ALCAM and CD6 — multiple sclerosis risk factors

Wagner, Marta; Bilińska, Małgorzata; Pokryszko−Dragan, Anna; Sobczyński, Maciej; Cyrul, Małgorzata; Kuśnierczyk, Piotr; Jasek, Monika

doi:10.1016/j.jneuroim.2014.08.621

Cited by 32 publications

(33 citation statements)

References 30 publications

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“…The controversy continues even for expression level of CD6 receptor. In autoimmune conditions such as multiple sclerosis, while one study showed lower expression of CD6 mRNA in patients than in healthy individuals [65], a recent report suggests higher CD6 expression in peripheral blood T-cells as well as cerebrospinal fluid (CSF) T-cells in patients with active lesions [66]. Another article reports about clones of Th17 cells derived from CSF of MS patients that show increased CD6 expression [19].…”

Section: Discussionmentioning

confidence: 99%

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

et al. 2017

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CD6 is associated with T-cell modulation and is implicated in several autoimmune diseases. We previously demonstrated that Itolizumab, a CD6 domain 1 (CD6D1) specific humanized monoclonal antibody, inhibited the proliferation and cytokine production by T lymphocytes stimulated with anti-CD3 antibody or when co-stimulated with ALCAM. Aberrant IL-17 producing CD4+ helper T-cells (Th17) have been identified as pivotal for the pathogenesis of certain inflammatory autoimmune disorders, including psoriasis. Itolizumab has demonstrated efficacy in human diseases known to have an IL-17 driven pathogenesis. Here, in in vitro experiments we show that by day 3 of human PBMC activation using anti-CD3 and anti-CD28 co-stimulation in a Th17 polarizing milieu, 15–35% of CD4+ T-cells overexpress CD6 and there is an establishment of differentiated Th17 cells. Addition of Itolizumab reduces the activation and differentiation of T cells to Th17 cells and decreases production of IL-17. These effects are associated with the reduction of key transcription factors pSTAT3 and RORγT. Further, transcription analysis studies in these conditions indicate that Itolizumab suppressed T cell activation by primarily reducing cell cycle, DNA transcription and translation associated genes. To understand the mechanism of this inhibition, we evaluated the effect of this anti-human CD6D1 mAb on ALCAM-CD6 as well as TCR-mediated T cell activation. We show that Itolizumab but not its F(ab’)2 fragment directly inhibits CD6 receptor hyper-phosphorylation and leads to subsequent decrease in associated ZAP70 kinase and docking protein SLP76. Since Itolizumab binds to CD6 expressed only on human and chimpanzee, we developed an antibody binding specifically to mouse CD6D1. This antibody successfully ameliorated the incidence of experimental autoimmune encephalitis in the mice model. These results position CD6 as a key molecule in sustaining the activation and differentiation of T cells and an important target for modulating autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

et al. 2017

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“…A genetic study showed that some of the ALCAM gene polymorphisms are associated with the risk as well as the development and progression of MS . Furthermore, in the case of the CD6 gene, not only polymorphisms, but also mRNA expression levels were reported to be associated with MS . These observations also suggest the important role of ALCAM in the pathogenesis of MS and a high potential of ALCAM as a therapeutic target.…”

Section: Alcammentioning

confidence: 99%

“…48 Notably, ALCAM in BMECs and its ligand of CD6 on the surface of lymphocytes localize together during the transmigration of lymphocytes across the BBB. 48 Furthermore, ALCAM blockade restricted the transmigration of lymphocytes across BMECs along with reduced severity and delay in the onset time of EAE, suggesting the great importance of ALCAM in the pathogenesis of MS. 48 A genetic study showed that some of the ALCAM gene polymorphisms are associated with the risk as well as the development and progression of MS. 49 Furthermore, in the case of the CD6 gene, not only polymorphisms, but also mRNA expression levels were reported to be associated with MS. 50 These observations also suggest the important role of AL-CAM in the pathogenesis of MS and a high potential of ALCAM as a therapeutic target.…”

Section: Madcam-1mentioning

confidence: 99%

Blood–brain barrier: A novel therapeutic target in multiple sclerosis

Kuwahara

Nishina

Yokota

2015

Clinical & Exp Neuroim

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Multiple sclerosis is an autoimmune inflammatory disorder of the central nervous system, and the entrance of pathogenic lymphocytes from blood circulation into the brain across the blood–brain barrier (BBB) is accepted as the initial step of pathogenesis. The migration of lymphocytes across the BBB is mediated by their sequential interactions with the brain microvascular endothelial cells, the central component of the BBB, including rolling (loose attachment), adhesion (firm attachment), crawling and transmigration. There are a variety of cell adhesion molecules that are expressed on brain microvascular endothelial cells and are involved in this process. The selectins are assumed to be associated with the rolling of lymphocytes. Vascular cell adhesion molecule‐1 contributes to the adhesion of lymphocytes by binding to very late antigen‐4 on their surface after the stimulation by cytokines. Intercellular adhesion molecule‐1 acts for the adhesion as well and the subsequent crawling of lymphocytes by binding to leukocyte function‐associated antigen‐1 on their surface. Activated leukocyte cell adhesion molecule, melanoma cell adhesion molecule, platelet endothelial cell adhesion molecule‐1, nerve injury‐induced protein‐1 and vascular adhesion protein‐1 are also considered to influence the migratory process of lymphocytes across the BBB, although the detailed mechanisms are not elucidated. Here we review the pathophysiology of multiple sclerosis at the BBB to present a possible molecular targeted therapy in the future, especially focused on the molecules expressing at the brain microvascular endothelial cells.

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“…ALCAM plays an important role in the survival, growth [5] and migration of cells [6,7] and cellular haemophilic (ALCAM-ALCAM) and heterophilic (ALCAM-CD6) reactions [8][9][10][11][12][13]. In addition, this protein performs a vital role in invasion and development of tumour in colorectal [14][15][16] and breast cancers [6].…”

Section: Introductionmentioning

confidence: 99%

Cloning and Expression of C2 and V Domains of ALCAM Protein in E. coli BL21 (DE3)

Dana¹,

Mazraeh²,

Chalbatani³

et al. 2017

Clin Microbiol

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Introduction: ALCAM as a glycoprotein is a member of the immunoglobulin family and plays an important role in cell growth, survival and motility. This protein also contributes to the development of tumour invasion in colorectal and breast cancers and is typically considered as a cancer stem cell marker. ALCAM as a cell-surface antigen, with high expression in some cancers as colorectal and breast, has the potential to diagnose and treat these cancers.

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ALCAM and CD6 — multiple sclerosis risk factors

Cited by 32 publications

References 30 publications

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

Blood–brain barrier: A novel therapeutic target in multiple sclerosis

Cloning and Expression of C2 and V Domains of ALCAM Protein in E. coli BL21 (DE3)

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