Immunoglobulins – Anatomy, Types, Functions

Immunoglobulins (Ig) or antibodies are glycoproteins that are produced by plasma cells. B cells are instructed by specific immunogens, for, example, bacterial proteins, to differentiate into plasma cells, which are protein-making cells that participate in humoral immune responses against bacteria, viruses, fungi, parasites, cellular antigens, chemicals, and synthetic substances.[rx] Immunoglobulins constitute about 20% of the protein in plasma.

The immunogen or antigen reacts with a B-cell receptor (BCR) on the cell surface of B lymphocytes, and a signal is produced that directs the activation of transcription factors to stimulate the synthesis of antibodies, which are highly specific for the immunogen that stimulated the B cell. Furthermore, one clone of B cell makes an immunoglobulin (specificity). Besides, the immune system remembers the antigens that caused a previous reaction (memory) due to the development of memory B cells. These are intermediate, differentiated B cells with the capability to quickly become plasma cells. Circulating antibodies recognize antigen in tissue fluids and serum.

Types of Immunoglobulins

The following are 5 types of immunoglobulins in humans:

1. IgM
2. IgG
3. IgA
4. IgE
5. IgD

Function

Basic immunoglobulin Structure and Function

Antibodies or immunoglobulins have two light chains and two heavy chains in a light-heavy-heavy-light structure arrangement. The heavy chains differ among classes. They have one Fc region that mediates biological functions (e.g., the binding capacity to cellular receptors) and a Fab region, where resides the antigen-binding sites. The chains are folded into regions called domains. There are 4 or 5 domains in the heavy chain, depending on their class, and two domains in the light chain. In the hypervariable regions (HRR) reside the antigen-binding sites. There are three HRR in the V domains of each light and heavy chain. These fold into regions that produce 2 antigen-binding sites at the tip of each monomer. All antibodies exhibit one or more functions (bifunctional) including activation of the complement system, opsonization of microbes to be easily phagocytosed, prevention of attachment of the microbes to mucosal surfaces, and neutralization of toxins and viruses.[rx]

• Immunoglobulin M – IgM has a molecular weight of 970 Kd and an average serum concentration of 1.5 mg/ml. It is mainly produced in the primary immune response to infectious agents or antigens. It is a pentamer and activates the classical pathway of the complement system. IgM is regarded as a potent agglutinin (e.g., anti-A and anti-B isoagglutinin present in type B and type A blood respectively) and a monomer of IgM is used as a B cell receptor (BCR).[rx]
• Immunoglobulin G – IgG is a monomer with an approximate molecular weight of 146 Kd and a serum concentration of 9.0 mg/mL. IgG is said to be divalent i-e it has two identical antigen-binding sites that comprise 2 L chains and 2 H chains joined by disulfide bonds. IgG is synthesized mostly in the secondary immune response to pathogens. IgG can activate the classical pathway of the complement system, and it also is highly protective. The four subclasses of IgG include IgG1, IgG2, IgG3, and IgG4. IgG1 is around 65% of the total IgG. IgG2 forms an important host defense against bacteria that are encapsulated. IgG is the only immunoglobulin that crosses the placentae as its Fc portion binds to the receptors present on the surface of the placenta?, protecting the neonate from infectious diseases.[rx] IgG is thus the most abundant antibody present in newborns.
• Immunoglobulin A – IgA appears in 2 different molecular structures: monomeric (serum) and dimeric structure (secretory). The serum IgA has a molecular weight of 160 Kd and a serum concentration of 3 mg/mL. Secretory IgA (sIgA) has a molecular weight of 385 Kd and a mean serum concentration of 0.05 mg/mL. Being the major antibody in secretions IgA is found in saliva, tears, colostrum, and intestinal, genital tract, and respiratory secretions. It appears in mucosa membranes as a dimer (with J chain when secreted) and protects the epithelial surfaces of the respiratory, digestive, and genitourinary systems. IgA possesses a secretory component that prevents its enzymatic digestion. It activates the alternative pathway of activation of the complement system.[rx]
• Immunoglobulin E – IgE is a monomer. It has a molecular weight of 188 Kd and a serum concentration of 0.00005 mg/mL. It protects against parasites and also binds to high-affinity receptors on mast cells and basophils causing allergic reactions.[rx][rx][rx][rx] IgE is regarded as the most important host defense against different parasitic infections which include Strongyloides stercoralis, Trichinella spiralis, Ascaris lumbricoides, and the hookworms Necator americanus and Ancylostoma duodenale.
• Immunoglobulin D – IgD is a monomer with a molecular weight of 184 Kd. IgD is present in a meager amount in the serum (0.03 mg/mL) and has an unknown function against pathogens. It is regarded as a BCR.[rx] IgD may play an essential role in antigen-triggered lymphocyte? differentiation.[rx]

Receptors for Immunoglobulins

For immunoglobulins to fulfill various biological functions, they should interact with receptors that are mainly expressed on mononuclear cells, mast cells, neutrophils, natural killer cells, and eosinophils. Again, binding to these receptors is essential for immunoglobulin functions. It promotes several activities including phagocytosis of bacteria (opsonization); mast cell degranulation (as seen in type I hypersensitivity or allergic response); killing of tumors; and activation of antigen-presenting cells including macrophages and dendritic cells, which present antigens to T lymphocytes for the generation of cellular and humoral immune responses.[rx]

The following are immunoglobulin receptors:

• Fc gamma RI (CD64) binds to monomeric IgG is expressed on phagocytes and is involved in the phagocytosis of immune complexes.
• Fc gamma RII (CD32) attaches to B-cells, monocyte/macrophages (phagocytes), and granulocytes. On B cells regulates cell activation in the presence of a high titer of antibodies.
• Fc gamma RIII (CD16) has 2 types. Fc gamma RIIIa is expressed on macrophages, NK cells, and some T cells. Fc gamma RIIIb is expressed on granulocytes and has a low affinity for IgG.
• Fc epsilon RI is a high-affinity receptor for IgE that is shown on mast cells and basophils. It involves an allergic response.
• Fc epsilon RII  is expressed on leukocytes and lymphocytes and has homology with mannose-binding lectin.

