In both scenarios, analysis of the T cells or antibodies specifically engaged in the autoimmune                  response and disease provides a fingerprint for uncovering the initiating infectious agent.

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A.  IgG

1. Structure
The structures of the IgG subclasses are presented in Figure 7. All IgG's are monomers (7S immunoglobulin). The subclasses differ in the number of disulfide bonds and length of the hinge region.

2. Properties
Most versatile immunoglobulin because it is capable of carrying out all of the functions of immunoglobulin molecules.

a) IgG is the major Ig in serum - 75% of serum Ig is IgG

b) IgG is the major Ig in extra vascular spaces

c) Placental transfer - IgG is the only class of Ig that crosses the placenta. Transfer is mediated by receptor on placental cells for the Fc region of IgG. Not all subclasses cross equally; IgG2 does not cross well.

d) Fixes complement - Not all subclasses fix equally well; IgG4 does not fix complement

e) Binding to cells - Macrophages, monocytes, PMN's and some lymphocytes have Fc receptors for the Fc region of IgG. Not all subclasses bind equally well; IgG2 and IgG4 do not bind to Fc receptors. A consequence of binding to the Fc receptors on PMN's, monocytes and macrophages is that the cell can now internalize the antigen better. The antibody has prepared the antigen for eating by the phagocytic cells. The term opsonin is used to describe substances that enhance phagocytosis. IgG is a good opsonin. Binding of IgG to Fc receptors on other types of cells results in the activation of other functions.

Figure 8    Pentameric serum IgM structure

  Figure 9   Cell surface IgM structure 

Figure 10   B cell antigen receptor (BcR) 

B. IgM

1. Structure
The structure of IgM is presented in Figure 8. IgM normally exists as a pentamer (19S immunoglobulin) but it can also exist as a monomer. In the pentameric form all heavy chains are identical and all light chains are identical. Thus, the valence is theoretically 10. IgM has an extra domain on the mu chain (C_H4) and it has another protein covalently bound via a S-S bond called the J chain. This chain functions in polymerization of the molecule into a pentamer.

2. Properties

a) IgM is the third most common serum Ig.

b) IgM is the first Ig to be made by the fetus and the first Ig to be made by a virgin B cells when it is stimulated by antigen.

c) As a consequence of its pentameric structure, IgM is a good complement fixing Ig. Thus, IgM antibodies are very efficient in leading to the lysis of microorganisms.

d) As a consequence of its structure, IgM is also a good agglutinating Ig . Thus, IgM antibodies are very good in clumping microorganisms for eventual elimination from the body.

e) IgM binds to some cells via Fc receptors.

f) B cell surface Ig
Surface IgM exists as a monomer and lacks J chain but it has an extra 20 amino acids at the C-terminus to anchor it into the membrane (Figure 9). Cell surface IgM functions as a receptor for antigen on B cells. Surface IgM is noncovalently associated with two additional proteins in the membrane of the B cell called Ig-alpha and Ig-beta as indicated in Figure 10. These additional proteins act as signal transducing molecules since the cytoplasmic tail of the Ig molecule itself is too short to transduce a signal. Contact between surface immunoglobulin and an antigen is required before a signal can be transduced by the Ig-alpha and Ig-beta chains. In the case of T-independent antigens, contact between the antigen and surface immunoglobulin is sufficient to activate B cells to differentiate into antibody secreting plasma cells. However, for T-dependent antigens, a second signal provided by helper T cells is required before B cells are activated.

  
Figure 11  IgA Structure

 
Figure 12   Origin of soluble IgA

C.  IgA

1. Structure
Serum IgA is a monomer but IgA found in secretions is a dimer as presented in Figure 11. When IgA exits as a dimer, a J chain is associated with it.

When IgA is found in secretions is also has another protein associated with it called the secretory piece or T piece; sIgA is sometimes referred to as 11S immunoglobulin. Unlike the remainder of the IgA which is made in the plasma cell, the secretory piece is made in epithelial cells and is added to the IgA as it passes into the secretions (Figure 12). The secretory piece helps IgA to be transported across mucosa and also protects it from degradation in the secretions.

