期刊
JOURNAL OF IMMUNOLOGY
卷 188, 期 1, 页码 487-496出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1102176
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资金
- Juvenile Diabetes Research Foundation (the Center for Translational Research at Benaroya Research Institute)
- Alliance for Lupus Research
- National Institutes of Health [R56-AI-090842]
- Pennsylvania Department of Health
The PTPN22 genetic variant 1858T, encoding Lyp620W, is associated with multiple autoimmune disorders for which the production of autoantibodies is a common feature, suggesting a loss of B cell tolerance. Lyp620W results in blunted BCR signaling in memory B cells. Because BCR signal strength is tightly coupled to central and peripheral tolerance, we examined whether Lyp620W impacts peripheral B cell homeostasis in healthy individuals heterozygous for the PTPN221858T variant. We found that these subjects display alterations in the composition of the B cell pool that include specific expansion of the transitional and anergic IgD(+) IgM(-)CD27(-) B cell subsets. The PTPN22 1858T variant was further associated with significantly diminished BCR signaling and a resistance to apoptosis in both transitional and naive B cells. Strikingly, parallel changes in both BCR signaling and composition of B cell compartment were observed in type 1 diabetic subjects, irrespective of PTPN22 genotype, revealing a novel immune phenotype and likely shared mechanisms leading to a loss of B cell tolerance. Our combined findings suggest that Lyp620W-mediated effects, due in part to the altered BCR signaling threshold, contribute to breakdown of peripheral tolerance and the entry of autoreactive B cells into the naive B cell compartment. The Journal of Immunology, 2012, 188: 487-496.
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