Editorial: [Autoimmune Diabetes: Molecular Mechanisms and Neoantigens, Volume II]

Arnaud Zaldumbide¹Sally C. Kent^2*

• ¹Department of Anatomy and Embryology, Leiden University Medical Center (LUMC), Leiden, Netherlands
• ²Department of Medicine, University of Massachusetts Medical School, Worcester, United States

T cell on the stressed beta cells. While the development of therapies targeting beta-cell dysfunction/destruction and the autoimmune attack for T1D remains challenging, this increased understanding of these processes in individuals at-risk for or with T1D is beneficial.In this research topic, in one form of beta-cell stress, Muñoz García et al. highlighted the importance of the islet microenvironement in the amplification of the inflammation during T1D progression, showing that a strong chemokine signature (CXCL1, CXCL2, CXCL3, and CXCL10) is found from the ductal and cells expressing a ductal-acinar cell phenotype from control islets treated with inflammatory cytokines and from islets from two donors with T1D. Interestingly, they found that CXCL8 expressed by endocrine cells may have a functional effect on beta cells by decreasing insulin secretion. This propagation of the inflammatory signals has also been illustrated by Dekkers et al. who showed that knockdown of Heat Shock Protein Family A (HSPA5) which encodes BiP/GRP78 in a beta-cell line resulted in upregulation of pathways in the unfolded protein response (UPR), an ER stress response and also changed the as well as for collagen type II in rheumatoid arthritis (RA). The authors also highlight the opportunities in therapies to modulate the immune response to these PTMs. In Wenzlau et al. the authors examine another category of PTM neo-epitope, the hybrid insulin peptide (HIP), which is formed by the fusion of a fragment of insulin with another fragement of a beta-cell granule protein. Here, the authors use a monoclonal antibody (mAb) generated to the HIP of an insulin C-peptide fragment fused to a cleavage product of pro-islet amyloid polypeptide (6.9HIP) which the murine BDC-6.9 T cell clone recognizes.They used this mAb to follow HIP formation in the islets of the NOD mouse during disease progression and found that the mAb detected the 6.9HIP only in insulin-positive beta cells and in intra-islet antigenpresenting cells in infiltrated islets in advanced disease. Exposing NOD islets to ER stress with tunicamycin increased levels of 6.9HIPin crinosomes and dense-core granules fronthe beta cells.Finally, as a reminder that effective therapies may not be effective for all manifestations of the autoimmune disease and the need to understand the function of all immune cell populations in autoimmune diseases, Marasco et al. show that reductions in memory and switched memory B cells and significant expansions of CXCR5 -PD1 + T peripheral helper cells (Tph cells) correlate with RA patients with bone erosions on disease-modifying anti-rheumatic drugs (DMARDS).Altogether the different studies presented in this issue, provide novel insights in the role of cellular stress and its consequence in the development of autoimmuniy.