Hybrid peptides represent novel target for auto-reactive T cells in autoimmune diabetes

This week Science published intriguing study showing that in type I diabetic individuals hybrid peptides derived from two unrelated proteins represent novel auto-antigens.  

Initially, the authors showed that chemically cross-linked or synthetic peptide that is made one half of proinsulin C-peptide and another half from chromogranin A (ChgA) peptide (both β cell proteins), could activate diabetogenic mouse T cell clones.

Next, the authors showed that T cells specific for such hybrid peptides can be detected in un-manipulated diabetes susceptible NOD female mice (it would have been more informative if the authors have included data from non-susceptible WT mice as a control).

Finally, the authors showed in T cells from T1D individuals could also recognize hybrid peptide made of human proinsulin C-peptide and neuropeptide Y.

In summary, this study suggests that in T1D susceptible individuals, diabetogenic auto-antigens could be generated by fusion of peptide derived from two unrelated proteins (a side reaction of the proteolytic hydrolysis of peptide in secretory granules). Whether generation of such immunogenic hybrid peptides happens only T1D susceptible individuals remains to be determined.  

David Usharauli

Chromogranin A is a disease-driving auto-antigen in type I diabetes

Type I diabetes is autoimmune disease leading to destruction of insulin-secreting endocrine β islets in pancreas and glucose intolerance. NOD mouse strain represents well established model of human type I diabetes. So far, researchers identified several potential auto-antigens targeted by self-reactive T cells, out of which so far only mutation in insulin B chain (B:9–23) showed effect on disease progression.

Now, this Cutting Edge study in Journal Immunology showed that absence of another auto-antigen, Chromogranin A (ChgA), fully protected NOD mice from diabetes development.

First, the authors showed that β islets of NOD.ChgA^-/- could not activate ChgA-specific T cell clones in an in vitro assay (reactivity to other auto-antigens insulin and IAPP was intact).

Importantly, the authors showed that NOD.ChgA^-/- mice were completely protected from development of diabetes [measured as excess of glucose in urine samples].

Finally, the authors showed that NOD.ChgA^-/- mice showed minimal β islets inflammation (insulitis) but developed comparable salivary gland inflammation (sialitis), implying that Chromogranin A effect was strictly β islets selective.

In summary, this study showed that at least Chromogranin A is necessary and sufficient for development of diabetes in NOD mice. Still, it is puzzling that NOD.ChgA^-/- mice is protected from diabetes when they still expressed another dominant auto-antigen insulin [because earlier study showed that NOD ins1^-/- ins2^-/- mice were protected from diabetes development too]. If both auto-antigens are "priming epitopes" then both NOD.ChgA^-/- and NOD ins1^-/- ins2^-/- mice should have developed diabetes. Strange.

David Usharauli