Role of PIR-B in autoimmune glomerulonephritis

Abstract

PIR-B, an inhibitory receptor expressed on murine B cells and myeloid cells, regulates humoral and cellular immune responses via its constitutive binding to the ligand, MHC class I molecules, on the same cells (cis) or on different cells (trans). Although it has been speculated that PIR-B is important for maintaining peripheral tolerance, PIR-B single deficiency does not cause overt autoimmune diseases. Recently, however, the combination of its deficiency with the Fas lpr mutation was found to result in augmented production of autoantibodies such as IgG rheumatoid factor and anti-DNA IgG, leading to glomerulonephritis in mice. Although the precise molecular mechanism for the overall scenario is unclear, PIR-B was found to suppress TLR9-mediated production of naturally autoreactive antibodies by innate B cells or B-1 cells by inhibiting the activation of Bruton's tyrosine kinase. Thus, PIR-B is an important regulator of innate immunity mediated by TLR9 in B-1 cells, which can otherwise provoke autoimmunity when overactivated.

Figure 1

Proposed mechanism for PIR-B-mediated regulation of TLR9-induced autoantibody production in B-1 cells. Unmethylated CpG-harboring DNA of bacterial and viral origin stimulates TLR9 in the endosomal compartments of various cells including B-1 cells via signal relay from MyD88, IRAK, and TRAF6, and then IκB phosphorylation, nuclear translocation of NF-κB, and initiation of the transcription of various mRNAs of innate responses, including those for autoreactive natural antibodies. Excess activation of the TLR9 system is thus potentially harmful, because excessive production of autoreactive IgM and, particularly, that switched to IgG might cause autoimmune disease. TLR9 in B-1 cells is regulated by PIR-B via Btk intersection, in which the phosphorylation of PIR-B is augmented immediately through TLR9-initiated Lyn activation, and the concomitantly enhanced SHP-1 recruitment to the phospho-ITIMs of PIR-B leads to accelerated dephosphorylation of Btk, which then attenuates the phosphorylation level of NF-κB p65RelA. Constitutive association of PIR-B with MHCI in cis on the surface of B-1 cells may be crucial for maintaining the TLR9 cascade being not overactivated, and once activated by CpG, immediate early suppression will occur via augmented SHP-1 recruitment to PIR-B-MHCI.