Research ArticleMultiple Sclerosis

Activated leukocyte cell adhesion molecule regulates B lymphocyte migration across central nervous system barriers

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Science Translational Medicine  13 Nov 2019:
Vol. 11, Issue 518, eaaw0475
DOI: 10.1126/scitranslmed.aaw0475

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Crossing barriers

Increasing evidence supports a critical role for B lymphocytes in multiple sclerosis (MS). Extravasation of B lymphocytes into the central nervous system promotes disease initiation and progression, and B lymphocyte–targeting therapies have shown potential benefits in experimental models and clinical trials. However, the mechanisms mediating B lymphocyte extravasation are unclear. Now, Michel et al. show that the adhesion molecule ALCAM promoted B lymphocyte extravasation. ALCAM-expressing B cells were increased in serum and brain of patients with MS, and the frequency of ALCAM-expressing B lymphocytes correlated with disease severity in a mouse model of autoimmune encephalomyelitis. Blocking ALCAM reduced disease severity in mice.

Abstract

The presence of B lymphocyte–associated oligoclonal immunoglobulins in the cerebrospinal fluid is a classic hallmark of multiple sclerosis (MS). The clinical efficacy of anti-CD20 therapies supports a major role for B lymphocytes in MS development. Although activated oligoclonal populations of pathogenic B lymphocytes are able to traffic between the peripheral circulation and the central nervous system (CNS) in patients with MS, molecular players involved in this migration have not yet been elucidated. In this study, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM/CD166) identifies subsets of proinflammatory B lymphocytes and drives their transmigration across different CNS barriers in mouse and human. We also showcased that blocking ALCAM alleviated disease severity in animals affected by a B cell–dependent form of experimental autoimmune encephalomyelitis. Last, we determined that the proportion of ALCAM+ B lymphocytes was increased in the peripheral blood and within brain lesions of patients with MS. Our findings indicate that restricting access to the CNS by targeting ALCAM on pathogenic B lymphocytes might represent a promising strategy for the development of next-generation B lymphocyte–targeting therapies for the treatment of MS.

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