Immunopathogenesis of lupus nephritis: new insights from experimental models.
Genetic analysis of systemic lupus erythematosus (SLE) in several lupus-prone mice has revealed that multiple, unlinked genes are required for the expression of various autoimmune manifestations, and that several, quite distinct genetic backgrounds are compatible with this disease. Although the nature of these genetic components has not been fully defined, it is becoming clear that certain genes such as the major histocompatibility complex class II genes and the genes regulating apoptosis apparently play a major role in the development of autoimmune responses characteristic in SLE. Analysis of the nephritogenic potential of monoclonal autoantibodies underlines the importance of qualitative features of autoantibodies in the pathogenesis of lupus nephritis. Strikingly, "wire-loop" glomerular lesions characteristic in human lupus nephritis can be induced by the direct localization of murine IgG3 antibodies with cryoglobulin activity without the involvement of immune complex formation. The remarkable correlation of IgG3 production with the development and acceleration of murine lupus nephritis, in association with enhanced activation of the TH1 subset which can lead to an increase in IgG3 production, is highly significant. The production process of more pathogenic autoantibodies appears to be genetically regulated. Further identification of the genetic defects present in lupus-prone mice, but lacking in mice with non-autoimmune backgrounds, is of paramount importance for the understanding of the immunopathogenetic mechanism of lupus nephritis and for the development of new therapeutic approaches for SLE.
Izui
S
S
Department of Pathology, University of Geneva, Switzerland.
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics; D003450:Cryoglobulins; D004195:Disease Models, Animal; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G; D008181:Lupus Nephritis / Q000209:etiology* / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D016176:T-Lymphocyte Subsets / Q000276:immunology
D001323:Autoantibodies; D003450:Cryoglobulins; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G