Wellcome Trust Case Control Consortium 2, Sawcer S, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Nature (Impact Factor: 41.46). 08/2011; 476(7359):214-9. DOI: 10.1038/nature10251
Source: PubMed


Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

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Available from: Helmut Butzkueven, Mar 05, 2014
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    • "Multiple sclerosis (Sawcer et al. 2011) Rheumatoid arthritis (Celik et al. 2009) Dermatitis (Kotani et al. 2012) Melanoma (Mortarini et al. 2005) Breast cancer (Gantsev et al. 2013) Hepatitis C (Celik et al. 2009) Obesity (Bassols et al. 2010) Atherosclerosis (Scholz et al. 2005) Vascular dementia (Kong et al. 2008) Stroke (Liu et al. 2008) Ulcerative interstitial cystitis (Ogawa et al. 2010) Amyotrophic lateral sclerosis (Aebischer et al. 2012) Sickle cell disease (Garrido et al. 2012) BTLA Rheumatoid arthritis (Lin et al. 2006; Oki et al. 2011; Shang et al. 2012a,b) Breast cancer (Fu et al. 2009) Chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (M'Hidi et al. 2009) HIV (Zhang et al. 2011) CMV (Cheung et al. 2005; Serriari et al. 2010) CD160 Dermatitis (Abecassis et al. 2007) CLL/hairy cell leukemia/mantle cell lymphoma (Farren et al. 2011) HIV (Peretz et al. 2012) Paroxysmal nocturnal hemoglobinuria (Giustiniani et al. 2012) "
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    ABSTRACT: The tumor necrosis factor superfamily (TNFSF) and its corresponding receptor superfamily (TNFRSF) form communication pathways required for developmental, homeostatic, and stimulus-responsive processes in vivo. Although this receptor-ligand system operates between many different cell types and organ systems, many of these proteins play specific roles in immune system function. The TNFSF and TNFRSF proteins lymphotoxins, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes), lymphotoxin-β receptor (LT-βR), and HVEM are used by embryonic and adult innate lymphocytes to promote the development and homeostasis of lymphoid organs. Lymphotoxin-expressing innate-acting B cells construct microenvironments in lymphoid organs that restrict pathogen spread and initiate interferon defenses. Recent results illustrate how the communication networks formed among these cytokines and the coreceptors B and T lymphocyte attenuator (BTLA) and CD160 both inhibit and activate innate lymphoid cells (ILCs), innate γδ T cells, and natural killer (NK) cells. Understanding the role of TNFSF/TNFRSF and interacting proteins in innate cells will likely reveal avenues for future therapeutics for human disease. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.
    Full-text · Article · Dec 2014 · Cold Spring Harbor perspectives in biology
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    • "The genetic background of MS is complex, and both HLA and non-HLA genes are known to influence the disease susceptibility [3]. HLA-DRB1*15:01 is the major risk allele for MS with an odds ratio (OR) of 3.1, whereas HLA-A*02:01 has been shown to have an independent protective effect with an OR of 0.73 [4]. Recently, 110 non-HLA MS susceptibility loci have been identified [4,5], all with relatively low ORs. "
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    ABSTRACT: Background Several environmental exposures, including infection with Epstein-Barr virus, low levels of vitamin D and smoking are established risk factors for multiple sclerosis (MS). Also, high hygienic standard and infection with parasites have been proposed to influence MS risk. The aim of this study was to investigate the influence of various environmental exposures on MS risk in a Norwegian cohort, focusing on factors during childhood related to the hygiene hypothesis.MethodsA questionnaire concerning environmental exposures, lifestyle, demographics and comorbidity was administrated to 756 Norwegian MS patients and 1090 healthy controls. Logistic regression was used to calculate odds ratio (OR) with 95% confidence interval (CI) for the risk of MS associated with the variables infectious mononucleosis, severe infection during childhood, vaccination and animals in the household during childhood. Age, gender, HLA-DRB1*15:01, smoking and infectious mononucleosis were included as covariates. General environmental exposures, including tobacco use, were also evaluated.ResultsInfectious mononucleosis was confirmed to be significantly associated with increased MS risk, also after adjusting for the covariates (OR¿=¿1.79, 95% CI: 1.12-2.87, p¿=¿0.016). The controls more often reported growing up with a cat and/or a dog in the household, and this was significant for ownership of cat also after adjusting for the covariates (OR¿=¿0.56, 95% CI: 0.40-0.78, p¿=¿0.001). More patients than controls reported smoking and fewer patients reported snuff use.Conclusions In this Norwegian MS case¿control study of environmental exposures, we replicate that infectious mononucleosis and smoking are associated with increased MS risk. Our data also indicate a protective effect on MS of exposure to cats during childhood, in accordance with the hypothesis that risk of autoimmune diseases like MS may increase with high hygienic standard.
    Full-text · Article · Oct 2014 · BMC Neurology
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    • "The etiology of MS is unknown, however, epidemiological and genetic studies suggest that MS is provoked following exposure to environmental factors, which are potentially responsible for loss of tolerance and peripheral activation of myelin-specific T cells [5], [6]. Genome-wide association studies (GWAS) have confirmed the complexity of MS and uncovered immune-related gene variants linked also to other autoimmune diseases, such as T1D and IBD [7]. The association between MS and IBD is strengthened by observations of an increased incidence of IBD, including both Crohn's disease (CD) and ulcerative colitis (UC), among MS patients [8], [9]. "
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    ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a pathogenesis involving a dysfunctional blood-brain barrier and myelin-specific, autoreactive T cells. Although the commensal microbiota seems to affect its pathogenesis, regulation of the interactions between luminal antigens and mucosal immune elements remains unclear. Herein, we investigated whether the intestinal mucosal barrier is also targeted in this disease. Experimental autoimmune encephalomyelitis (EAE), the prototypic animal model of MS, was induced either by active immunization or by adoptive transfer of autoreactive T cells isolated from these mice. We show increased intestinal permeability, overexpression of the tight junction protein zonulin and alterations in intestinal morphology (increased crypt depth and thickness of the submucosa and muscularis layers). These intestinal manifestations were seen at 7 days (i.e., preceding the onset of neurological symptoms) and at 14 days (i.e., at the stage of paralysis) after immunization. We also demonstrate an increased infiltration of proinflammatory Th1/Th17 cells and a reduced regulatory T cell number in the gut lamina propria, Peyer's patches and mesenteric lymph nodes. Adoptive transfer to healthy mice of encephalitogenic T cells, isolated from EAE-diseased animals, led to intestinal changes similar to those resulting from the immunization procedure. Our findings show that disruption of intestinal homeostasis is an early and immune-mediated event in EAE. We propose that this intestinal dysfunction may act to support disease progression, and thus represent a potential therapeutic target in MS. In particular, an increased understanding of the regulation of tight junctions at the blood-brain barrier and in the intestinal wall may be crucial for design of future innovative therapies.
    Full-text · Article · Sep 2014 · PLoS ONE
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