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FRI0028 Cellular source of tnf defines its pathogenic and protective functions during autoimmune arthritis
  1. A. Kruglov1,2,
  2. L. Morawietz3,
  3. S. Nedospasov1,2,4
  1. 1German Rheumatism Research Center (DRFZ), a Leibnitz Institute, Berlin, Germany
  2. 2Moscow State University, Moscow, Russian Federation
  3. 3Charite Virchow Klinikum, Berlin, Germany
  4. 4Engelhardt Institute of Molecular Biology, Moscow, Russian Federation


Background TNF overexpression is tightly linked to pathogenesis of various autoimmune diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis, Crohn’s disease and etc. Despite the success of TNF blockade in RA treatment, various side effects were reported, including increased susceptibility to intracellular pathogens, spontaneous development of autoimmune syndromes and others, suggesting that systemic ablation of TNF from the body may subsequently abolish protective functions of this cytokine.

Objectives In order to delineate pathogenic and protective cellular sources of TNF produced by various cell types in arthritis and define potential targets for cell-specific anti-TNF therapy, we studied collagen-induced arthritis in the panel of mice with cell-specific TNF ablation.

Methods We have previously generated panel of mice with cell-type specific TNF ablation in various cell types of immune system, such as T and B lymphocytes and myeloid cells[1]. Collagen-induced arthritis model was induced in mice lacking TNF in particular cell types and disease incidence as well as disease severity were analyzed daily. Additionally, we analyzed humoral and cellular responses in all mouse strains at various stages of arthritis development.

Results Mice with TNF deletion in B cells, characterized by reduced germinal center formation and diminished anti-collagen antibody titres, developed arthritis with significantly reduced severity, suggesting a critical role for TNF in autoantibody production and arthritis development. When TNF was depleted in macrophages and neutrophils, mice exhibited reduced arthritis incidence revealing pathogenic role of myeloid cellderived TNF in arthritis development. Surprisingly, ablation of TNF in T cells (T-TNF KO mice) resulted in exacerbated disease and significantly higher incidence. Further analysis revealed that T-TNF KO mice exhibited high numbers of autoreactive T cells in secondary lymphoid organs during arthritis, suggesting that T-TNF is critical for dampening of autoreactive T cell responses. Furthermore, mice lacking from both T and B cells developed exacerbated disease, similar to T-TNF KO animals, despite the lack of anti-collagen antibodies, indicating that autoantibodies are not important for disease manifestation in the context of increased autoreactive T cell response. Finally, depletion of TNF from both myeloid cells and T cells lead to significantly decreased incidence of arthritis, suggesting that initial step for arthritis induction mediated by myeloid cell - derived TNF and cannot be compenstaed by increased autoreactive T cell development.

Conclusions Thus, our data uncover non-redundant effects of TNF in arthritis: direct pathogenic role of TNF derived from myeloid cells in arthritis induction, control of autoreactive T cell development by T-cell derived TNF, and regulation of autoantibody production via control of FDCs development and GC formation, presumably by soluble TNF produced by B cells.

  1. Grivennikov SI, Tumanov AV, Liepinsh DJ, Kruglov AA, Marakusha BI, Shakhov AN, Murakami T, Drutskaya LN, Förster I, Clausen BE, Tessarollo L, Ryffel B, Kuprash DV, Nedospasov SA. Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. Immunity. 2005 Jan; 22(1):93-104

Disclosure of Interest None Declared

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