Long-Term Decrease in VLA-4 Expression and Functional Impairment of Dendritic Cells during Natalizumab Therapy in Patients with Multiple Sclerosis

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From: PLoS ONE(Vol. 7, Issue 4)
Publisher: Public Library of Science
Document Type: Article
Length: 6,118 words
Lexile Measure: 1590L

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Author(s): Clara de Andrés 1 , * , Roseta Teijeiro 1 , Bárbara Alonso 2 , Francisco Sánchez-Madrid 3 , M. Luisa Martínez 2 , Juan Guzmán de Villoria 2 , Eduardo Fernández-Cruz 2 , Silvia Sánchez-Ramón 2


Multiple sclerosis (MS) is a multifocal chronic inflammatory perivascular demyelinating disease of the central nervous system (CNS) that is thought to be immune-mediated. Inflammatory infiltrates in MS lesions consist mainly of macrophages, CD8 cells, CD4 cells, and B cells, all of which play a role in the disease [1]. The most accepted hypothesis is that peripheral activated self-reactive lymphocytes invade the CNS through the blood-brain barrier (BBB) and, together with the resident microglia and/or dendritic cells (DCs), elicit local CNS immune responses and cause demyelination and damage to oligodendrocytes and axons [2]. DCs are central to the maintenance of immunological tolerance, as well as the initiation and regulation of immune responses. DCs, and plasmacytoid DCs (pDCs) in particular, are found in MS lesions [3] and are functionally altered in patients with MS [4], [5]. Circulating DCs comprise at least 2 well-characterized subsets, namely myeloid DCs (mDCs) and pDCs, which are distinguished by their function and by their reactivity with a panel of monoclonal antibodies. mDCs are a major subpopulation of blood DCs that are CD4+ Lin- CD11c+ CD123dim CD45RO+ HLA-DR+ . They express myeloid markers (CD13, CD33) and have a monocytoid appearance. A major subset of mDCs also expresses the CD1c (BDCA-1) antigen and drives differentiation of T cells into Th1 lymphocytes. Blood pDCs express a specific CD303 (BDCA-2) marker. Phenotyping of peripheral BDCA-2+ DCs characterizes these cells as being CD4+ Lin- CD11c- CD123bright CD45RA+ and lacking myeloid lineage markers. Both DC subsets and the inflammatory environment in which DCs become activated can influence the type of T-cell response they elicit and thus contribute to MS lesions. In addition, both subsets have been found in the cerebrospinal fluid (CSF) of MS patients, especially during relapses [6], [7], [8].

Transmigration of immune cells into the CNS is regulated by chemokines, cytokines, and adhesion molecules on immune cells. Breakdown of the BBB is well documented in the pathogenesis of MS [9]. In MS lesions, activated endothelial cells express abnormally elevated levels of adhesion molecules, including intercellular adhesion molecule I (ICAM-I) and vascular cell adhesion molecule I (VCAM-I), and their elevated levels correlate with the extent of immune cell infiltration. Ligands for these adhesions molecules, lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) integrins, respectively, have been identified on perivascular inflammatory cells in MS lesions [10], [11], [12]. VLA-4 (CD49d/CD29), the [alpha]-4 submember of the [beta]1 integrin family expressed on most mononuclear hematopoietic cells, plays a role in several immunological tasks, including immune cell trafficking, activation of myeloid cells and naïve T and B lymphocytes, and differentiation of effector T cells into Th1, Th2, or Th17 [13]. Indeed, VLA-4 constitutes an essential part of the immunological synapse, and binding of VLA-4...

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Gale Document Number: GALE|A477149801