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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.00903

MAdCAM-1-mediated intestinal lymphocyte homing is critical for the development of active experimental autoimmune encephalomyelitis

 Kristina Kuhbandner1, 2, Anna Hammer1, 2, Stefanie Haase1, 2, Elisa Terbrack1, 2, Alana Hoffmann3,  Angela Schippers4, Norbert Wagner4, Rehana Z. Hussain5, William A. Miller-Little5,  Andrew Y. Koh5, Joshua S. Stoolman6, Benjamin M. Segal6, Ralf A. Linker7 and  Olaf Stuve5, 8*
  • 1Department of Neurology, University Hospital Erlangen, Germany
  • 2University of Erlangen Nuremberg, Germany
  • 3Department of Molecular Neurology, University Hospital Erlangen, Germany
  • 4Department of Pediatrics, University Hospital RWTH Aachen, Germany
  • 5Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, United States
  • 6Department of Neurology, School of Medicine, University of Michigan, United States
  • 7Department of Neurology, University of Regensburg, Germany
  • 8Neurology Section, VA North Texas Health Care System, United States

Lymphocyte homing into the intestine is mediated by binding of leukocytes to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), expressed on endothelial cells. Currently, the immune system of the gut is considered a major modulator not only of inflammatory bowel disease, but also of extra-intestinal autoimmune disorders, including multiple sclerosis (MS). Despite of intense research in this field, the exact role of the intestine in the pathogenesis of (neuro-)inflammatory disease conditions remains to be clarified. This prompted us to investigate the role of MAdCAM-1 in immunological processes in the intestine during T cell mediated autoimmunity of the central nervous system (CNS). Using the experimental autoimmune encephalomyelitis model of MS, we show that MAdCAM-1 deficient (MAdCAM-1-KO) mice are less susceptible to actively MOG35-55-induced disease. Protection from disease was accompanied by decreased numbers of immune cells in the lamina propria and Peyer’s patches as well as reduced immune cell infiltration into the spinal cord. MOG35-55-recall responses were intact in other secondary lymphoid organs of MAdCAM-1-KO mice. The composition of specific bacterial groups within the microbiome did not differ between MAdCAM-1-KO mice and controls, while MAdCAM-1 deficiency severely impaired migration of MOG35-55 activated lymphocytes to the gut. Our data indicate a critical role of MAdCAM-1 in the development of CNS inflammation by regulating lymphocyte homing to the intestine, and may suggest a role for the intestinal tract in educating lymphocytes to become encephalitogenic.

Keywords: MAdCAM-1, Lymphocyte homing, intestine, EAE (experimental autoimmune encephalomyelitis), multiple sclerois, Neuroinflammation

Received: 01 Oct 2018; Accepted: 08 Apr 2019.

Edited by:

Scott S. Zamvil, University of California, San Francisco, United States

Reviewed by:

Lawrence Steinman, Stanford University, United States
Martin S. Weber, University Medical Center Göttingen, Germany  

Copyright: © 2019 Kuhbandner, Hammer, Haase, Terbrack, Hoffmann, Schippers, Wagner, Hussain, Miller-Little, Koh, Stoolman, Segal, Linker and Stuve. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Olaf Stuve, University of Texas Southwestern Medical Center, Department of Neurology and Neurotherapeutics, Dallas, 75390, Texas, United States, Olaf.Stuve@UTSouthwestern.edu