title: The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans.
abstract: Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene polymorphisms are associated with many autoimmune diseases. The major risk allele encodes an R620W amino acid change that alters B cell receptor (BCR) signaling involved in the regulation of central B cell tolerance. To assess whether this PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s) encoding the PTPN22 R620W variant. We found that new emigrant/transitional and mature naive B cells from carriers of this PTPN22 risk allele contained high frequencies of autoreactive clones compared with those from non-carriers, revealing defective central and peripheral B cell tolerance checkpoints. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection before any onset of autoimmunity. In addition, gene array experiments analyzing mature naive B cells displaying PTPN22 risk allele(s) revealed that the association strength of PTPN22 for autoimmunity may be due not only to the impaired removal of autoreactive B cells but also to the upregulation of genes such as CD40, TRAF1, and IRF5, which encode proteins that promote B cell activation and have been identified as susceptibility genes associated with autoimmune diseases. These data demonstrate that early B cell tolerance defects in autoimmunity can result from specific polymorphisms and precede the onset of disease.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, 300 George Street, New Haven, Connecticut 06511, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Menard
authors.forename: David
authors.initials: D
authors.lastname: Saadoun
authors.forename: Isabelle
authors.initials: I
authors.lastname: Isnardi
authors.forename: Yen-Shing
authors.initials: YS
authors.lastname: Ng
authors.forename: Greta
authors.initials: G
authors.lastname: Meyers
authors.forename: Christopher
authors.initials: C
authors.lastname: Massad
authors.forename: Christina
authors.initials: C
authors.lastname: Price
authors.forename: Clara
authors.initials: C
authors.lastname: Abraham
authors.forename: Roja
authors.initials: R
authors.lastname: Motaghedi
authors.forename: Jane H
authors.initials: JH
authors.lastname: Buckner
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D000483:Alleles; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D007527:Isoenzymes; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22