Page 1186 - Veterinary Immunology, 10th Edition

lymphocytes directed against normal body components. The fact
VetBooks.ir that they tend to develop late in life suggests that these diseases,

like cancer, are probably the result of multiple random defects.
Thus while one defect alone may be insufficient to permit an

autoimmune response, multiple problems may eventually permit
self-reactive lymphocytes to develop. Given the ubiquity of
microbial and environmental antigens, lymphocytes are under
constant pressure to proliferate. The presence of a constant supply

of self-antigens is especially significant. Much of the complexity of
the immune system is determined by the need to keep this
lymphocyte proliferation in check.
Lymphocyte proliferation is regulated by multiple mechanisms.

These include negative selection within the thymus, the
requirement for multiple co-stimulatory signals, lymphocyte
cooperation, and the activities of regulatory cell populations. These
regulatory mechanisms often overlap so that the development of

self-reactive rogue clones does not occur suddenly. It likely takes
multiple accumulated defects, acting collectively in regulatory
pathways, to lead to the loss of control of lymphocyte proliferation.
By evolving receptor systems that can bind to as many microbial

antigens as possible, vertebrates also developed the potential for
self-destruction. The random generation of antigen-binding
receptors ensures that many lymphocytes are produced with
receptors that can bind self-antigens. It has been estimated that as

many as 50% of newly produced T cell and B cells may bind self-
antigens with high affinity. These self-reactive cells are usually
rigorously suppressed so that only a few animals develop
autoimmune disease. However, the reasons why these individuals

eventually develop autoimmune diseases while others do not are
still unclear. Many factors influence susceptibility to autoimmunity.
These include sex and age, genetic background, the microbiota, and
virus infections. We also know that the development of

autoantibodies is a relatively common event that by itself does not
inevitably lead to autoimmune disease. Indeed, some
autoantibodies serve a physiological function.
Because we do not know precisely what triggers autoimmunity,
this chapter reviews some of the many different predisposing

factors that have been identified or proposed as well as the

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