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Published ahead of print on April 8, 2009
J Am Soc Nephrol 20: 980-989, 2009
© 2009 American Society of Nephrology
doi: 10.1681/ASN.2008080891
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BASIC RESEARCH

IL-23, not IL-12, Directs Autoimmunity to the Goodpasture Antigen

Joshua D. Ooi, Richard K.S. Phoon, Stephen R. Holdsworth and A. Richard Kitching

Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia

Correspondence: Dr. Richard Kitching, Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia. Phone: 61-3-9594-5520; Fax: 61-3-9594-6495; E-mail: richard.kitching{at}med.monash.edu.au

Received for publication August 26, 2008. Accepted for publication December 16, 2008.

The autoantigen in Goodpasture disease is the noncollagenous domain of {alpha}3 type IV collagen [{alpha}3(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 {alpha}3(IV)NC1. Wild-type mice developed autoreactivity to {alpha}3(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.


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