Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
PTPN22 Risk Allele Interferes with the Removal of Developing Autoreactive B Cells in Humans.
Saadoun1, David, Menard2, Laurence, Isnardi2, Isabelle, Ng3, Yen-shing, Meyers2, Greta, Abraham4, Clara, Moyaghedi5, Roja
Department of Internal Medicine and Laboratory I3 "Immunology, Immunopathology, Immunotherapy", UMR CNRS 7211, INSERM U959, Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, Paris 6, Paris
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA;, New haven
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA;, New Haven
Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06509, USA,, New Haven
Department of Pediatrics, Weill Medical College of Cornell University, New York, NY 10021, USA,, New York
Translational Research Program, Benaroya Research Institute, Seattle, WA 98101, USA,, Seattle
Feinstein Institute Medical Reschearch, Manhasset, NY
Yale University School of Medicine, New Haven, CT
Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene polymorphisms associate 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 the PTPN22 riskallele 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).
We found that new emigrant/transitional and mature naive B cells from PTPN22 risk allele carriers contained high frequencies of autoreactive clones compared to non-carrier donors, 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 naïve B cells displaying PTPN22 risk allele(s) revealed that the association strength of PTPN22 for autoimmunity may not only be due to the impaired removal of autoreactive B cells but also to the upregulation of genes such as CD40, TRAF1 and IRF5, which promote B cell activation and have been identified as susceptibility genes associated with autoimmune diseases.
We demonstrated that the PTPN22 risk allele interferes with the removal of developing autoreactive B cells and allows the accumulation of large numbers of self-reactive mature naïve B cells in the periphery.
To cite this abstract, please use the following information:
Saadoun, David, Menard, Laurence, Isnardi, Isabelle, Ng, Yen-shing, Meyers, Greta, Abraham, Clara, et al; PTPN22 Risk Allele Interferes with the Removal of Developing Autoreactive B Cells in Humans. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1743