A Novel Inhibitory Function Of FcγRⅡB Relying On Its Transmembrane Domain In The Initiation Of B Cell Activation

To balance immunoprotection and immunopathology, B cell activation is under strict control by BCR co-receptor Fc?RIIB and CD19. Aberrant B cell activationis associated with autoimmune diseases such as systemic lupus erythematosus(SLE), rheumatoid arthritis(RA) or Sj?gren’s syndrome(SS), however the underlining mechanism is incompletely understood. Here, we systemically investigated the function of FcγRIIB in the initiation of B cell activation by combining mutagenesis, advanced live cell imaging and epidemiological approaches. We found that when co-ligated to the BCR the Fc?RIIB can inhibit B cell activation by efficiently blocking the colocalization of BCR and CD19 microclusters in B cell immunological synapse, and such function of Fc?RIIB is unexpectedly dependent on its transmembrane domain(TM) but not its well-characterized ITIM(immunoreceptor tyrosine-based inhibitory motif)-containing cytoplasmic domain.Human primary B cells from SLE patients homozygous for gene encoding a loss-of-function TM SNP(rs1050501) Fc?RIIB-I232 T, also fail to block the synaptic colocalization of the BCR with CD19, leading to dysregulated recruitment of downstream signaling molecule pPI3 K to membrane proximal signalosome. The dysregulated signaling in these patients B cells appears to be of clinical relevance as Fc?RIIB-I232 T homozygous SLE patients are more likely to develop severe clinical symptoms compared to patients carrying either one or both WT copies of Fc?RIIB. To further assess the relevance of Fc?RIIB-I232 T polymorphism in autoimmune diseases, we did an epidemiological examination of Fc?RIIB-I232 T in 778 healthy control individuals, 711 SLE, 514 RA and 314 SS patients in Han Chinese population. The results showed that homozygous Fc?RIIB-I232 T is significantly associated with SLE and RA but not SS. More importantly, this SNP associates with early-onset of SLE and RA, and with high disease activity score. However such correlation is not evidence in SS patients. These results suggest that Fc?RIIB-WT could potentially serve as an auxiliary disease severity prediction biomarker for early diagnosis and disease progress evaluation of SLE and RA patients.Conclusively, all these studies may help explain the hyper-reactive features of autoimmune disease patient B cells and provide new targets for therapies.