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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Available from: Danica Stanimirovic, Oct 06, 2015
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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.
    Neurobiology of Disease 11/2014; 74C:14-24. DOI:10.1016/j.nbd.2014.09.016 · 5.08 Impact Factor
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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.
    Journal of neuroimmunology 06/2014; 271(1). DOI:10.1016/j.jneuroim.2014.03.014 · 2.47 Impact Factor
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    • "HLA-G expression in brain specimens from patients with multiple sclerosis implies HLA-G as a contributor to the mechanisms regulating immune reactivity in the central nervous system (Wiendl et al., 2005). ALCAM fulfills important functions in the recruitment of leukocytes into the brain (Cayrol et al., 2008). A list of all one hundred genes used in the Pathway analysis is provided in the Supplementary Table 1. "
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    ABSTRACT: Multi-modal data analysis techniques, such as the Parallel Independent Component Analysis (pICA), are essential in neuroscience, medical imaging and genetic studies. The pICA algorithm allows the simultaneous decomposition of up to two data modalities achieving better performance than separate ICA decompositions and enabling the discovery of links between modalities. However, advances in data acquisition techniques facilitate the collection of more than two data modalities from each subject. Examples of commonly measured modalities include genetic information, structural magnetic resonance imaging (MRI) and functional MRI. In order to take full advantage of the available data, this work extends the pICA approach to incorporate three modalities in one comprehensive analysis. Simulations demonstrate the three-way pICA performance in identifying pairwise links between modalities and estimating independent components which more closely resemble the true sources than components found by pICA or separate ICA analyses. In addition, the three-way pICA algorithm is applied to real experimental data obtained from a study that investigate genetic effects on alcohol dependence. Considered data modalities include functional MRI (contrast images during alcohol exposure paradigm), gray matter concentration images from structural MRI and genetic single nucleotide polymorphism (SNP). The three-way pICA approach identified links between a SNP component (pointing to brain function and mental disorder associated genes, including BDNF, GRIN2B and NRG1), a functional component related to increased activation in the precuneus area, and a gray matter component comprising part of the default mode network and the caudate. Although such findings need further verification, the simulation and in-vivo results validate the three-way pICA algorithm presented here as a useful tool in biomedical data fusion applications.
    NeuroImage 04/2014; 98. DOI:10.1016/j.neuroimage.2014.04.060 · 6.36 Impact Factor
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