Both MyD88 and Fc Receptor (FcR) common gamma chain signaling
drive proinflammatory responses. In B
cells, MyD88 is required for anti-DNA and anti-RNA autoantibody responses in
vivo. Mechanisms within innate immune cell types during this response are not
well understood. Transgenic mice have
been useful in elucidating how autoreactive Rheumatoid Factor (RF) B cells are
activated. In lupus-prone mice, RF B cells undergo an isotype-switched extrafollicular
(EF) plasmablast response. A similar response ensues when these cells are
exposed in vivo to anti-chromatin antibodies, which presumably form immune
complexes (ICs) with chromatin shed from dying cells. ICs could also stimulate
myeloid cells via FcR and TLRs, which in turn could influence the EF response.
To investigate this, we transferred RF B cells and anti-chromatin antibodies
into mice lacking FcR common gamma chain, MyD88 or both. Initially, expansion
and differentiation of RF B cells was equivalent in all hosts. Unexpectedly, by
day 7, the response contracted in the WT environment, whereas dysregulated
expansion continued in the deficient environments. Furthermore, MyD88 and FcR
are non-redundant, as responses were larger and more prolonged in mice lacking
both compared with mice deficient in either factor alone. By day 10, 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 receptors
that are typically proinflammatory. Targeting these pathways may provide a way
to curtail dysregulated autoreactive B cell activation.