Loss of B-Cell Anergy in Type 1 Diabetes Is Associated With High-Risk HLA and Non-HLA Disease Susceptibility Alleles

• Published in: Diabetes (New York, N.Y.) Vol. 67; no. 4; pp. 697 - 703
• Main Authors: Smith, Mia J., Rihanek, Marynette, Wasserfall, Clive, Mathews, Clayton E., Atkinson, Mark A., Gottlieb, Peter A., Cambier, John C.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.04.2018
• Subjects: Affinity; Alleles; Allelopathy; Anergy; Autoantibodies; Autoantibodies - immunology; Autoantigens; B-Lymphocytes - immunology; Beta cells; Binding sites; Cell growth; Clonal Anergy - immunology; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Genetic factors; Genetic Predisposition to Disease; Genotype & phenotype; Genotypes; Histocompatibility antigen HLA; HLA-DQ Antigens - genetics; HLA-DR Antigens - genetics; Humans; Ikaros Transcription Factor - genetics; Immunological tolerance; Immunology and Transplantation; Insulin; Insulin - genetics; Islets of Langerhans; Lymphocytes T; Pancreas; Peripheral blood; Prediabetic State - genetics; Prediabetic State - immunology; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics; PTPN2 protein
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db17-0937

Although B cells reactive with islet autoantigens are silenced by tolerance mechanisms in healthy individuals, they can become activated and contribute to the development of type 1 diabetes. We previously demonstrated that high-affinity insulin-binding B cells (IBCs) occur exclusively in the anergic (BND) compartment in peripheral blood of healthy subjects. Consistent with their activation early in disease development, high-affinity IBCs are absent from the BND compartment of some first-degree relatives (FDRs) as well as all patients with autoantibody-positive prediabetes and new-onset type 1 diabetes, a time when they are found in pancreatic islets. Loss of BND IBCs is associated with a loss of the entire BND B-cell compartment consistent with provocation by an environmental trigger or predisposing genetic factors. To investigate potential mechanisms operative in subversion of B-cell tolerance, we explored associations between HLA and non-HLA type 1 diabetes–associated risk allele genotypes and loss of BNDs in FDRs. We found that high-risk HLA alleles and a subset of non-HLA risk alleles (i.e., PTPN2 [rs1893217], INS [rs689], and IKZF3 [rs2872507]), relevant to B- and T-cell development and function are associated with loss of anergy. Hence, the results suggest a role for risk-conferring alleles in perturbation of B-cell anergy during development of type 1 diabetes.