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Rodriguez-Calvo, T. ; Laiho, J.E.* ; Oikarinen, M.* ; Akhbari, P.* ; Flaxman, C.* ; Worthington, T.* ; Apaolaza Gallegos, S.P. ; Kaddis, J.S.* ; Kusmartseva, I.* ; Tauriainen, S.* ; Campbell-Thompson, M.* ; Atkinson, M.A.* ; von Herrath, M.* ; Hyöty, H.* ; Morgan, N.G.* ; Pugliese, A.* ; Richardson, S.J.*

Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes.

Diabetologia 68, 1197-1210 (2025)

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AIMS/HYPOTHESIS: Earlier studies of pancreases from donors with type 1 diabetes demonstrated enteroviral capsid protein VP1 in beta cells. In the context of a multidisciplinary approach undertaken by the nPOD-Virus group, we assessed VP1 positivity in pancreas and other tissues (spleen, duodenum and pancreatic lymph nodes) from 188 organ donors, including donors with type 1 diabetes and donors expressing autoantibody risk markers. We also investigated whether VP1 positivity is linked to the hyperexpression of HLA class I (HLA-I) molecules in islet cells. METHODS: Organ donor tissues were collected by the Network for Pancreatic Organ Donors with Diabetes (nPOD) from donors without diabetes (ND, n=76), donors expressing a single or multiple diabetes-associated autoantibodies (AAb⁺, n=20; AAb⁺⁺, n=9) and donors with type 1 diabetes with residual insulin-containing islets (T1D-ICIs, n=41) or only insulin-deficient islets (T1D-IDIs, n=42). VP1 was assessed using immunohistochemistry (IHC) and HLA-I using IHC and immunofluorescence, in two independent laboratories. We determined assay concordance across laboratories and overall occurrence of positive assays, on a case-by-case basis and between donor groups. RESULTS: Islet cell VP1 positivity was detected in most T1D-ICI donors (77.5%) vs only 38.2% of ND donors (p<0.001). VP1 positivity was associated with HLA-I hyperexpression. Of those donors assessed for HLA-I and VP1, 73.7% had both VP1 immunopositivity and HLA-I hyperexpression (p<0.001 vs ND). Moreover, VP1⁺ cells were detected at higher frequency in donors with HLA-I hyperexpression (p<0.001 vs normal HLA-I). Among VP1⁺ donors, the proportion with HLA-I hyperexpression was significantly higher in the AAb⁺⁺ and T1D-ICI groups (94.9%, p<0.001 vs ND); this was not restricted to individuals with recent-onset diabetes. Critically, for all donor groups combined, HLA-I hyperexpression occurred more frequently in VP1⁺ compared with VP1^- donors (45.8% vs 16%, p<0.001). CONCLUSIONS/INTERPRETATION: We report the most extensive analysis to date of VP1 and HLA-I in pancreases from donors with preclinical and diagnosed type 1 diabetes. We find an association of VP1 with residual beta cells after diagnosis and demonstrate VP1 positivity during the autoantibody-positive preclinical stage. For the first time, we show that VP1 positivity and HLA-I hyperexpression in islet cells are both present during the preclinical stage. While the study of tissues does not allow us to demonstrate causality, our data support the hypothesis that enterovirus infections may occur throughout the natural history of type 1 diabetes and may be one of multiple mechanisms driving islet cell HLA-I hyperexpression.

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