2. Properties

a) IgA is the 2nd most common serum Ig.

b) IgA is the major class of Ig in secretions - tears, saliva, colostrum, mucus. Since it is found in secretions secretory IgA is important in local (mucosal) immunity.

c) Normally IgA does not fix complement, unless aggregated.

d) IgA can binding to some cells - PMN's and some lymphocytes.

D. IgD

1. Structure
The structure of IgD is presented in the Figure 13. IgD exists only as a monomer.

2. Properties

a) IgD is found in low levels in serum; its role in serum uncertain.

b) IgD is primarily found on B cell surfaces where it functions as a receptor for antigen. IgD on the surface of B cells has extra amino acids at C-terminal end for anchoring to the membrane. It also associates with the Ig-alpha and Ig-beta chains.

c) IgD does not bind complement.

E. IgE

1. Structure
The structure of IgE is presented in Figure 14. IgE exists as a monomer and has an extra domain in the constant region.

2. Properties

a) IgE is the least common serum Ig since it binds very tightly to Fc receptors on basophils and mast cells even before interacting with antigen.

b) Involved in allergic reactions - As a consequence of its binding to basophils an mast cells, IgE is involved in allergic reactions. Binding of the allergen to the IgE on the cells results in the release of various pharmacological mediators that result in allergic symptoms.

c) IgE also plays a role in parasitic helminth diseases. Since serum IgE levels rise in parasitic diseases, measuring IgE levels is helpful in diagnosing parasitic infections. Eosinophils have Fc receptors for IgE and binding of eosinophils to IgE-coated helminths results in killing of the parasite.

d) IgE does not fix complement.

Adapted from:F.T. Fischbach in "A Manual of Laboratory Diagnostic Tests," 2nd Ed., J.B. Lippincott Co., Philadelphia, PA, 1984.

1. Increases in:

a) Chronic granulomatous infections
b) Infections of all types
c) Hyperimmunization
d) Liver disease
e) Malnutrition (severe)
f) Dysproteinemia
g) Disease associated with hypersensitivity granulomas, dermatologic disorders, and IgG myeloma
h) Rheumatoid arthritis

2. Decreases in:

a) Agammaglobulinemia
b) Lymphoid aplasia
c) Selective IgG, IgA deficiency
d) IgA myeloma
e) Bence Jones proteinemia
f) Chronic lymphoblastic leukemia

 

1. Increases (in adults) in:

a) Waldenström's macroglobulinemia
b) Trypanosomiasis
c) Actinomycosis
d) Carrión's disease (bartonellosis)
e) Malaria
f) Infectious mononucleosis
g) Lupus erythematosus
h) Rheumatoid arthritis
I) Dysgammaglobulinemia (certain cases)

Note: In the newborn, a level of IgM above 20 ng./dl is an indication of in utero stimulation of the immune system and stimulation by the rubella virus, the cytomegalovirus, syphilis, or toxoplasmosis.

2. Decreases in:

a) Agammaglobulinemia
b) Lymphoproliferative disorders (certain cases)
c) Lymphoid aplasia
d) IgG and IgA myeloma
e) Dysgammaglobulinemia
f) Chronic lymphoblastic leukemia

 

1. Increases in:

a) Wiskott-Aldrich syndrome
b) Cirrhosis of the liver (most cases)
c) Certain stages of collagen and other autoimmune disorders such as rheumatoid arthritis and lupus erythematosus
d) Chronic infections not based on immunologic deficiencies
e) IgA myeloma

2. Decreases in:

a) Hereditary ataxia telangiectasia
b) Immunologic deficiency states (e.g., dysgammaglobulinemia, congenital and acquired agammaglobulinemia, and hypogammaglobulinemia)
c) Malabsorption syndromes
d) Lymphoid aplasia
e) IgG myeloma
f) Acute lymphoblastic leukemia
g) Chronic lymphoblastic leukemia

1. Increases in:

a) Chronic infections
b) IgD myelomas

1. Increases in:

a) Atopic skin diseases such as eczema
b) Hay fever
c) Asthma
d) Anaphylactic shock
e) IgE-myeloma

2. Decreases in:

a) Congenital agammaglobulinemia
b) Hypogammaglobulinemia due to faulty metabolism or synthesis of immunoglobulins