Page 1199 - Veterinary Immunology, 10th Edition

VetBooks.ir Predisposing Factors

Genetic Predisposition

Although viruses or other infectious agents may trigger
autoimmunity, it is clear that not all infected individuals develop
autoimmune disease. This is because genetic factors are key

determinants of disease susceptibility. Genome-wide association
studies have identified hundreds of loci that harbor risk factors for
autoimmune diseases. Many of these are shared by multiple
diseases and perhaps identify certain common pathways (such as
JAK-STAT pathways) acting in multiple diseases. It is clear from

these studies, however, that the associations so far identified do not
account for all genetic effects, and the effect size at any individual
locus is very small.

In mice, at least 25 loci that contribute to autoimmunity if deleted
or overexpressed have been identified. These include genes that
code for cytokines, cytokine receptors, co-stimulators, molecules
that regulate apoptosis, molecules that regulate antigen clearance,
and members of cytokine or antigen-signaling cascades. Some

diseases result from a defect in a single gene such as the lpr or gld
mutations. Their gene products play a key role in the destruction of
self-reactive T cells. In their absence, excessive T cell proliferation

and autoimmunity result. Others result from inherited complement
deficiencies. More commonly, the role of genes is complex. Thus
genes influence the severity of disease, and no specific gene is
necessary or sufficient for disease expression. Even if an animal has
a complete set of susceptibility alleles at multiple loci, presence of

overt disease may depend on the genetic background of the animal.
This genetic complexity probably also contributes to differences in
disease presentation since these may be determined by different

sets of contributing genes. Genetic analysis is also complicated
because susceptibility genes may or may not interact with each
other. The vulnerability of a target organ to autoimmune damage
may also be inherited.
The genes that most commonly associated with naturally

occurring autoimmune diseases are those in the MHC. MHC

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