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The relationship between methylation abnormality and autoimmune pancreatitis (AIP)-a representative IgG4-related disease-has not yet been elucidated. We identified SKI might have a significant methylation abnormality in AIP through methylation array analysis using the Illumina Infinium Human Methylation 450K BeadChip array, and investigated the relationship of SKI with AIP clinicopathological features. The methylation rate of SKI was assessed by quantitative SYBR green methylation-specific PCR, and the degree of SKI expression in tissue specimens was assessed by immunohistochemistry in 10 AIP cases, 14 cases of obstructive pancreatitis area in pancreatic ductal adenocarcinoma (PDA) without a history of AIP, and 9 normal pancreas (NP) cases. The SKI methylation ratio was significantly lower in AIP than in PDA and NP. Additionally, the immunohistochemical staining-index (SI) score for SKI was significantly higher in AIP than NP, although there was no significant difference between AIP and PDA. There was a strong negative correlation between SI score and SKI methylation ratio, and between the serum concentrations of IgG4 and the SKI methylation ratio. There was a moderate positive correlation between the serum concentrations of IgG4 and SI. SKI is thought to be an oncogene indicating that SKI hypomethylation and carcinogenesis might be linked to AIP. Furthermore, the correlation between serum concentrations of IgG4 and SKI methylation levels suggest SKI might be involved in the pathogenesis of AIP. However, the role of SKI has not been clearly elucidated. Further studies are needed to understand further the function of SKI., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Objectives: Autoimmune pancreatitis (AIP) is a representative IgG4-related and inflammatory disease of unknown etiology. To clarify mechanisms of carcinogenesis resulting from AIP, we focused on methylation abnormalities and KRAS mutations in AIP., Methods: Six tumor suppressor genes (NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16) that exhibited hypermethylation in pancreatic carcinoma were selected for quantitative SYBR green methylation-specific polymerase chain reaction in 10 AIP specimens, 10 pancreatic adenocarcinoma cases without history of AIP containing carcinoma areas (CAs) and noncarcinoma areas (NCAs), and 11 normal pancreas (NP) samples. KRAS mutation in codons 12, 13, and 61 were also investigated using direct sequencing., Results: Hypermethylation events (≥10%) were identified in NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16 in 1, 2, 2, 0, 2, and 0 CA cases, respectively, but not in these 6 candidate genes in AIP, NCA, and NP. However, the TFPI2 methylation ratio was significantly higher in AIP than NCA and NP. Direct sequencing results for KRAS showed no single-point mutations in AIP., Conclusions: These are the first studies characterizing methylation abnormalities in AIP. AIP's inflammatory condition may be related to carcinogenesis. Further study will elucidate methylation abnormalities associated with carcinogenesis in AIP.

Interleukin-17 (IL-17)-producing γδ T (γδ17) cells have been implicated in inflammatory diseases, but the underlying pathogenic mechanisms remain unclear. Here, we show that both CD4(+) and γδ17 cells are required for the development of autoimmune arthritis in IL-1 receptor antagonist (IL-1Ra)-deficient mice. Specifically, activated CD4(+) T cells direct γδ T-cell infiltration by inducing CCL2 expression in joints. Furthermore, IL-17 reporter mice reveal that the Vγ6(+) subset of CCR2(+) γδ T cells preferentially produces IL-17 in inflamed joints. Importantly, because IL-1Ra normally suppresses IL-1R expression on γδ T cells, IL-1Ra-deficient mice exhibit elevated IL-1R expression on Vγ6(+) cells, which play a critical role in inducing them to produce IL-17. Our findings demonstrate a pathogenic mechanism in which adaptive and innate immunity induce an autoimmune disease in a coordinated manner.

IL-1 receptor antagonist (IL-1Ra)-deficient mice spontaneously develop several inflammatory diseases, resembling rheumatoid arthritis, aortitis, and psoriasis in humans. As adoptive T cell transplantation could induce arthritis and aortitis in recipient mice, it was suggested that an autoimmune process is involved in the development of diseases. In contrast, as dermatitis developed in scid/scid-IL-IRa-deficient mice and could not be induced by T cell transfer, a T cell-independent mechanism was suggested. The expression of proinflammatory cytokines was augmented at the inflammatory sites. The development of arthritis and aortitis was significantly suppressed by the deficiency of TNFalpha or IL-17. The development of dermatitis was also inhibited by the deficiency of TNFalpha. These observations suggest that TNFalpha and IL-17 play a crucial role in the development of autoimmunity downstream of IL-1 signaling, and excess IL-1 signaling-induced TNFalpha also induces skin inflammation in a T cell-independent manner.

Introduction: A high proportion of IL-17-producing gamma-delta T (gd17) cells was detected in joints of Il1rn −/− mice, a model of rheumatoid arthritis, whose development depends on IL-17 and T cells. However, their pathogenic roles are not well understood. Methods: We assessed the effect of gdT cell or CD4+T cell depletion in Il1rn −/− mice using a monoclonal antibodies. Then, we examined the pathogenic activity of gd17 cells by adoptive transfer. Results: To clarify the roles of gdT cells and CD4+ T cells in the development of arthritis, gdT cells or CD4+ T cells were depleted in Il1rn −/− miceusing antibodies. The development of disease was suppressed in both cases, suggesting both gdT cells and CD4+ T cells were involved in the pathogenesis. Then, the pathogenic role of gd17 cells in the absence of Th17 cells was examined. We generated mice with gd17 cells, but without Th17 cells, by adoptively transferring Il17 −/− Il1rn −/−-CD4+ T cells into nu/nu mice in which gd17 cells are present. We found that these mice still developed arthritis and that only gdT cells produced IL-17. To corroborate that the development of arthritis in this transfer system is dependent on IL-17, we adoptively transferred Il17 −/− Il1rn −/−-CD4+ T cells into Il17 −/−-nu/nu mice. The development of arthritis was significantly suppressed in Il17 −/−-nu/nu mice transferred with Il17 −/− Il1rn −/−-CD4+ T cells compared with Il17 +/+-nu/nu mice transferred with Il17 −/− Il1rn −/−-CD4+ T cells, suggesting that extrathymic gd17 cells are also important for the development of arthritis. Interestingly, Il1rn −/− mice on the nu/nu mice background, in which only gd17 cells but not thymus-derived T cells are present, also developed arthritis. Thus, gd17 cells alone can induce arthritis without involvement of CD4+ T cells only in Il1rn −/− background mice in which excess IL-1 signaling is introduced. In contrast, a combination of CD4+ T cells and gd17 cells was required for the development of arthritis when scid/scid mice were used as recipients. These observations suggest that gd17 cells are required for the amplification of inflammation and CD4+ T cells direct the tissue specificity. Conclusion: These results indicate that gdT cell-derived IL-17 plays an important role in the pathogenesis of arthritis in Il1rn −/−mice. [Copyright &y& Elsevier]