresis may be ordered at regular intervals to monitor the course of the disease and the effectiveness of treatment. Some examples of when an electrophoresis test may be ordered are listed below.

Aspirin, bicarbonates, chlorpromazine (Thorazine), corticosteroids, and neomycin can affect protein electrophoresis results.

Serum protein electrophoresis

Serum protein electrophoresis tests give a health practitioner a rough estimate of how much of each protein fraction is present and whether any abnormal proteins are present. The value of immunofixation electrophoresis is in the identification of the presence of a particular type of immunoglobulin. The laboratory report may include an interpretation of the results.

Serum electrophoresis may be ordered:

• As a follow up to abnormal findings on other laboratory tests, such as total protein and/or albumin level, elevated urine protein levels, elevated calcium levels, or low white or red blood cell counts
• When symptoms suggest an inflammatory condition, an autoimmune disease, an acute or chronic infection, a kidney or liver disorder, or a protein-losing condition
• When a health practitioner is investigating symptoms that suggest multiple myeloma, such as bone pain, anemia, fatigue, unexplained fractures, or recurrent infections, to look for the presence of a characteristic band (monoclonal immunoglobulin) in the beta or gamma region; if a sharp band is seen, its identity as a monoclonal immunoglobulin is typically confirmed by immunofixation electrophoresis.
• To monitor treatment of multiple myeloma to see if the monoclonal band is reduced in quantity or disappears completely with treatment

Urine electrophoresis

Usually there is very little protein in urine.

Urine protein electrophoresis may be ordered:

• When protein is present in urine in higher than normal amounts to determine the source of the abnormally high protein; it may be used to determine whether the protein is escaping from the blood plasma (suggesting compromised kidney function) or is an abnormal protein coming from a different source (such as a plasma cell cancer like multiple myeloma).
• When multiple myeloma is suspected, to determine whether any of the monoclonal immunoglobulins or fragments of monoclonal immunoglobulin are escaping into the urine; if a sharp band suggestive of a monoclonal protein is observed, its identity is typically confirmed by immunofixation electrophoresis.

Typically, if a significant amount of protein is present in urine, it appears in one of three main patterns:

1. Normally, the glomeruli prevent protein from leaking into the urine. When the glomeruli are damaged, albumin and other plasma proteins may leak through and be detected in the urine.
2. Normally, some very small proteins can pass through the glomeruli but are removed from the urine by the tubules. When the tubules are damaged, these proteins will appear in the urine.
3. Some other small proteins are not normally present in significant amounts in serum, for example, free light chains, myoglobin and hemoglobin. When they are present in the serum, they can pass through the glomeruli and appear in the urine.

Immunofixation electrophoresis

Identifies the type of immunoglobulin protein(s) present in monoclonal bands on a protein electrophoresis pattern; typically immunofixation determines the presence of a heavy chain (IgG, IgM or IgA) and a light chain (kappa or lambda).

Immunofixation electrophoresis may be ordered:

• When an abnormal band suggestive of a monoclonal immunoglobulin is seen on either a serum or a urine electrophoresis pattern.

CSF electrophoresis

CSF (cerebrospinal fluid) protein electrophoresis may be ordered:

• To search for the characteristic banding seen in multiple sclerosis; the presence of multiple distinct bands in the CSF (that are not also present in serum) are referred to as oligoclonal bands. Most people with multiple sclerosis, as well as some other inflammatory conditions of the brain, have such oligoclonal bands.
• To evaluate people having headaches or other neurologic symptoms to look for proteins suggestive of inflammation or infection

CSF (cerebrospinal fluid) electrophoresis results:

• Presence of multiple bands in the gamma region (oligoclonal bands) that are not present in serum is indicative of multiple sclerosis.
• Presence of higher than normal polyclonal immunoglobulins, antibodies produced and secreted by many different plasma cells, suggests an infection.

What does abnormal immune globulins test result mean?

The results of the tests for IgG, IgA, and IgM levels are usually evaluated together. Abnormal test results typically indicate that there is something affecting the immune system and suggest the need for further testing. Immunoglobulins testing is not diagnostic but can be a strong indicator of a disease or condition. There are a number of conditions that are associated with increased and decreased immunoglobulins.

Immunizations within the previous six months can increase immune globulins as can drugs such as phenytoin (Dilantin), procainamide, oral contraceptives, methadone, and therapeutic gamma globulin.

Table 2. What does abnormal immune globulins test result mean

Protein	May be decreased in:	May be increased in:
Albumin	Malnutrition and malabsorption Pregnancy Kidney disease (especially nephrotic syndrome) Liver disease Inflammatory conditions Protein-losing syndromes	Dehydration
Alpha 1 globulin	Congenital emphysema (alpha-1 antitrypsin deficiency, a rare genetic disease) Severe liver disease	Acute or chronic inflammatory diseases
Alpha 2 globulin	Malnutrition Severe liver disease Hemolysis	Kidney disease (nephrotic syndrome) Acute or chronic inflammatory disease
Beta globulin	Malnutrition Cirrhosis	High blood cholesterol (hypercholesterolemia) Iron deficiency anemia Some cases of multiple myeloma or monoclonal gammopathy of unknown significance (MGUS)
Gamma globulin (Immune globulin)	Variety of genetic immune disorders Secondary immune deficiency	Polyclonal, antibody produced by or derived from different plasma cells: Chronic inflammatory disease Rheumatoid arthritis Lupus Cirrhosis Chronic liver disease Acute and chronic infection Recent immunization Monoclonal, antibody produced by or derived from a single type (clone) of plasma cell: Malignancy Multiple myeloma Lymphoma Waldenstrom’s macroglobulinemia

High immune globulins levels

Increased polyclonal immunoglobulins may be seen with a variety of conditions.

