NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells Academic Article uri icon

abstract

  • We examined the role of NFκB1 in the homeostasis and function of peripheral follicular (Fo) B cells. Aging mice lacking NFκB1 (Nfκb1−/−) develop lymphoproliferative and multiorgan autoimmune disease attributed in large part to the deregulated activity ofNfκb1−/−Fo B cells that produce excessive levels of the proinflammatory cytokine interleukin 6 (IL-6). Despite enhanced germinal center (GC) B cell differentiation, the formation of GC structures was severely disrupted in theNfκb1−/−mice. Bone marrow chimeric mice revealed that the Fo B cell–intrinsic loss of NFκB1 led to the spontaneous generation of GC B cells. This was primarily the result of an increase in IL-6 levels, which promotes the differentiation of Fo helper CD4+T cells and acts in an autocrine manner to reduce antigen receptor and toll-like receptor activation thresholds in a population of proliferating IgM+Nfκb1−/−Fo B cells. We demonstrate that p50-NFκB1 repressesIl-6transcription in Fo B cells, with the loss of NFκB1 also resulting in the uncontrolled RELA-driven transcription ofIl-6.Collectively, our findings identify a previously unrecognized role for NFκB1 in preventing multiorgan autoimmunity through its negative regulation ofIl-6gene expression in Fo B cells.

authors

  • de Valle, Elisha
  • Grigoriadis, George
  • O’Reilly, Lorraine A
  • Willis, Simon N
  • Maxwell, Mhairi J
  • Corcoran, Lynn M
  • Tsantikos, Evelyn
  • Cornish, Jasper KS
  • Fairfax, Kirsten A
  • Vasanthakumar, Ajithkumar
  • Febbraio, Mark A
  • Hibbs, Margaret L
  • Pellegrini, Marc
  • Banerjee, Ashish
  • Hodgkin, Philip D
  • Kallies, Axel
  • Mackay, Fabienne
  • Strasser, Andreas
  • Gerondakis, Steve
  • Gugasyan, Raffi

publication date

  • 2016