Cayrol R, Wosik K, Berard JL, et al. Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system

Neuroimmunology Research Laboratory, Center for Excellence in Neuromics, Centre Hospitalier de l'Université de Montréal-Notre-Dame Hospital, Université de Montréal, H2L 4M1, Montréal, Québec, Canada.
Nature Immunology (Impact Factor: 20). 03/2008; 9(2):137-45. DOI: 10.1038/ni1551
Source: PubMed


Adhesion molecules of the immunoglobulin superfamily are crucial effectors of leukocyte trafficking into the central nervous system. Using a lipid raft-based proteomic approach, we identified ALCAM as an adhesion molecule involved in leukocyte migration across the blood-brain barrier (BBB). ALCAM expressed on BBB endothelium localized together with CD6 on leukocytes and with BBB endothelium transmigratory cups. ALCAM expression on BBB cells was upregulated in active multiple sclerosis and experimental autoimmune encephalomyelitis lesions. Moreover, ALCAM blockade restricted the transmigration of CD4+ lymphocytes and monocytes across BBB endothelium in vitro and in vivo and reduced the severity and delayed the time of onset of experimental autoimmune encephalomyelitis. Our findings indicate an important function for ALCAM in the recruitment of leukocytes into the brain and identify ALCAM as a potential target for the therapeutic dampening of neuroinflammation.

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    • "These clinical outcomes emphasize the necessity to develop tools blocking the migration of specific lymphocyte subsets. In EAE models, blockade of either ALCAM or MCAM, which are both up-regulated in MS and EAE lesions, reduced the transmigration of CD4 T lymphocytes and decreased disease severity (Cayrol et al. 2008; Larochelle et al. 2012). Mice deficient for MCAM specifically on endothelial cells developed less severe EAE "
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    ABSTRACT: Multiple sclerosis (MS) is the prototypic inflammatory disease of the central nervous system (CNS) characterized by multifocal areas of demyelination, axonal damage, activation of glial cells, and immune cell infiltration. Despite intensive years of research, the etiology of this neurological disorder remains elusive. Nevertheless, the abundance of immune cells such as T lymphocytes and their products in CNS lesions of MS patients supports the notion that MS is an immune-mediated disorder. An important body of evidence gathered from MS animal models such as experimental autoimmune encephalomyelitis (EAE), points to the central contribution of CD4 T lymphocytes in disease pathogenesis. Both Th1 (producing interferon-γ) and Th17 (producing interleukin 17) CD4 T lymphocytes targeting CNS self-antigens have been implicated in MS and EAE pathobiology. Moreover, several publications suggest that CD8 T lymphocytes also participate in the development of MS lesions. The migration of activated T lymphocytes from the periphery into the CNS has been identified as a crucial step in the formation of MS lesions. Several factors promote such T cell extravasation including: molecules (e.g., cell adhesion molecules) implicated in the T cell-blood brain barrier interaction, and chemokines produced by neural cells. Finally, once in the CNS, T lymphocytes need to be reactivated by local antigen presenting cells prior to enter the parenchyma where they can initiate damage. Further investigations will be necessary to elucidate the impact of environmental factors (e.g., gut microbiota) and CNS intrinsic properties (e.g., microglial activation) on this inflammatory neurological disease.
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    • "The BBB plays an active neuroinflammatory role as ECs express and up-regulate cytokines and chemokines known to influence immune cell access, survival and effector functions (Alvarez et al., 2011a; Ifergan et al., 2008; Takeshita and Ransohoff, 2012). More importantly, BBB- ECs can upregulate cell adhesion molecules (CAMs) such as Vascular CAM-1 (VCAM-1), Intercellular CAM-1 (ICAM-1), Activated Leukocyte CAM (ALCAM) and Melanoma CAM (MCAM), which are known to facilitate leukocyte transmigration into the CNS (Cayrol et al., 2008; Alvarez et al., 2011b; Larochelle et al., 2012). This study aimed to characterize the changes occurring in the various components of the BBB before disease onset and established a correlation with the immune status in the periphery using a spontaneous relapsing–remitting experimental autoimmune encephalomyelitis (sRR-EAE) model that closely resembles MS. "
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    ABSTRACT: Early changes in the normal appearing white matter of multiple sclerosis (MS) patients precede the appearance of gadolinium-enhancing lesions. Although these findings suggest blood-brain barrier (BBB) breakdown as an important feature in MS pathogenesis, limited information is available on the BBB alterations during lesion genesis. Here, we perform a longitudinal characterization of the vascular, neuropathological and immunological changes before lesion formation in mice developing spontaneous relapsing-remitting experimental autoimmune encephalomyelitis (sRR-EAE). We found a significant upregulation of Th1 and Th17 cytokines in the periphery of sRR-EAE mice before any evident neuropathology. In the CNS, BBB and astroglial activations were the first pathological changes occurring after 45days of age and were followed by immune cell infiltration by day 50. These pathological alterations subsequently led to perivascular demyelination and disease onset. In MS, (p)reactive lesions mirrored the changes seen in early sRR-EAE by displaying considerable BBB disruption, perivascular astrogliosis, redistribution of junctional proteins and increased expression of endothelial cell adhesion molecules. Our findings suggest that BBB breach occurs before significant immune cell infiltration and demyelination. In addition, peripheral immune activation during sRR-EAE precedes CNS pathology, suggesting that outside in signaling mechanisms play a role in the development of neuroinflammatory lesions. Copyright © 2014 Elsevier Inc. All rights reserved.
    Full-text · Article · Nov 2014 · Neurobiology of Disease
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    • "CXCL16 acts as a chemokine for CXCR6-expressing T cells and promotes inflammation in experimental autoimmune encephalomyelitis (Fukumoto et al., 2004), but may also protect the CNS during inflammation (Rosito et al., 2012). ALCAM is expressed on brain endothelia and is a crucial adhesion molecule for T cells (Cayrol et al., 2008), but has not been extensively studied in Fig. 1. Mean vitamin and inflammation marker levels during the whole study period. "
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    ABSTRACT: To explore the relationships between vitamin A, D and E and inflammation in relapsing remitting multiple sclerosis, we assessed their associations with 11 inflammation markers in 9 serial serum samples from 85 patients, before and during interferon-β1a treatment. A negative association was found between vitamin A and pentraxin 3 independent of interferon-β1a use, whereas positive associations between vitamin D and interleukin-1 receptor antagonist and secreted frizzled-related protein 3 were seen before, and between vitamin E and chemokine (C-X-C motif) ligand 16 during interferon-β1a treatment. These findings suggest associations with diverse inflammatory pathways, which may be differentially influenced by interferon-β1a treatment.
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