Validation of the CD6 and TNFRSF1A loci as risk factors for multiple sclerosis in Spain

Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), Leioa, Spain.
Journal of neuroimmunology (Impact Factor: 2.47). 06/2010; 223(1-2):100-3. DOI: 10.1016/j.jneuroim.2010.03.020
Source: PubMed


A recent meta-analysis of genome-wide association screens coupled to a replication exercise in a combined US/UK collection led to the identification of 4 single nucleotide polymorphisms (SNPs) in three gene loci, i.e. TNFRSF1A, CD6 and IRF8, as novel risk factors for multiple sclerosis with genome-wide level of significance. In the present study, using a combined all-Spain collection of 2515 MS patients and 2942 healthy controls, we demonstrate significant association of rs17824933 in CD6 (P(CMH)=0.004; OR=1.14; 95% CI 1.04-1.24) and of rs1860545 in TNFRSF1A (P(CMH)=0.001; OR=1.15; 95% CI 1.06-1.25) with MS, while the low-frequency coding non-synonymous SNP rs4149584 in TNFRSF1A displayed a trend for association (P(CMH)=0.062; OR=1.27; 95% CI 0.99-1.63). This data reinforce a generic role for CD6 and TNFRSF1A in susceptibility to MS, extending to populations of southern European ancestry.

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    • "Initial studies demonstrated that CD6 negative T cells show less alloreactivity than their CD6 positive counterparts , while anti-CD6 monoclonal antibodies (mAbs) prevent renal and bone marrow grafts rejection [26] [27]. More recently, the finding of CD6 as a susceptibility gene in multiple sclerosis, a prototypic autoimmune disease [28] [29] [30], supports the role of CD6 in pathological autoimmunity leading to tissue inflammation and reinforces its relevance for targeted therapy. It is worth noting that the therapeutic effectiveness of anti-human CD6 mAbs has been primarily associated with their ability to deplete CD6 cells by a complement-mediated mechanism [27] or the capacity of blocking the interaction between CD6 and its ligand ALCAM [31] [32]. "
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    ABSTRACT: T cells are involved in the pathogenesis of rheumatoid arthritis (RA). CD6 is a co-stimulatory molecule, predominantly expressed on lymphocytes, that has been linked to autoreactive responses. The purpose of this study was to evaluate the safety, immunogenicity and preliminary efficacy of itolizumab, a humanized anti-CD6 monoclonal antibody, in patients with active rheumatoid arthritis. Fifteen patients were enrolled in a phase I, open-label, dose-finding study. Five cohorts of patients received a weekly antibody monotherapy with a dose-range from 0.1 to 0.8 mg/kg. Itolizumab showed a good safety profile, with no severe or serious adverse events reported so far. No signs or symptoms associated with immunosuppression were observed in the study. Objective clinical responses were achieved in more than 80% of patients after treatment completion, and these responses tend to be sustained afterwards. This clinical study constitutes the first evidence of the safety and positive clinical effect of a monotherapy using an anti-CD6 antibody in patients with rheumatoid arthritis.
    Results in Immunology 12/2012; 2:204-211. DOI:10.1016/j.rinim.2012.11.001
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    • "As the capacity for TNFα therapy to neutralize CNS TNFα was not directly examined, these data may imply that peripheral TNFα is somehow required for maintaining demyelinating disease quiescence. Although the underlying mechanism remains unknown the recent finding that increased susceptibility to MS is associated with a single nucleotide polymorphism within the sixth intron of the tnfr1 gene calls upon further investigation as to the role the TNFα/TNFR1 pathway in this disease [62,63]. "
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    ABSTRACT: Activation of glial cells via toll-like receptors (TLRs) and other intracellular pathogen recognition receptors promotes the release of potentially toxic acute phase reactants such as TNFα and nitric oxide into the extracellular space. As such, prolonged glial activation, as is thought to occur during a persistent viral infection of the CNS, may contribute to both neurodegeneration and demyelination. However, the effects of virus-induced glial activation on oligodendrocytes are not fully understood. To determine the effects of glial activation on oligodendrocyte viability we treated primary glial cultures isolated from neonatal rats or mice with the RNA viral mimic poly(I:C) and in some cases other TLR ligands. TLR3 expression was determined by western blot. Cytokine levels were measured by RT-PCR, ELISA, and intracellular cytokine staining. Oligodendrocyte precursor (preOL) viability was determined by Alamar blue assays and immunocytochemistry. Stimulation of mixed glial cultures with poly(I:C) resulted in microglia activation, TNFα production and preOL toxicity. This toxic effect of poly(I:C) was indirect as it failed to affect preOL viability in pure cultures despite the fact that preOLs express TLR3. Poly(I:C)-induced loss of preOLs was abolished in TNFα or TNFR1 deficient mixed glial cultures, suggesting that TNFα/TNFR1 signaling is required for poly(I:C) toxicity. Furthermore, although both microglia and astrocytes express functional TLR3, only microglia produced TNFα in culture. Consistent with these findings, other TLR agonists similarly triggered TNFα production and preOL toxicity in mixed glial cultures. Activation of microglia by poly(I:C) promotes TNFα/TNFR1-dependent oligodendroglial cell death. These data indicate that during an ongoing viral infection of the CNS, microglial TNFα may be detrimental to oligodendrocytes.
    Journal of Neuroinflammation 08/2011; 8(1):89. DOI:10.1186/1742-2094-8-89 · 5.41 Impact Factor
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    • "Exons 1 and 2 encode the 24-aa signal sequence, exons 3 through 5 encode each a 101/117-aa SRCR domain, exon 6 encodes a 22-aa spacer that separates the SRCR-D3 from the exon 7-encoded 26-aa transmembrane domain, while exons 8 through 13 encode the cytoplasmic domain of CD6 (Figure 2). Analysis of single-nucleotide polymorphisms (SNPs) in the cd6 locus has unveiled association between MS and the SNP rs17824933 in exon 1 [19] [20]. Besides this wellknown SNP which is associated with CD6 lower expression [21], another 8 nonsynonymous SNPs characterize the coding region but their effects are unknown. "
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    ABSTRACT: CD6 is a 105-130 kDa surface glycoprotein expressed on the majority of T cells and a subset of B cells. The human cd6 gene maps to chromosome 11, and the expression of its protein product is tightly regulated. CD6 mediates cellular adhesion migration across the endothelial and epithelial cells. In addition, it participates in the antigen presentation by B cells and the subsequent proliferation of T cells. CD6 may bind in trans to surface glycoproteins (such as ALCAM and 3A11), or to microbial lipopolysaccharides, and may bind in cis to endogenous ligands (such as CD3 and CD5), and thereby deliver a costimulatory signal. Transinteractions are reinforced during autoimmune diseases (e.g., rheumatoid arthritis (RA), Sjögren's syndrome, and multiple sclerosis) and some cancers. Based on experimental data and on clinical results in RA and psoriasis, we believe that the recent humanized anti-CD6-specific mAb T1h may act as a regulator of the immunological response in addition to its function as an anti-T- and -B cell agent.
    01/2010; 2010(6):130646. DOI:10.1155/2010/130646
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