Autoimmunity : Mechanisms of Induction of the Autoimmune State

A. Release of sequestered antigen-

A sequestered antigen is one that under normal conditions is not readily available for recognition by the immune system, even though it is present in the body. Release of sequestered antigens is often caused by tissue injury. When the antigens are released, normal immunologic response occurs, i.e. antibody production, but since these antibodies are directed against self-antigens, they are called autoantibodies.

Examples:

• anti-sperm antibody following vasectomy
• anti-lens antibody following eye injury
• Sympathetic Ophthalmia
• anti-cardiac muscle antibody following MI
• anti-corneal antibody following contact lens trauma

B. Altered Antigen (Neoantigen)

It is known that autocoupling haptens can cause formation of neoantigens that are recognized as foreign by the body (i.e. poison ivy, etc.). While the altered antigen theory is technically possible in the development of autoimmune disease, no convincing evidence of this etiology has been presented to date.

C. Shared or Cross-Reactive Antigen Theory

The cause of this autoimmune mechanism is exogenous antigens that share with the body several, if not many cross-reacting epitopes. Exposure and response to these exogenous antigens results in the formation of antibody which will then cross react with self antigens.

Examples:

• Autoantibody induction in paroxysmal cold hemoglobinuria secondary to T. pallidum infection (syphilis)
• Hemolytic anemia associated with mycoplasma infections
• Post-vaccinial and post-infectious encephalomyelitis
• Group streptococcus induced rheumatic fever

Autoantibodies not associated with true autoimmune disease:

Syphilis-

T. Pallidum infection -----> tissue destruction Tissue destruction -----> exposure of Ag determinants (Specifically cardiolipin) Abs formed against cardiolipin.

D. Polyclonal Stimulation of T cells and/or B Cells

A variety of bacterial products, some viruses and viral components (such as EBV), parasites, and some drugs may act as B cell mitogens. Normally in the body, according to theory, there are a certain number of clones of B cells that are not tolerant to self. These cells are not normally stimulated because there is no enhancement by Th (helper) cells. In the presence of a B cell mitogen, however, B cell clonal proliferation would occur in the absence of T cell enhancement, resulting in the formation of antibody by these non-tolerant cells, i.e. autoantibody. This type of mechanism has been demonstrated in vitro, and the antibodies produced appear to be:

1. Transient
2. Of low affinity
3. IgM primarily

E. Alteration of Normal Homeostatic Mechanisms

"Forbidden clone" theory

In the normal individual, Ts (suppressor) cells tend to prevent activation of non-tolerant clones of lymphocytes. Loss of a given antigen-specific Ts cell subset could result in the activation of non-tolerant clones and formation of autoimmune disease. There is evidence of Ts deficiency in many of the autoimmune disorders, and this theory lends considerable support for the increased incidence of autoimmune disease in the elderly. There have been a number of studies that document Ts deficiency in aged patients with autoimmune disease.

F. Genetic Factors

There have been a number of studies that show an association between certain MHC haplotypes and autoimmune diseases. SLE: A1,B8,DR3; RA:Dw4,DRw4). It has not yet been possible to attribute autoimmune disease predisposition to a single genetic locus, however. However evidence is clear that genetic factors play a definite role in the mechanisms of these diseases.

G. Hormonal Factors

Sex hormones, and or X or Y linked genes may play a role in the formation of autoimmune disease. In general, females are more susceptible to connective tissue diseases than are males. The incidence of SLE in females after puberty is 9 times that of men. The incidence of ankylosing spondylitis is higher in males than in females. Experimental and clinical studies in humans and animals tend to incriminate the sex hormones, rather than some X or Y linked genetic locus.

Category: Pathology Notes