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

2014; American Diabetes Association; Volume: 64; Issue: 5 Linguagem: Inglês

10.2337/db13-1798

1939-327X

Mia J. Smith, Thomas Packard, Shannon O’Neill, Carole J. Henry Dunand, Min Huang, Lisa Fitzgerald-Miller, Daniel Stowell, Rochelle M. Hinman, Patrick C. Wilson, Peter A. Gottlieb, John C. Cambier,

Pancreatic function and diabetes

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 (BND) 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 BND 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.