title: Integrin CD11b negatively regulates BCR signalling to maintain autoreactive B cell tolerance.
abstract: A variant of the integrin-α-M (CD11b) gene has been linked to the pathogenesis of systemic lupus erythematosus. However, how this genotype results in the lupus phenotype is not fully understood. Here we show that autoreactive B cells lacking CD11b exhibit a hyperproliferative response to B cell receptor (BCR) crosslinking and enhanced survival. In vivo engagement of BCR in CD11b-deficient mice leads to increased autoAb production and kidney Ig deposition. In addition, CD11b-deficient autoreactive B cells have decreased tyrosine phosphorylation including Lyn and CD22 with decreased phosphatase SHP-1 recruitment but increased calcium influx. Results obtained using B cells transfected with the wild type or rs1143679 lupus-associated variant of CD11b suggest that this mutation completely abrogates the regulatory effect of CD11b on BCR signalling. This is through disruption of CD22-CD11b direct binding. These results reveal a previously unrecognized role of CD11b in maintaining autoreactive B cell tolerance.
authors.affiliation: 1] Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA [2] Division of Hematology/Oncology, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA [3].
authors.forename: Chuanlin
authors.initials: C
authors.lastname: Ding
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Ma
authors.forename: Xingguo
authors.initials: X
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Yihua
authors.initials: Y
authors.lastname: Cai
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Hu
authors.forename: Dong
authors.initials: D
authors.lastname: Xiang
authors.forename: Swapan
authors.initials: S
authors.lastname: Nath
authors.forename: Huang-ge
authors.initials: HG
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: David
authors.initials: D
authors.lastname: Powell
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis* / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D039481:CD11b Antigen / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D005260:Female; D007108:Immune Tolerance; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020125:Mutation, Missense; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D001323:Autoantibodies; D039481:CD11b Antigen; D011947:Receptors, Antigen, B-Cell