title: Altered B cell homeostasis is associated with type I diabetes and carriers of the PTPN22 allelic variant.
abstract: 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.
authors: Translational Research Program, Benaroya Research Institute, Seattle, WA 98101, USA.
authors: Tania
authors: T
authors: Habib
authors: Andrew
authors: A
authors: Funk
authors: Mary
authors: M
authors: Rieck
authors: Archana
authors: A
authors: Brahmandam
authors: Xuezhi
authors: X
authors: Dai
authors: Anil K
authors: AK
authors: Panigrahi
authors: Eline T
authors: ET
authors: Luning Prak
authors: Almut
authors: A
authors: Meyer-Bahlburg
authors: Srinath
authors: S
authors: Sanda
authors: Carla
authors: C
authors: Greenbaum
authors: David J
authors: DJ
authors: Rawlings
authors: Jane H
authors: JH
authors: Buckner
mesh_terms: D000483:Alleles; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D005260:Female; D005838:Genotype; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D008297:Male; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D011947:Receptors, Antigen, B-Cell; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22