The extrafollicular (EF) B cell reaction is emerging as a lynchpin of systemic autoimmune responses. External factors that limit this response remain undefined. AM14 transgenic mice have been useful in elucidating how autoreactive Rheumatoid Factor B cells are activated. On a lupus-prone genetic background, AM14 B cells undergo an isotype-switched EF plasmablast response. A similar response ensues when these cells are exposed in vivo to IgG2aa anti-chromatin antibodies, which presumably form immune complexes (ICs) with chromatin shed from dying cells. ICs have Fc that could also stimulate myeloid cells via FcRγ and TLRs, which in turn could influence the EF response. To investigate this, we transferred AM14 B cells into mice lacking FcRγ, MyD88 or both. Initial expansion and differentiation of AM14 B cells was equivalent in all hosts. However, by day 7, whereas the AM14 B cell response contracted in the WT environment, dysregulated expansion continued in the deficient environments. Furthermore, MyD88 and FcRγ are non-redundant, as responses in mice lacking both proteins were larger and more prolonged compared with mice deficient in either factor alone. By d10, the AFC frequency was 40-fold larger in double-deficient compared to WT recipients. These results reveal novel regulatory roles in the EF B cell response for two receptors that are typically considered proinflammatory. Targeting these pathways may provide a way to curtail dysregulated autoreactive B cell activation.
- Copyright © 2011 by The American Association of Immunologists, Inc.