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Loss of Anergic B Cells in Prediabetic and New-Onset Type 1 Diabetic Patients

Although dogma predicts that under normal circumstances, potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, islet antigen–reactive B lymphocytes are known to play a crucial role in the development of autoimmunity in type 1 diabetes (T1D). Thus, participation of...

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Autores principales: Smith, Mia J., Packard, Thomas A., O’Neill, Shannon K., Henry Dunand, Carole J., Huang, Min, Fitzgerald-Miller, Lisa, Stowell, Daniel, Hinman, Rochelle M., Wilson, Patrick C., Gottlieb, Peter A., Cambier, John C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407867/
https://www.ncbi.nlm.nih.gov/pubmed/25524915
http://dx.doi.org/10.2337/db13-1798
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author Smith, Mia J.
Packard, Thomas A.
O’Neill, Shannon K.
Henry Dunand, Carole J.
Huang, Min
Fitzgerald-Miller, Lisa
Stowell, Daniel
Hinman, Rochelle M.
Wilson, Patrick C.
Gottlieb, Peter A.
Cambier, John C.
author_facet Smith, Mia J.
Packard, Thomas A.
O’Neill, Shannon K.
Henry Dunand, Carole J.
Huang, Min
Fitzgerald-Miller, Lisa
Stowell, Daniel
Hinman, Rochelle M.
Wilson, Patrick C.
Gottlieb, Peter A.
Cambier, John C.
author_sort Smith, Mia J.
collection PubMed
description Although dogma predicts that under normal circumstances, potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, islet antigen–reactive B lymphocytes are known to play a crucial role in the development of autoimmunity in type 1 diabetes (T1D). Thus, participation of these cells in T1D may reflect escape from silencing mechanisms. Consistent with this concept, we found that in healthy subjects, high-affinity insulin-binding B cells occur exclusively in the anergic naive IgD(+), IgM(−) B-cell (B(ND)) compartment. Antigen receptors expressed by these cells are polyreactive and have N-region additions, Vh usage, and charged complementarity-determining region 3 consistent with autoreactivity. Consistent with a potential early role in autoimmunity, these high-affinity insulin-binding B cells are absent from the anergic compartment of some first-degree relatives and all prediabetic and new-onset (<1 year) T1D patients tested, but return to normal levels in individuals diabetic for >1 year. Interestingly, these changes were correlated by transient loss of the entire B(ND) compartment. These findings suggest that environmental events such as infection or injury may, by disrupting B-cell anergy, dispose individuals toward autoimmunity, the precise nature of which is specified by genetic risk factors, such as HLA alleles.
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spelling pubmed-44078672016-05-01 Loss of Anergic B Cells in Prediabetic and New-Onset Type 1 Diabetic Patients Smith, Mia J. Packard, Thomas A. O’Neill, Shannon K. Henry Dunand, Carole J. Huang, Min Fitzgerald-Miller, Lisa Stowell, Daniel Hinman, Rochelle M. Wilson, Patrick C. Gottlieb, Peter A. Cambier, John C. Diabetes Immunology and Transplantation Although dogma predicts that under normal circumstances, potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, islet antigen–reactive B lymphocytes are known to play a crucial role in the development of autoimmunity in type 1 diabetes (T1D). Thus, participation of these cells in T1D may reflect escape from silencing mechanisms. Consistent with this concept, we found that in healthy subjects, high-affinity insulin-binding B cells occur exclusively in the anergic naive IgD(+), IgM(−) B-cell (B(ND)) compartment. Antigen receptors expressed by these cells are polyreactive and have N-region additions, Vh usage, and charged complementarity-determining region 3 consistent with autoreactivity. Consistent with a potential early role in autoimmunity, these high-affinity insulin-binding B cells are absent from the anergic compartment of some first-degree relatives and all prediabetic and new-onset (<1 year) T1D patients tested, but return to normal levels in individuals diabetic for >1 year. Interestingly, these changes were correlated by transient loss of the entire B(ND) compartment. These findings suggest that environmental events such as infection or injury may, by disrupting B-cell anergy, dispose individuals toward autoimmunity, the precise nature of which is specified by genetic risk factors, such as HLA alleles. American Diabetes Association 2015-05 2014-12-18 /pmc/articles/PMC4407867/ /pubmed/25524915 http://dx.doi.org/10.2337/db13-1798 Text en © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Immunology and Transplantation
Smith, Mia J.
Packard, Thomas A.
O’Neill, Shannon K.
Henry Dunand, Carole J.
Huang, Min
Fitzgerald-Miller, Lisa
Stowell, Daniel
Hinman, Rochelle M.
Wilson, Patrick C.
Gottlieb, Peter A.
Cambier, John C.
Loss of Anergic B Cells in Prediabetic and New-Onset Type 1 Diabetic Patients
title Loss of Anergic B Cells in Prediabetic and New-Onset Type 1 Diabetic Patients
title_full Loss of Anergic B Cells in Prediabetic and New-Onset Type 1 Diabetic Patients
title_fullStr Loss of Anergic B Cells in Prediabetic and New-Onset Type 1 Diabetic Patients
title_full_unstemmed Loss of Anergic B Cells in Prediabetic and New-Onset Type 1 Diabetic Patients
title_short Loss of Anergic B Cells in Prediabetic and New-Onset Type 1 Diabetic Patients
title_sort loss of anergic b cells in prediabetic and new-onset type 1 diabetic patients
topic Immunology and Transplantation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407867/
https://www.ncbi.nlm.nih.gov/pubmed/25524915
http://dx.doi.org/10.2337/db13-1798
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