Roles of interferon-gamma and interleukin-4 in murine lupus.
The systemic autoimmune syndrome of MRL/Mp-lpr/lpr (MRL/lpr) mice consists of severe pan-isotype hypergammaglobulinemia, autoantibody production, lymphadenopathy, and immune complex-associated end-organ disease. Its pathogenesis has been largely attributed to helper alphabeta T cells that may require critical cytokines to propagate pathogenic autoantibody production. To investigate the roles of prototypical Th1 and Th2 cytokines in the pathogenesis of murine lupus, IFN-gamma -/- and IL-4 -/- lupus-prone mice were generated by backcrossing cytokine knockout animals against MRL/lpr breeders. IFN-gamma -/- animals produced significantly reduced titers of IgG2a and IgG2b serum immunoglobulins as well as autoantibodies, but maintained comparable levels of IgG1 and IgE in comparison to cytokine-intact controls; in contrast, IL-4 -/- animals produced significantly less IgG1 and IgE serum immunoglobulins, but maintained comparable levels of IgG2a and IgG2b as well as autoantibodies in comparison to controls. Both IFN-gamma -/- and IL-4 -/- mice, however, developed significantly reduced lymphadenopathy and end-organ disease. These results suggest that IFN-gamma and IL-4 play opposing but dispensable roles in the development of lupus-associated hypergammaglobulinemia and autoantibody production; however, they both play prominent roles in the pathogenesis of murine lupus-associated tissue injury, as well as in lpr-induced lymphadenopathy.
Peng
S L
SL
Section of Rheumatology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Moslehi
J
J
Craft
J
J
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D005260:Female; D007132:Immunoglobulin Isotypes / Q000097:blood; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009154:Mutation; D012469:Salivary Glands / Q000473:pathology
D001323:Autoantibodies; D007132:Immunoglobulin Isotypes; D015847:Interleukin-4; D007371:Interferon-gamma