1. Academic Validation
  2. Smad7 in intestinal CD4+ T cells determines autoimmunity in a spontaneous model of multiple sclerosis

Smad7 in intestinal CD4+ T cells determines autoimmunity in a spontaneous model of multiple sclerosis

  • Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25860-25869. doi: 10.1073/pnas.1905955116.
Steffen Haupeltshofer 1 Teresa Leichsenring 1 Sarah Berg 1 Xiomara Pedreiturria 1 Stephanie C Joachim 2 Iris Tischoff 3 Jan-Michel Otte 4 Tobias Bopp 5 6 Massimo C Fantini 7 Charlotte Esser 8 Dieter Willbold 9 10 Ralf Gold 1 Simon Faissner 1 Ingo Kleiter 11 12
Affiliations

Affiliations

  • 1 St. Josef-Hospital, Department of Neurology, Ruhr-University Bochum, 44791 Bochum, Germany.
  • 2 University Eye Clinic, Experimental Eye Research Institute, Ruhr-University Bochum, 44892 Bochum, Germany.
  • 3 Institut für Pathologie, Bergmannsheil, 44789 Bochum, Germany.
  • 4 Department of Internal Medicine I, Klinikum Links der Weser, 28277 Bremen, Germany.
  • 5 Institute for Immunology, Universitätsmedizin Mainz, 55131 Mainz, Germany.
  • 6 Research Center for Immunotherapy (FZI), Universitätsmedizin Mainz, 55131 Mainz, Germany.
  • 7 Department of Systems Medicine, University of Rome "Tor Vergata," 00133 Roma RM, Italy.
  • 8 Leibniz-Institut für Umweltmedizinische Forschung, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • 9 Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • 10 Institute of Complex Systems (ICS-6), Forschungszentrum Jülich, 52425 Jülich, Germany.
  • 11 St. Josef-Hospital, Department of Neurology, Ruhr-University Bochum, 44791 Bochum, Germany; [email protected].
  • 12 Marianne-Strauss-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, 82335 Berg, Germany.
Abstract

Environmental triggers acting at the intestinal barrier are thought to contribute to the initiation of autoimmune disorders. The transforming growth factor beta inhibitor Smad7 determines the phenotype of CD4+ T cells. We hypothesized that Smad7 in intestinal CD4+ T cells controls initiation of opticospinal encephalomyelitis (OSE), a murine model of multiple sclerosis (MS), depending on the presence of gut microbiota. Smad7 was overexpressed or deleted in OSE CD4+ T cells to determine the effect on clinical progression, T cell differentiation, and T cell migration from the intestine to the central nervous system (CNS). Smad7 overexpression worsened the clinical course of OSE and increased CNS inflammation and demyelination. It favored expansion of intestinal CD4+ T cells toward an inflammatory phenotype and migration of intestinal CD4+ T cells to the CNS. Intestinal biopsies from MS patients revealed decreased transforming growth factor beta signaling with a shift toward inflammatory T cell subtypes. Smad7 in intestinal T cells might represent a valuable therapeutic target for MS to achieve immunologic tolerance in the intestine and suppress CNS inflammation.

Keywords

Smad7; T helper cell; TGF-beta; gut–brain axis; multiple sclerosis.

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