Résumé :
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Background. Duchenne muscular dystrophy (DMD) affects 1:3,500 male births, and is caused by mutations in the dystrophin gene. Even though the genetic mutation results in decreased resistance of muscle fibers, the immune response may contribute to disease progression, through the generation of deleterious inflammatory infiltrates. However, the molecular mechanisms involved in lymphocyte migration into the muscle remain unclear. Methods. We studied a cohort of 71 DMD patients at different stages of the disease, and assayed by multicolor cytofluorometry and immunohistochemistry the expression levels of CD49d (the a4 integrin chain of the fibronectin receptor VLA-4) in circulating and intramuscular T lymphocyte subsets. Additionally, we performed functional tests, which comprised transendothelial and fibronectin-driven migratory responses of blood-derived lymphocyte subsets in transwell chambers, as well as adhesion to human myotube monolayers. Results. Increased percentages of circulating CD4+ and CD8+ T lymphocytes expressing high levels of CD49d correlated with both the severity and a more rapid evolution of the disease. CD49d+CD4+ and CD49d+CD8+ cells were also found in muscular inflammatory infiltrates, particularly in fibronectin enriched niches. Moreover, T cells from patients either with rapid progression or in an advanced phase of the disease exhibited higher transendothelial and fibronectin-driven migratory responses (when compared with mildly affected patients or control individuals), and increased adhesion to myotubes. These migratory responses were largely blocked with an anti-CD49d monoclonal antibody. Conclusions. CD49d can be applied as a novel biomarker to predict disease progression in DMD patients. Moreover, inhibition of VLA-4-mediated interactions can be envisioned as a novel therapeutic strategy for ameliorating the disease course of DMD patients.Financial support: PAPES/Fiocruz, CAPES, CNPq (Brazil), United Parent's Project for Muscular Dystrophies (UPPMD ), Inserm, UPMC, CNRS, AFM, ANR (Genopath INAFIB), MyoAge (EC 7th FP, contract 223576),Inserm/Fiocruz and CNPq/Inserm Conjoint Programs. This work was developed in the context of the CNPq/Inserm/Fiocruz/UPMC International Associated Laboratory of Cell Therapy and Immunotherapy.
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