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Accelerated Pathological and Clinical Nephritis in Systemic Lupus Erythematosus-Prone New Zealand Mixed 2328 Mice Doubly Deficient in TNF Receptor 1 and TNF Receptor 2 via a Th17-Associated Pathway¹

Noam Jacob^*,, Haitao Yang^*,, Luminita Pricop^¶, Yi Liu^¶, Xiaoni Gao^¶, Song Guo Zheng^*,, Juhua Wang^*,, Hua-Xin Gao^||, Chaim Putterman^||, Michael N. Koss, William Stohl^*, and Chaim O. Jacob^2,*,

^* Department of Medicine, Division of Gastrointestinal and Liver Diseases, Division of Rheumatology, and Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033; ^¶ Department of Medicine, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY 10021; and ^|| Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10461

TNF- has both proinflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in systemic lupus erythematosus (SLE)-prone (New Zealand Black x New Zealand White)F₁ mice has been established, it remains uncertain whether this effect segregates at the individual TNFR. We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNFR1, in TNFR2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4⁺ T lymphocytes, especially activated memory (CD44^highCD62L^low) CD4⁺ T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNFR alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNF--mediated signaling was highly deleterious to the host in the New Zealand Mixed 2328 SLE model. These observations may have profound ramifications for the use of TNF and TNFR antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 AI057473 (to C.O.J.), R01 AR050193 (to W.S.), and P30 DK04522 (core).

² Address correspondence and reprint requests to Dr. Chaim O. Jacob, University of Southern California, 2011 Zonal Avenue, HMR 705, Los Angeles, CA 90033. E-mail address: Jacob{at}usc.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; DKO, double knockout; GC, germinal center; KBS, kidney biopsy score; NZB, New Zealand Black; NZM, New Zealand Mixed; NZW, New Zealand White; SLE, systemic lupus erythematosus; TRAF2, TNFR-associated factor 2; WT, wild type; neg, negative.

⁴ The online version of this article contains supplementary material.