6. The Origins of Autoimmune Disease

Because otherwise healthy individuals show very low levels of autoantibodies, it is suspected that there is a function for them. A moderate, regulated amount of autoimmunity is probably required to dispose of old cells and cellular debris. Disease apparently arises when this regulatory or recognition apparatus goes awry. Although there is not yet a complete explanation for autoimmune diseases, several theories have been proposed.

The sequestered antigen theory explains that during embryonic growth, some tissues are immunologically privileged; that is, they are sequestered behind anatomical barriers and cannot be scanned by the immune system. Examples of these sites are regions of the central nervous system, which are shielded by the meninges and blood-brain barrier; the lens of the eye, which is enclosed by a thick sheath; and antigens in the thyroid and testes, which are sequestered behind an epithelial barrier. Eventually, the antigen becomes exposed by means of infection, trauma, or deterioration and is perceived by the immune system as a foreign substance.

According to the clonal selection theory, the immune system of a fetus develops tolerance to self by eradicating or silencing all selfreacting lymphocyte clones, called forbidden clones, while retaining only those clones that react to foreign antigens. Some of these forbidden clones may survive; and because they have not been subjected to this tolerance process, they can attack tissues carrying self molecules, which they mistake as antigens.

The theory of immune deficiency proposes that mutations in the receptor genes of some lymphocytes render them reactive to self or that a general breakdown in the normal T-suppressor function sets the scene for inappropriate immune responses. Inappropriate expression of MHC II markers on cells that don’t normally express them has been found to cause abnormal immune reactions to self. In a related phenomenon, T-cell activation may incorrectly “turn on” B cells that can react with self antigens. This phenomenon is called the bystander effect.

Some autoimmune diseases appear to be caused by molecular mimicry, in which microbial antigens bear molecular determinants similar to normal human cells. An infection could cause formation of antibodies that can cross-react with tissues. This is one purported explanation for the pathology of rheumatic fever. Another probable example of mimicry leading to autoimmune disease is the skin condition psoriasis. Although the etiology of this condition is complex and involves the inheritance of certain types of MHC alleles, infection with group A streptococci also plays a role. Scientists report that T cells primed to react with streptococcal surface proteins also react with keratin cells in the skin, causing them to proliferate. For this reason, psoriasis patients often report flare-ups after a streptococcal throat infection.

Autoimmune disorders such as type I diabetes and multiple sclerosis are likely triggered by viral infection. Viruses can noticeably alter cell receptors, thereby causing immune cells to attack the tissues bearing viral receptors.

Some researchers believe that many, if not most, autoimmune diseases will someday be discovered to have an underlying microbial etiology, either through molecular mimicry or viral alteration of host antigens (just described) or due to the presence of as yet undetectable microbes in the sites affected by autoimmunity.