[HTML][HTML] CCR2+ CCR5+ T cells produce matrix metalloproteinase-9 and osteopontin in the pathogenesis of multiple sclerosis

W Sato, A Tomita, D Ichikawa, Y Lin… - The Journal of …, 2012 - journals.aai.org
W Sato, A Tomita, D Ichikawa, Y Lin, H Kishida, S Miyake, M Ogawa, T Okamoto, M Murata…
The Journal of Immunology, 2012journals.aai.org
Multiple sclerosis (MS) is a demyelinating disease of the CNS that is presumably mediated
by CD4+ autoimmune T cells. Although both Th1 and Th17 cells have the potential to cause
inflammatory CNS pathology in rodents, the identity of pathogenic T cells remains unclear in
human MS. Given that each Th cell subset preferentially expresses specific chemokine
receptors, we were interested to know whether T cells defined by a particular chemokine
receptor profile play an active role in the pathogenesis of MS. In this article, we report that …
Abstract
Multiple sclerosis (MS) is a demyelinating disease of the CNS that is presumably mediated by CD4+ autoimmune T cells. Although both Th1 and Th17 cells have the potential to cause inflammatory CNS pathology in rodents, the identity of pathogenic T cells remains unclear in human MS. Given that each Th cell subset preferentially expresses specific chemokine receptors, we were interested to know whether T cells defined by a particular chemokine receptor profile play an active role in the pathogenesis of MS. In this article, we report that CCR2+ CCR5+ T cells constitute a unique population selectively enriched in the cerebrospinal fluid of MS patients during relapse but not in patients with other neurologic diseases. After polyclonal stimulation, the CCR2+ CCR5+ T cells exhibited a distinct ability to produce matrix metalloproteinase-9 and osteopontin, which are involved in the CNS pathology of MS. Furthermore, after TCR stimulation, the CCR2+ CCR5+ T cells showed a higher invasive potential across an in vitro blood–brain barrier model compared with other T cells. Of note, the CCR2+ CCR5+ T cells from MS patients in relapse are reactive to myelin basic protein, as assessed by production of IFN-γ. We also demonstrated that the CCR6−, but not the CCR6+, population within CCR2+ CCR5+ T cells was highly enriched in the cerebrospinal fluid during MS relapse (p< 0.0005) and expressed higher levels of IFN-γ and matrix metalloproteinase-9. Taken together, we propose that autoimmune CCR2+ CCR5+ CCR6− Th1 cells play a crucial role in the pathogenesis of MS.
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