Monoclonal immunoglobulins are seen in blood cell tumors that involve lymphocytes or plasma cells. In these disorders, there is typically a marked increase in one class of immunoglobulin and a decrease in the other two classes. Although affected people may have an increase in total immunoglobulins, they are actually immunocompromised because most of the immunoglobulins produced are abnormal and do not contribute to the immune response.

The following table lists some examples of conditions that may cause increased immunoglobulins:

Table 3. Causes of high immune globulin levels

Immune globulin Result	Associated Conditions
Polyclonal increase in any or all of the three classes (IgG, IgA and/or IgM)	Infections, acute and chronic Autoimmune disorders (rheumatoid arthritis, systemic lupus erythematosus, scleroderma) Cirrhosis Chronic inflammation, inflammatory disorders Hyperimmunization reactions Wiskott-Aldrich syndrome In a newborn, infection during pregnancy (congenital—syphilis, toxoplasmosis, rubella, CMV)
Monoclonal increase in one class with or without decrease in other two classes	Multiple myeloma Chronic lymphocytic leukemia (CLL) MGUS (monoclonal gammopathy of undetermined significance) Lymphoma Waldenstrom’s macroglobulinemia (IgM)

Low immune globulins levels

The most common causes of decreased immunoglobulins are acquired underlying (secondary) conditions that either affect the body’s ability to produce immunoglobulins or that increase the loss of protein from the body. Deficiencies may also be due to drugs such as immunosuppressants, corticosteroids, phenytoin, and carbamazepine or due to toxins.

Inherited immune deficiencies are rare and are often referred to as primary immunodeficiencies. They may affect the production of all immunoglobulins, a single class, or one or more subclasses. Some of these disorders include agammaglobulinemia, common variable immunodeficiency (CVID), x-linked agammaglobulinemia, ataxia telangiectasia, Wiskott-Aldrich syndrome, hyper-IgM syndrome, and severe combined immunodeficiency (SCID).

In CSF, immunoglobulins normally are present in very low concentrations. Increases may be seen, for example, with central nervous system infections (meningitis, encephalitis), inflammatory conditions, and multiple sclerosis.

Decreases in salivary IgA may be seen in those with recurrent respiratory infections.

The table below lists some of the common causes of low immune globulins levels:

Table 4. Causes of low immune globulin levels

Conditions/factors that affect immunoglobulin production	Drugs such as phenytoin, carbamazepine, immunosuppressant drugs Complications from conditions such as kidney failure or diabetes Transient delay in production in newborns, particularly premature infants (transient hypogammaglobulinemia of infancy)
Conditions that cause an abnormal loss of protein	Nephrotic syndrome—kidney disease in which protein is lost in the urine Burns Protein-losing enteropathy—any condition of the gastrointestinal tract that affects the digestion or absorption of protein

People with conditions that cause decreased immunoglobulin levels often do not have a strong immune response to vaccinations; they may not produce a sufficient level of antibody to ensure protection and may not be able to receive live vaccines, such as those for polio or measles.

Many laboratory tests measure antibodies in the blood. Those with immunoglobulin deficiencies may have false-negative results on these types of tests. For example, one test for celiac disease detects the IgA class of anti-tissue transglutaminase antibody (anti-tTG). If a person has a deficiency in IgA, then results of this test may be negative when the person, in fact, has celiac disease. If this is suspected to be the case, then a quantitative test for IgA may be performed.

If IgG or IgA concentrations are decreased, or a deficiency in one of their subclasses is suspected, then subclass testing may be performed to detect and further define the deficiency. Subclass deficiencies can be present even when an immunoglobulin class concentration, such as IgG, is normal.

Some people with IgA deficiencies may develop anti-IgA antibodies. When those with anti-IgA are given blood component transfusions that contain IgA (such as plasma or immunoglobulin treatments), they may experience a severe anaphylactic transfusion reaction.

If I have an abnormal monoclonal immune globulin in my blood, does it mean that I have multiple myeloma or some other type of cancer?

Not necessarily. Monoclonal protein production is most commonly due to monoclonal gammopathy of undetermined significance (MGUS). Most people with monoclonal gammopathy of undetermined significance (MGUS) have a benign course, but they must continue to be monitored regularly with a serum protein electrophoresis test, or sometimes a free light chain test, depending on which monoclonal protein is being produced. Some of these people may develop multiple myeloma after a number of years.

What are free light chains and how are they related to immune globulins?

Immune globulins are molecules composed of four protein chains: two identical light chains, either kappa or lambda light chains, and two identical heavy chains of which there are several types. These proteins are produced by plasma cells in the bone marrow. A particular plasma cell only produces one type of immunoglobulin. It uses the protein chains as component parts to assemble immunoglobulins, antibodies that target specific threats to the body. The chains that are used to form the immunoglobulins are said to be “immunoglobulin-bound.” Normally, there is also a slight excess of kappa and lambda light chains produced. Low levels of these “free” light chains can be detected in the blood and urine with a free light chain test, and ratios between the kappa and lambda free light chains can be evaluated.

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