title: FcγRIIB mediates antigen-independent inhibition on human B lymphocytes through Btk and p38 MAPK.
abstract: BACKGROUND
  The inhibitory Fc receptor, FcγRIIB, has emerged as a key negative regulator of B cell activation and as such is predicted to play an essential role in controlling antibody-mediated autoimmune diseases in humans. Recent studies have shown that crosslinking the FcγRIIB independently of the B-cell receptor (BCR) results in apoptosis in both mouse and chicken B cells. However, the human B cell subpopulations that are susceptible to BCR-independent, FcγRIIB-mediated regulation are not known. How FcγRIIB mediates this inhibition to affect B cell homeostasis is also not determined.
  
  
  RESULTS
  We isolated naïve B cells, memory B cells and plasma cells (PCs) from peripheral blood of healthy donors and used differentiated PCs in culture to examine the effects on them by FcγRIIB crosslinking. We showed that human PCs, memory and naïve B cells all expressed FcγRIIB with expression on PCs being the highest in circulation. Moreover, they were sensitive to direct inhibition by FcγRIIB through Btk and p38 MAPK. Similarly, PCs resulting from the antigen-independent differentiation of memory B cells in vitro were inhibited by FcγRIIB cross-linking but memory B cell activation itself, as measured by proliferation, was unaffected. In contrast, both the proliferation and differentiation of naïve B cells to PCs were blocked by FcγRIIB crosslinking.
  
  
  CONCLUSIONS
  These results suggest a mechanism to control antibody levels involving the differential expression of FcγRIIB on B cell subpopulations, in which the FcγRIIB functions independently of the BCR to eliminate antibody-secreting effector cells and inhibit naïve B cell proliferation without compromising the long-lived antigen-specific memory B cells. Importantly, FcγRIIB requires Btk and p38 MAPK to mediate antigen-independent inhibition in human B cells. Taken together, our data underscore the importance of antigen-independent inhibition by FcγRIIB in the prevention from antibody-mediated autoimmune diseases and in the regulation of B cell homeostasis.
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Room 1118, No.1, Section 1, Ren-Ai Road, Taipei, 10051, Taiwan. sjtzeng@ntu.edu.tw.
authors.forename: Shiang-Jong
authors.initials: SJ
authors.lastname: Tzeng
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Room 1118, No.1, Section 1, Ren-Ai Road, Taipei, 10051, Taiwan.
authors.forename: Wan-Yu
authors.initials: WY
authors.lastname: Li
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Room 1118, No.1, Section 1, Ren-Ai Road, Taipei, 10051, Taiwan.
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000941:Antigens / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002645:Chickens; D006801:Humans; D007156:Immunologic Memory; D051379:Mice; D010950:Plasma Cells / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology*
chemical_list: D000941:Antigens; C499173:FCGR2B protein, human; D017452:Receptors, IgG; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D048051:p38 Mitogen-Activated Protein Kinases