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

Abstract

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.

Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes

“…Eligible subjects were healthy controls who did not meet the American Diabetes Association criteria for classification of disease. Cells were stained and enriched for insulin-binding B cells, as previously described (17). Briefly, PBMC were stained with 0.1 μg of biotinylated insulin and other B cell surface antibodies/10 6 cells/25 μl of biotinylated insulin and other B cell surface antibodies, followed by streptavidin-Alexa Fluor 647.…”

“…Moreover, TCR overlap among pathogenic CD4 + effector T cells and protective Treg have yet to be investigated in human T1D. Likewise, B cell receptor (BCR) sequencing efforts have been limited overall (15,16) and, in particular, in patients with T1D (17), despite a known role for B cells in contributing to T1D through their capacity to present antigens (18).…”

“…Following our analysis of autoreactive T cells, we sought to characterize the BCR signature from pLN samples, as B cells are thought to play a key role in antigen presentation. We specifically limited the analysis of our immunosequencing data to IGH CDR3 (CDRH3) AA sequences of B cells that were isolated based on binding to an insulin antigen (IBC) adsorbent followed by single-cell sorting (17). Thirty-one IBC CDRH3 sequences were determined de novo from the peripheral blood of healthy subjects without diabetes.…”

CD4 T cell differentiation in type 1 diabetes

“…Interestingly, resistance to T reg suppression has been reported in both mice [77] and humans with T1D [89,90], although many other factors in addition to IL-21 are likely to contribute to this effect [91]. IL-21 is also known to play key roles in orchestrating T cell : B cell interactions, and this may be relevant in the light of the possible contribution of B cells to diabetes pathogenesis [92][93][94]. IL-21 can promote the formation of antibody-producing plasma cells [95,96], and can also instruct germinal centre B cell development by upregulating expression of the transcription factor B cell lymphoma 6 protein (Bcl6) [97,98].…”

Follicular T Helper Cells: A New Marker of Type 1 Diabetes Risk?

“…Recent work has revealed that diabetes is associated with loss of anergy in insulin-binding B cells (13), and skewing B-cell specificity toward islet antigens can promote diabetes in mouse models (14,15). Although it is not believed that B cells or autoantibodies directly trigger b-cell destruction, recent evidence suggests that a high relative frequency of B cells within inflamed islets is associated with more aggressive and earlier onset T1D (16).…”