Using single-gene deletions to identify checkpoints in the progression of systemic autoimmunity.
Systemic lupus erythematosus is a multigenic disorder of unknown etiology. To investigate the roles that specific genes play in lupus, we have examined the disease profiles in mice with single-gene deletions. In total, some 17 genes have been studied. Absence of certain genes, such as CD40L, CD28, or Igh6, abrogated induction of autoimmunity. Other genes, such as Igh5, IL-4, or ICAM-1, had little effect on the development of disease. Intermediate effects were observed in IL-6-deficient mice, while absence of beta2-microglobulin resulted in loss of hypergammaglobulinemia and IgG1 autoantibodies, but produced little change in anti-chromatin antibodies or glomerular deposits. The most interesting observations were obtained with genes related to the expression or function of interferon-gamma (IFN-gamma). Reductions in IFN-gamma levels in murine lupus are associated with reductions in both autoantibody levels and immune-complex- mediated pathology. Genes involved in up-regulation of IFN-gamma expression, such as IL-12, STAT-4, or ICE, did not significantly influence autoimmunity, whereas absence of IFN-gamma or IFN-gamma receptor led to greatly reduced autoantibody response and immunopathology. Absence of IRF-1, a gene ex-pressed in response to IFN-gamma, resulted in selective retention of anti-chromatin antibodies but little glomerular pathology. These studies suggest that the presence of a baseline level of IFN-gamma, rather than increased expression, is important for autoimmunity. Furthermore, as the IRF-1 knockout demonstrates, specific defects in signaling pathways and gene expression subsequent to IFN-gamma/IFN-gamma receptor interaction may influence only certain disease parameters. It has not escaped our attention that IFN-gamma influences the expression and function of other immunologically relevant genes, such as IL-4, IL-6, and beta2-microglobulin. Thus, these genes may be part of the downstream events following IFN-gamma/IFN-gamma receptor interaction that promote the development of autoimmunity.
Pollard
K Michael
KM
Department of Molecular and Experimental Medicine, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. mpollard@scripps.edu
Hultman
Per
P
Kono
Dwight H
DH
D000818:Animals; D018450:Disease Progression; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D007371:Interferon-gamma / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000473:pathology; D051379:Mice; D017471:Receptors, Interferon / Q000502:physiology; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor