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Immunology and Transplantation

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

  1. Mia J. Smith1,2,
  2. Marynette Rihanek3,
  3. Clive Wasserfall4,
  4. Clayton E. Mathews4,
  5. Mark A. Atkinson4,5,
  6. Peter A. Gottlieb3 and
  7. John C. Cambier1⇑
  1. 1Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO
  2. 2Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO
  3. 3Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
  4. 4Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL
  5. 5Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL
  1. Corresponding author: John C. Cambier, john.cambier{at}ucdenver.edu.
Diabetes 2018 Apr; 67(4): 697-703. https://doi.org/10.2337/db17-0937
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Abstract

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.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db17-0937/-/DC1.

  • Received August 8, 2017.
  • Accepted January 12, 2018.
  • © 2018 by the American Diabetes Association.
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Loss of B-Cell Anergy in Type 1 Diabetes Is Associated With High-Risk HLA and Non-HLA Disease Susceptibility Alleles
Mia J. Smith, Marynette Rihanek, Clive Wasserfall, Clayton E. Mathews, Mark A. Atkinson, Peter A. Gottlieb, John C. Cambier
Diabetes Apr 2018, 67 (4) 697-703; DOI: 10.2337/db17-0937

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Loss of B-Cell Anergy in Type 1 Diabetes Is Associated With High-Risk HLA and Non-HLA Disease Susceptibility Alleles
Mia J. Smith, Marynette Rihanek, Clive Wasserfall, Clayton E. Mathews, Mark A. Atkinson, Peter A. Gottlieb, John C. Cambier
Diabetes Apr 2018, 67 (4) 697-703; DOI: 10.2337/db17-0937
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