Prevention of murine antiphospholipid syndrome by BAFF blockade

Philip Kahn, Meera Ramanujam, Ramalingam Bethunaickan, Weiqing Huang, Haiou Tao, Michael P. Madaio, Stephen M. Factor, Anne Davidson

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Objective. This study was undertaken to determine whether BAFF blockade can be used to prevent or treat antiphospholipid syndrome in a mouse model. Methods. Eight- and 12-week-old (NZW x BXSB)F1 mice were treated with BAFF-R-Ig or TACI-Ig alone or in addition to a short course of CTLA-4Ig. Mice were monitored for thrombocytopenia and proteinuria. Sera were tested for anticardiolipin antibodies (aCL), BAFF levels, and levels of soluble vascular cell adhesion molecule and E-selectin. Mice were killed at 17, 22, or 32 weeks of age, and kidneys and hearts were subjected to histologic examination. Spleen cells were phenotyped and enzyme-linked immunospot assays for autoantibody-producing B cells were performed. Results. Both BAFF-R-Ig and TACI-Ig prevented disease onset and significantly prolonged survival. Treated mice had significantly smaller spleens than controls, with fewer B cells and fewer activated and memory T cells. BAFF blockade did not prevent the development of aCL, and there was only a modest delay in the development of thrombocytopenia. However, treated mice had significantly less nephritis and myocardial infarcts than did controls. Conclusion. Our findings suggest that aCL are generated in the germinal center, which is relatively independent of BAFF. Effector function of antiplatelet antibodies was only modestly affected by BAFF blockade. In contrast, myocardial infarctions were prevented, suggesting that triggering of thromboses requires both autoantibodies and mediators of inflammation. Similarly, renal damage requires both immune complexes and effector cells. The dissociation between autoantibody production and inflammation that may occur with B cell-depleting therapies underscores the role of B cells as effector cells in the autoimmune response.

Original languageEnglish (US)
Pages (from-to)2824-2834
Number of pages11
JournalArthritis and Rheumatism
Volume58
Issue number9
DOIs
StatePublished - Sep 1 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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    Kahn, P., Ramanujam, M., Bethunaickan, R., Huang, W., Tao, H., Madaio, M. P., Factor, S. M., & Davidson, A. (2008). Prevention of murine antiphospholipid syndrome by BAFF blockade. Arthritis and Rheumatism, 58(9), 2824-2834. https://doi.org/10.1002/art.23764