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2. Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects

Author

Rigoni, R, Fontana, E, Guglielmetti, S, Fosso, B, D'Erchia, A, Maina, V, Taverniti, V, Castiello, M, Mantero, S, Pacchiana, G, Musio, S, Pedotti, R, Selmi, C, Rodrigo Mora, J, Pesole, G, Vezzoni, P, Poliani, P, Grassi, F, Villa, A, Cassani, B, Rigoni R., Fontana E., Guglielmetti S., Fosso B., D'Erchia A. M., Maina V., Taverniti V., Castiello M. C., Mantero S., Pacchiana G., Musio S., Pedotti R., Selmi C., Rodrigo Mora J., Pesole G., Vezzoni P., Poliani P. L., Grassi F., Villa A., Cassani B., Rigoni, R, Fontana, E, Guglielmetti, S, Fosso, B, D'Erchia, A, Maina, V, Taverniti, V, Castiello, M, Mantero, S, Pacchiana, G, Musio, S, Pedotti, R, Selmi, C, Rodrigo Mora, J, Pesole, G, Vezzoni, P, Poliani, P, Grassi, F, Villa, A, Cassani, B, Rigoni R., Fontana E., Guglielmetti S., Fosso B., D'Erchia A. M., Maina V., Taverniti V., Castiello M. C., Mantero S., Pacchiana G., Musio S., Pedotti R., Selmi C., Rodrigo Mora J., Pesole G., Vezzoni P., Poliani P. L., Grassi F., Villa A., and Cassani B.

Abstract

Omenn syndrome (OS) is caused by hypomorphic Rag mutations and characterized by a profound immunodeficiency associated with autoimmune-like manifestations. Both in humans and mice, OS is mediated by oligoclonal activated T and B cells. The role of microbial signals in disease pathogenesis is debated. Here, we show that Rag2R229Q knock-in mice developed an inflammatory bowel disease affecting both the small bowel and colon. Lymphocytes were sufficient for disease induction, as intestinal CD4 T cells with a Th1/Th17 phenotype reproduced the pathological picture when transplanted into immunocompromised hosts. Moreover, oral tolerance was impaired in Rag2R229Q mice, and transfer of wild-type (WT) regulatory T cells ameliorated bowel inflammation. Mucosal immunoglobulin A (IgA) deficiency in the gut resulted in enhanced absorption of microbial products and altered composition of commensal communities. The Rag2R229Q microbiota further contributed to the immunopathology because its transplant into WT recipients promoted Th1/Th17 immune response. Consistently, long-term dosing of broad-spectrum antibiotics (ABXs) in Rag2R229Q mice ameliorated intestinal and systemic autoimmunity by diminishing the frequency of mucosal and circulating gut-tropic CCR9+ Th1 and Th17 T cells. Remarkably, serum hyper-IgE, a hallmark of the disease, was also normalized by ABX treatment. These results indicate that intestinal microbes may play a critical role in the distinctive immune dysregulation of OS.

Published
2016

3. Dendritic cell migration and lymphocyte homing imprinting

Author

Villablanca, Eduardo J., Russo, Vicenzo, and Rodrigo Mora, J.

Subjects
616 - Patología. Medicina clínica. Oncología, Homing, Dendritic cells
Abstract

For an effective adaptive immune response to occur, dendritic cells (DC), which are the most efficient antigen-presenting cells, must be able to sample the peripheral microenvironment and migrate towards secondary lymphoid organs (SLO) where they activate naïve lymphocytes. Upon activation, lymphocytes proliferate and acquire the capacity to migrate to extralymphoid compartments. Although the molecular mechanisms controlling lymphocyte homing to lymphoid and to some extralymphoid tissues have been described in significant detail, it is much less clear how DC migration is controlled. Do DC obey similar adhesion cues that lymphocytes do, or do they have their own “zip codes”? This is relevant from a therapeutic standpoint because effective DC-based vaccines should be able to reach the appropriate tissues in order to generate protective immune responses. Here, we discuss some of the mechanisms used by DC to reach their target tissues. Once DC arrive at their destination, they are exposed to the tissue microenvironment, which likely modulates their functional properties in a tissue-specific fashion. This local DC “education” is probably responsible among other things; for the acquisition of tissue-specific homing imprinting capacity by which DC instruct lymphocytes to migrate to specific tissues. Finally, we discuss how dysregulation of these signals may play a key role in disease.

Published
2008

5. β7 integrins are required to give rise to intestinal mononuclear phagocytes with tolerogenic potential.

Author

Villablanca, Eduardo J., De Calisto, Jaime, Paredes, Patricia Torregrosa, Cassani, Barbara, Nguyen, Deanna D., Gabrielsson, Susanne, and Rodrigo Mora, J.

Subjects
INTEGRINS, GLYCOPROTEINS, IMMUNE system, MACROPHAGES, CELL adhesion molecules
Abstract

Background and objective While pro-inflammatory monocyte trafficking to the intestine has been partially characterised, the molecules required for migration of tolerogenic mononuclear phagocytes (dendritic cells (DC) and macrophages) are unknown. We hypothesised that the gut-homing receptor integrin α4β7 is required for this process. Methods We used a T cell-mediated colitis model to study the role of α4β7 in the innate immune compartment. We then performed competitive bone marrow (BM) reconstitution experiments to assess the requirement of α4β7 in the generation of intestinal retinoic acid (RA)-producing CD11chi DC (ALDE+DC) and CD64 macrophages. Using mixed BM chimeras we also asked whether α4β7 is required to give rise to tolerogenic mononuclear phagocytes. Results Lack of β7 integrins in the innate immune compartment (β7-/-RAG2-/- mice) markedly accelerated T cell-mediated colitis, which was correlated with lower numbers and frequencies of ALDE+DC in mesenteric lymph nodes. Consistent with a role of α4β7 in the generation of intestinal mononuclear phagocytes, BM cells from β7-/- mice poorly reconstituted small intestine ALDE+DC and Mϕ when compared to their wild type counterparts. In addition, mice lacking β7 integrins in the CD11chi compartment showed decreased ability to induce Foxp3+ TREG and IL-10-producing T cells. Conclusions Mice lacking β7 integrins in the innate immune compartment are more susceptible to intestinal inflammation, which is correlated with a requirement of β7 integrins to reconstitute gut mononuclear phagocytes with tolerogenic potential. [ABSTRACT FROM AUTHOR]

Published
2014
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6. Vitamin effects on the immune system: vitamins A and D take centre stage.

Author

Rodrigo Mora, J., Iwata, Makoto, von Andrian, Ulrich H., and Mora, J Rodrigo

Subjects
*VITAMINS in human nutrition, *IMMUNOREGULATION, *VITAMIN A, *VITAMIN D, *IMMUNOLOGY of inflammation, *AUTOIMMUNITY, *VITAMIN A metabolism, *VITAMIN D metabolism, *VITAMIN metabolism, *COMPARATIVE studies, *IMMUNE system, *IMMUNOTHERAPY, *LYMPHOCYTES, *RESEARCH methodology, *MEDICAL cooperation, *RESEARCH, *RESEARCH funding, *VITAMINS, *EVALUATION research
Abstract

Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. We present and discuss our current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response. Finally, we discuss the clinical potential of vitamin A and D metabolites for modulating tissue-specific immune responses and for preventing and/or treating inflammation and autoimmunity. [ABSTRACT FROM AUTHOR]

Published
2008
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