A direct association between beta cell destruction was established with the discovery of islet autoreactive CD8 T cells in insulitic lesions from patients with T1D [
11]. Islets from patients with T1D also had hyper-expression of HLA class I molecules, indicating that during insulitis, beta cells could be active in their own demise by becoming easier targets for pathogenic CD8 T cells [
11]. Beta cells could be passive victims to autoimmune destruction (“Homicide” model) and/or actively contribute to their own demise (“Suicide” model), as was first conceived by Bottazzo [
12]. Supporting the “beta cell suicide” model is data showing production of the chemokine CXCL10 within distressed islets and expression of the cognate receptor CXCR3 on CD8 T cells in insulitic lesions in patients with T1D, indicating that the pancreas can actively recruit pathogenic CD8 T cells and communicate with the immune system [
13].
When considering the impact of PTM on the development and progression of T1D, it is important to consider the location and local activity of the modifying enzymes involved. PTM in celiac disease (CD) occurs in the intestinal lumen at the site where key substrates, such as gliadin peptides, are concentrated. Tissue transglutaminase (tTG) activity is increased in the mucosal epithelium of patients with CD [
14], and the ensuing cross talk between immune cells in the lamina propria during CD has been well studied [
15]. In human islets, tTG is active during insulin secretion, acting on cytosolic, mitochondrial, and nuclear substrates [
16]. Therefore, islets have the potential to generate neo-autoantigens through tTG-mediated deamidation. We recently confirmed that human islets generate neo-autoantigens; an inflammatory stimulus resulted in deamidation of the proinsulin C-peptide [
17•]. T cells reactive to this deamidated C-peptide were found in patients with T1D [
5••], linking neo-antigen generation in human islets with the induction of autoreactive T cells. tTG is also present in cells of the myeloid lineage [
18]. Direct vesicular transfer of islet material to resident APC has been demonstrated in both mice and humans, suggesting that islet proteins can be deamidated by tTG during antigen processing within the APC [
19]. Recent results extend these findings to T1D, as dendritic cells (DC) pulsed with native islet antigen 2 (IA-2) naturally processed and presented deamidated peptides from IA-2 [
17•]. Thus, it appears that tTG activity in both islets and DC contributes to islet neo-epitope formation. Besides the diverse subcellular localization of tTG, it is also a secreted, extracellular protein important for cell-extracellular matrix interactions [
20,
21]. However, the contribution of extracellular tTG to the deamidation of islet proteins within the pancreas has not yet been investigated. PAD expression and activity have not been investigated in human islets, but antigen presenting cells (APC), such as human monocytes and macrophages, contain both PAD2 and PAD4 transcripts and active PAD2 and PAD4, indicating that cells of the monocytic lineage have the potential to citrullinate self-proteins [
22]. Mouse APC from both splenic and thymic tissue can citrullinate and present citrullinated peptides to activate epitope-specific CD4 T cells, a process requiring autophagy [
23]. While not conclusive, these studies indicate that islet protein citrullination may occur in APC within human islets or in the draining lymph nodes.