Integrin CD11b negatively regulates BCR signalling to maintain autoreactive B cell tolerance

Chuanlin Ding, Yunfeng Ma, Xingguo Chen, Min Liu, Yihua Cai, Xiaoling Hu, Dong Xiang, Swapan Nath, Huang-ge Zhang, Hong Ye, David Powell and Jun Yan ()
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Chuanlin Ding: Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine
Yunfeng Ma: Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine
Xingguo Chen: Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine
Min Liu: Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine
Yihua Cai: Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine
Xiaoling Hu: Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine
Dong Xiang: Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine
Swapan Nath: Arthritis and Clinical Immunology Group, Oklahoma Medical Research Foundation
Huang-ge Zhang: University of Louisville School of Medicine
Hong Ye: Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine
David Powell: University of Louisville School of Medicine
Jun Yan: Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3813

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