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 pathway

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, Chaim O. Jacob

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

TNF-α 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 highCD62Llow) 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-α-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.

Original languageEnglish (US)
Pages (from-to)2532-2541
Number of pages10
JournalJournal of Immunology
Volume182
Issue number4
DOIs
StatePublished - Feb 15 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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