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In multiple sclerosis, encephalitogenic CD4⁺ lymphocytes require adhesion molecules to accumulate into central nervous system inflammatory lesions. Using proteomic techniques, we identified expression of melanoma cell adhesion molecule (MCAM) on a subset of human effector memory CD4⁺ lymphocytes and on human blood–brain barrier endothelium. Herein, we demonstrate that MCAM is a stable surface marker that refines the identification of interleukin 17⁺, interleukin 22⁺, RAR-related orphan receptor γ and interleukin 23 receptor⁺ cells within the CD161⁺CCR6⁺ subset of memory CD4⁺ lymphocytes. We also show that MCAM⁺ lymphocytes express significantly more granulocyte/macrophage colony stimulating factor and granzyme B than MCAM⁻ lymphocytes. Furthermore, the proportion of MCAM⁺ CD4⁺ lymphocytes is significantly increased in the blood and in the central nervous system of …