Decoy receptor 3 (DCR3) halts both Fas ligand– and LIGHT-induced cell deaths, which are required for pancreatic β cell damage in autoimmune diabetes. To directly investigate the therapeutic potential of DCR3 in preventing this disease, we generated transgenic nonobese diabetic mice, which overexpressed DCR3 in β cells. Transgenic DCR3 protected mice from autoimmune and cyclophosphamide-induced diabetes in a dose-dependent manner and significantly reduced the severity of insulitis. Local expression of the transgene did not alter the diabetogenic properties of systemic lymphocytes or the development of T helper 1 or T regulatory cells. The transgenic islets had a higher transplantation success rate and survived for longer than wild-type islets. We have demonstrated for the first time that the immune-evasion function of DCR3 inhibits autoimmunity and that genetic manipulation of grafts may improve the success and survival of islet transplants.

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Background & Aims Autoimmune pancreatitis (AIP) underlies 5%–11% of cases of chronic pancreatitis. An association between AIP and the HLA-DRB1* 0405/DQB1*0401 haplotype has been reported, but linkage disequilibrium has precluded the identification of predisposing HLA gene(s). We studied the role of single HLA genes in the development of AIP in transgenic mice. Methods CD4+ T cell-negative I-Aβ chain−/− (Ab0) mice develop AIP spontaneously, likely due to dysregulation of CD8+ T cell responses. We generated Ab0 NOD mice transgenic for HLA-DR*0405, leading to rescue of CD4+ T cells; we compared their susceptibility to AIP with HLA-DQ8 or HLA-DR* 0401 (single) transgenic, or HLA-DR*0405/DQ8 (double) transgenic mice. Results CD4+ T cell-competent HLA-DR*0405 transgenic Ab0 NOD mice develop AIP with high prevalence after sublethal irradiation and adoptive transfer of CD90+ T cells, leading to complete pancreatic atrophy. HLA-DR* 0405 transgenic mice can also develop unprovoked AIP, whereas HLA-DR* 0401, HLA-DQ8 and HLA-DR*0405/DQ8 transgenic Ab0 NOD controls all remained normal, even after irradiation and adoptive transfer of CD90+ T cells. Pancreas histology in HLA-DR*0405 transgenic mice was characterized by destructive infiltration of the exocrine tissue with CD4+ and CD8+ T cells, B cells and macrophages. Mice with complete pancreatic atrophy lost weight, developed fat stools, and had reduced levels of serum lipase activity. Conclusions Since HLA-DR*0405 expression fails to protect mice from AIP, the HLA-DRB1*0405 allele appears to be an important risk factor for AIP on the HLA-DRB1*0405/DQB1*0401 haplotype. This humanized mouse model should be useful for studying immunopathogenesis, diagnostic markers, and therapy of human AIP.

Background Mutations in the PB1 subunit of RNA-dependent RNA polymerase (RdRp) of influenza A virus can affect replication fidelity. Before the influenza A/H1N1 pandemic in 2009, most human influenza A/H1N1 viruses contained the avian-associated residue, serine, at position 216 in PB1. However, near the onset of the 2009 pandemic, human viruses began to acquire the mammalian-associated residue, glycine, at PB1–216, and PB1–216G became predominant in human viruses thereafter. Methods Using entropy-based analysis algorithm, we have previously identified several host-specific amino-acid signatures that separated avian and swine viruses from human influenza viruses. The presence of these host-specific signatures in human influenza A/H1N1 viruses suggested that these mutations were the result of adaptive genetic evolution that enabled these influenza viruses to circumvent host barriers, which resulted in cross-species transmission. We investigated the biological impact of this natural avian-to-mammalian signature substitution at PB1–216 in human influenza A/H1N1 viruses. Results We found that PB1–216G viruses had greater mutation potential, and were more sensitive to ribavirin than PB1–216S viruses. In oseltamivir-treated HEK293 cells, PB1–216G viruses generated mutations in viral neuraminidase at a higher rate than PB1–216S viruses. By contrast, PB1–216S viruses were more virulent in mice than PB1–216G viruses. These results suggest that the PB1-S216G substitution enhances viral epidemiological fitness by increasing the frequency of adaptive mutations in human influenza A/H1N1 viruses. Conclusions Our results thus suggest that the increased adaptability and epidemiological fitness of naturally arising human PB1–216G viruses, which have a canonical low-fidelity replicase, were the biological mechanisms underlying the replacement of PB1–216S viruses with a high-fidelity replicase following the emergence of pdmH1N1. We think that continued surveillance of such naturally occurring PB1–216 variants among others is warranted to assess the potential impact of changes in RdRp fidelity on the adaptability and epidemiological fitness of human A/H1N1 influenza viruses. Electronic supplementary material The online version of this article (10.1186/s12929-019-0547-4) contains supplementary material, which is available to authorized users.

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