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

Smith, Mia J; Rihanek, Marynette; Wasserfall, Clive; Mathews, Clayton E; Atkinson, Mark A; Gottlieb, Peter A; Cambier, John C

Smith, Mia J; Rihanek, Marynette; Wasserfall, Clive; Mathews, Clayton E; Atkinson, Mark A; Gottlieb, Peter A; Cambier, John C.

Afiliação

Smith MJ; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.
Rihanek M; Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO.
Wasserfall C; Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
Mathews CE; Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL.
Atkinson MA; Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL.
Gottlieb PA; Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL.
Cambier JC; Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL.

Diabetes ; 67(4): 697-703, 2018 04.

Article em En | MEDLINE | ID: mdl-29343548

RESUMO

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.

Assuntos

Autoanticorpos/imunologia; Linfócitos B/imunologia; Anergia Clonal/imunologia; Diabetes Mellitus Tipo 1/imunologia; Estado Pré-Diabético/imunologia; Diabetes Mellitus Tipo 1/genética; Predisposição Genética para Doença; Antígenos HLA-DQ/genética; Antígenos HLA-DR/genética; Humanos; Fator de Transcrição Ikaros/genética; Insulina/genética; Ilhotas Pancreáticas; Estado Pré-Diabético/genética; Proteína Tirosina Fosfatase não Receptora Tipo 2/genética

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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Estado Pré-Diabético / Autoanticorpos / Linfócitos B / Anergia Clonal / Diabetes Mellitus Tipo 1 Tipo de estudo: Etiology_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Diabetes Ano de publicação: 2018 Tipo de documento: Article País de publicação: Estados Unidos

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