IL-23, not IL-12, directs autoimmunity to the Goodpasture antigen.
The autoantigen in Goodpasture disease is the noncollagenous domain of alpha3 type IV collagen [alpha3(IV)NC1]. We previously demonstrated that IL-12p40(-/-) mice are protected from experimental autoimmune anti-glomerular basement membrane (anti-GBM) glomerulonephritis, seemingly defining a role for IL-12 in this disease; however, the recent identification of IL-23, a heterodimer composed of IL-12p40 and IL-23p19 subunits, raises the possibility that IL-23, rather than IL-12, may modulate this disease instead. We immunized wild-type, IL-12p35(-/-) (IL-12 deficient, IL-23 intact), IL-12p40(-/-) (deficient in both IL-12 and IL-23), and IL-23p19(-/-) (IL-12 intact, IL-23 deficient) mice with recombinant mouse alpha3(IV)NC1. Wild-type mice developed autoreactivity to alpha3(IV)NC1: Humoral responses, cellular responses, renal histologic abnormalities, leukocyte accumulation, autoantibody deposition, and IL-17A mRNA expression (a cytokine produced by the IL-23-maintained Th17 subset). IL-23 but not IL-12 was detected in the immune system. Regardless of the presence of IL-12, mice deficient in IL-23 were protected, but mice with IL-23 were not. Both IL-23-deficient strains exhibited lower autoantibody titers, reduced cellular reactivity, diminished cytokine production (IFN-gamma [Th1], IL-17A [Th17], TNF, and monocyte chemoattractant protein 1), and less renal disease and glomerular IgG deposition. The deficient responses in the absence of IL-23 were not due to increased regulatory T cells; IL-12p40(-/-) and IL-23p19(-/-) mice did not show increased proportions of CD4(+)CD25(+)FoxP3(+) cells or IL-10 levels early in the immune response. In conclusion, autoreactivity to the Goodpasture antigen is directed primarily by IL-23, absence of which results in hyporeactivity including but extending beyond a deficient Th17 response.
Ooi
Joshua D
JD
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia.
Phoon
Richard K S
RK
Holdsworth
Stephen R
SR
Kitching
A Richard
AR
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology*; D000917:Antibody Formation; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D018664:Interleukin-12 / Q000172:deficiency / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D053759:Interleukin-23 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D001324:Autoantigens; D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger; D018664:Interleukin-12; D005620:Freund's Adjuvant