The genes of systemic autoimmunity

Area of Science:

• Immunology
• Genetics
• Autoimmunity

Background:

• Autoimmune diseases encompass systemic and organ-specific disorders.
• Systemic lupus erythematosus (SLE) is characterized by female predominance, multiorgan pathology, and autoantibodies against nuclear antigens.
• Lupus exhibits heterogeneity in organ involvement, serology, and clinical course, with susceptibility influenced by polygenic inheritance, environmental, and stochastic factors.

Purpose of the Study:

• To define the genetic basis of lupus in predisposed mice and humans.
• To clarify the roles of apoptosis-promoting genes (e.g., Fas/FasL) in tolerance and immunoregulation.
• To identify genetic contributions to systemic autoimmunity and their mechanisms.

Main Methods:

• Analysis of spontaneous mutations in lupus-prone mice (lpr and gld models).
• Transgenic and gene knockout mouse studies to assess gene effects on autoimmunity.
• Genome-wide association studies (GWAS) to identify predisposing loci in mice and humans.

Main Results:

• Identification of Fas/FasL defects as the first example of spontaneous mutations in apoptosis genes linked to systemic autoimmunity.
• Demonstration that specific genes can independently induce or modify systemic autoimmunity in mice.
• Identification of predisposing loci for lupus-like diseases in various mouse strains and humans.

Conclusions:

• Multiple genetic factors can independently contribute to systemic autoimmunity.
• Human lupus is likely composed of diverse genetic underpinnings (genotypes).
• Defining predisposing alleles and their mechanisms is crucial for understanding lupus pathogenesis and developing targeted therapies.