Autoimmune neurologic diseases
Markus Schramm, M.D.
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston; Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Germany
Cysteinyl leukotrienes receptors CysLTR1 and CysLTR2 are members of a trans-membrane G-coupled receptor family known for its role in airway inflammation. They can mediate leukocyte chemotaxis, vascular leakage and endothelial cell migration upon binding of the cysteinyl leukotrienes (cysLTs) LTC4, LTD4 and LTE4. The particular role of CysLTR2 in T cell mediated immune responses, and its participation in autoimmune diseases has not been studied. We investigated the expression of CysLTR2 on murine CD4+ T helper cell subsets and found the highest expression on pathogenic Th17 cells.
These cells are important contributors to the pathogenesis of a variety of autoimmune diseases, including Multiple Sclerosis (MS). To elucidate the potential role of CysLTR2 in the pathogenesis of MS we used the murine model of experimental autoimmune encephalomyelitis (EAE). Immunizing CysLTR2-/- mice with MOG35-55 we demonstrated that deficiency of CysLTR2 led to ameliorated disease with lower degree of paralysis, histopathologically decreased number of inflammatory parenchymal and meningeal lesions and lower frequencies of CNS-infiltrating IFNg and IL-17A producing CD4+ T cells.
This clinical phenotype was reproducible in LTC4s-/- mice, which are lacking all CysLTs. To further establish if loss of CysLTR2 was T cell intrinsic we utilized MOG35-55 transgenic mice and could indeed recapitulate our findings from the global KO mice. Together these results show that CysLTR2 signaling on CD4 T cells is required for autoimmune CNS inflammation.
Therapeutic blocking antibodies selectively binding to CysLTR2 might therefore be a promising future therapy in inflammatory diseases of the CNS and other autoimmune diseases.