Genetics of Immunoglobulins

The immune system can respond to many antigens by generating a vast diversity in immunoglobulins produced by plasma cells. V and J gene segments encode immunoglobulin light chains. The above genes, in addition to D gene segments, encode the heavy chains. The mechanisms that contribute to this great diversity of immunoglobulin specificities include somatic mutation (immunoglobulin heavy and light chain genes undergo structural modifications after antigen stimulation) and the presence of multiple V-region genes in the germline (antibody diversity also arises when numerous V genes are recombining with J and D segments). Gene conversion, recombinational inaccuracies, nucleotide addition, and assorted heavy and light chains also contribute to the diversity of immunoglobulin molecules.[rx][rx][rx]

Clinical? Significance

Immunoglobulins or antibodies play an essential role in the protection against bacteria, viruses, and fungi. When there is a deficiency of these glycoproteins, recurrent? infectious diseases occur as seen in the following antibody deficiency disorders[rx]:

• X-linked agammaglobulinemia
• Transient hypogammaglobulinemia of infancy
• IgA deficiency
• IgG subclass deficiency
• Immunodeficiency? with increased IgM
• Common variable immunodeficiency

The most common immunodeficiency is Selective IgA deficiency, characterized by recurrent infections that affect the respiratory, digestive, and genitourinary systems. Recurrent pneumonia?, Giardia lamblia infestation, and urinary sepsis? are prevalent. The majority of patients can, however, be asymptomatic?. They are at higher risks for autoimmune? diseases, atopy, and anaphylaxis? to IgA-containing products.[rx]

Another common problem is the transient hypogammaglobulinemia of infancy. During the first 3 to 5 months the child is healthy, but he becomes sick because of a physiological deficit of immunoglobulins. This disease is characterized by recurrent bacterial infections including pneumonia, meningitis?, otitis, arthritis?, osteomyelitis?, among others. This problem heals once the child starts producing immunoglobulins.[rx]

X-linked agammaglobulinemia is also called Bruton agammaglobulinemia. It occurs due to a defect in Bruton Tyrosine Kinase (BTK) gene that prevents B-cell maturation. This condition is X-linked recessive and seen mostly in males. They present with recurrent bacterial and enteroviral infections after 6 months, once the maternal IgG is low. No B cells are seen in peripheral blood and immunoglobulins of all classes are absent. Patients also have absent or scanty lymph nodes? and tonsils. Live vaccines are contraindicated?.[rx]

In common variable immunodeficiency (CVID), individuals acquire the immunodeficiency in the second or third decade of life or later. Both males and females can develop this problem.[rx] CVID may follow a viral infection?, such as infectious mononucleosis. Giardia lamblia infestation and recurrent pyogenic infections characterize CVID. It may be due to a defect in B-cell differentiation.[rx] The patients have a risk of autoimmune disease?, bronchiectasis?, lymphoma?, and sinopulmonary infections.

Laboratory Assessment? of Immunoglobulins

The quantification of immunoglobulins and the study of their functions are vital for the immunodiagnosis of immunodeficiencies, autoimmunity, hypersensitivity reactions, and inflammatory disorders. The following examinations are routinely performed for the study of the behavior of antibodies[rx]

Quantitative serum immunoglobulins (classes and subclasses)

• IgG
• IgM
• IgA
• IgE

This assay is used to test for the presence of immunodeficiency disorders such as those in X-linked agammaglobulinemia. There are insufficient amounts of all classes of immunoglobulins, or they are absent. The presence of low IgA may be associated with recurrent diarrhea? and lung and sinus? infections. Low IgG is associated with pyogenic infections, and a high IgE may be found in parasitic infections.

IgG antibodies (post-immunization)

• Tetanus toxoid
• Diphtheria toxoid
• Pneumococcal polysaccharide
• Polio

This assay evaluates the quality of the immune response after vaccination. In healthy individuals, there is at least a 1:16 titer of antibody.

IgG antibodies (post-exposure)

• Measles
• Varicella-Zoster

This test is to evaluate the production of antibodies against antigens after the infectious disease has occurred.

Detection of isohemagglutinins (IgM)

• Anti-type A blood
• Anti-type B blood

Isohemagglutinins are IgM antibodies produced by the immune system in response to bacterial antigens present in the digestive system. It has been shown that their titers may be below 1:4 in antibody deficiency disorders.

Other assays

• Test for heterophile antibody to measure the presence of antibodies against Epstein-Barr virus
• Serum protein electrophoresis evaluates the level of antibodies qualitatively. For example, in multiple myeloma?, it shows a monoclonal peak in the gamma region of the electrophoresis that is consistent with a monoclonal antibody.

Clinical use of immunoglobulins

Immunoglobulins or antibodies can be used as a form of immunotherapy?. Like drugs, they are prepared from a pool of blood donated at blood collection centers and processed through fractionation to separate the protein fraction from the cellular component. The purified immunoglobulin can be used in the treatment of many immunological problems, including antibody deficiencies, severe? combined immunodeficiency disorders (SCID), multiple sclerosis?, myasthenia gravis, Kawasaki disease, systemic lupus erythematosus? (SLE), organ transplantations, and many others.[rx][rx][rx]