The recruitment of extra-intestinal cells to the injured mucosa promotes healing in radiation enteritis and chemical colitis in a mouse parabiosis model.

Mucosal healing occurs through migration and proliferation of cells within injured epithelium, yet these processes may be inadequate for mucosal healing after significant injury where the mucosa is denuded. We hypothesize that extra-intestinal cells can contribute to mucosal healing after injury to the small and large intestine. We generated parabiotic pairs between wild-type and tdTomato mice, which were then subjected to radiation-induced enteritis and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. We now show that as compared with singleton mice, mice with a parabiotic partner were protected against intestinal damage as revealed by significantly reduced weight loss, reduced expression of pro-inflammatory cytokines, reduced enterocyte apoptosis, and improved crypt proliferation. Donor cells expressed CD45-, Sca-1+, c-kit+, and CXCR4+ and accumulated around the injured crypts but did not transdifferentiate into epithelia, suggesting that extra-intestinal cells play a paracrine role in the healing response, while parabiotic pairings with Rag1-/- mice showed improved healing, indicating that adaptive immune cells were dispensable for mucosal healing. Strikingly, ablation of the bone marrow of the donor parabionts removed the protective effects. These findings reveal that the recruitment of extra-intestinal, bone marrow-derived cells into the injured intestinal mucosa can promote mucosal healing, suggesting novel therapeutic approaches for severe intestinal disease.

Susceptibility to autoimmune myocarditis is associated with intrinsic differences in CD4(+) T cells.

A.SW and B10.S mice share the same major histocompatibility complex (MHC) haplotype (H-2(s)). However, A.SW mice are susceptible to experimental autoimmune myocarditis (EAM) and develop severe disease after immunization with myosin, whereas B10.S mice are resistant. We found that naive A.SW mice have intrinsically increased total CD4(+) T cell counts and increased proportions of CD4(+) T cells in their spleens compared to B10.S mice. Among total CD4(+) T cells, naive A.SW mice have a lower relative frequency of forkhead box protein 3 (FoxP3(+))CD25(+) regulatory T cells (T(regs)). A.SW mice also had a higher proportion of CD4(+) T cells and a lower proportion of T(regs) in their hearts and spleen during EAM, with greater T cell activation and proliferation, compared to B10.S mice. These differences in the T cell compartment were not antigen-specific, as ovalbumin/complete Freund's adjuvant (OVA/CFA) or CFA immunization elicited the same differences in CD4(+) T cells and T(regs) between A.SW and B10.S mice. Moreover, A.SW mice had more T helper type 17 (Th17) cells and B10.S had more Th1 cells in their hearts. The higher percentage of CD4(+) T cells and their enhanced potential to differentiate towards the Th17 pathway was also observed in naive A.SW mice. Interleukin (IL)-6 is required for Th17 induction. Interestingly, IL-6Rα expression was greater on naive A.SW CD4(+) T cells, compared to B10.S CD4(+) T cells, indicating that this intrinsic difference, together with a relatively lower T(reg) proportion of CD4(+) T cells, might lead to heightened Th17 responses and greater susceptibility to autoimmunity in A.SW mice.

Sjögren syndrome: advances in the pathogenesis from animal models.

Sjögren syndrome is an autoimmune disease characterized by hyposecretion of the lacrimal and salivary glands, resulting in dryness of the eyes and mouth. Individuals may experience primary Sjögren syndrome or a secondary form accompanying another rheumatic autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus. The pathogenic mechanisms of Sjögren syndrome remain largely unknown, in part a consequence of the heterogeneity of the disease. Animal models have shed light on the connections between specific pathways and symptoms, but an ideal system is wanting. Improved disease models will enable a better understanding of Sjögren syndrome, including how immune tolerance is lost and potential therapeutic interventions. Most importantly, an optimal model will enable detection of disease biomarkers, since injury to the salivary glands may precede lymphocytic infiltration. This review aims to characterize available mice models of Sjögren syndrome, including advantages and disadvantages, from the researcher's perspective.

Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive disorder that results in several autoimmune diseases due to the mutations in the AIRE (autoimmune regulator) gene. APECED patients develop several autoimmune endocrine disorders and are characterized by the high titer autoantibodies to organ-specific antigens such as the steroidogenic P450 cytochromes. So far, 38 mutations have been identified in the AIRE gene. We report here the genetic and autoantibody analysis of 27 APECED patients of Eastern and Central European origins and one Egyptian patient. From 54 analyzed APECED chromosomes, eight mutations were detected, four of which (T16M, W78R, IVS1_IVS4, 30-53dup23bp) are novel. The most prevalent reason for APECED in these populations was the occurrence of R257X (36 chromosomes) that has been described earlier as a common and recurrent mutation in several other populations. The analysis of humoral immunity to steroidogenic P450 cytochromes by the immunoblotting of E. coli expressed antigens in the 18 APECED patients showed that 67%, 44%, and 61% of the Eastern and Central European APECED patients had autoantibodies to P450c17, P450c21, and P450scc, respectively.