Multiple sclerosis: doubling down on MHC

Martin, Roland; Sospedra, Mireia; Eiermann, Thomas; Olsson, Tomas

doi:10.1016/j.tig.2021.04.012

Cited by 30 publications

(31 citation statements)

References 84 publications

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“… African control frequencies are from Gragert, et al [ 26 ], European control frequencies are from the WTCCC [ 13 , 14 ], and AA control frequencies are from the AA dataset reported here. African CEHs are highlighted in orange whereas European CEHs are highlighted in yellow ( see Text ).…”

Section: Resultsmentioning

confidence: 99%

“…By contrast, the considerable variability of CEH composition between African, European, and other populations [ 27 – 31 ] indicates a the CEH composition of different populations must be remarkably divergent over much longer periods of time. Presumably, such divergence is due to specific environmental and/or biological pressures that vary with time, with geographic location, or with both [ 26 – 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Despite this focus on single alleles of specific genes, however, these HLA alleles don’t really exist in isolation. Indeed, it has been known for decades that multiple HLA alleles within both the Class I and II regions of the MHC influence, often interactively, the risk of developing MS [ 26 ]. For example, within the MHC , most HLA alleles are in tight linkage disequilibrium with each other and, overall, the HLA region consists of a relatively small collection of highly conserved extended haplotypes ( CEHs ), which stretch (at least) across the “classical” HLA genes ( HLA-A , HLA-C , HLA-B , HLA-DRB1 , and HLA-DQB1 )–a distance spanning nearly 3 mb of DNA [ 27 – 31 ].…”

Section: Introductionmentioning

confidence: 99%

“…This haplotypic structure is found in all human populations, including Africans and persons of European descent [ 28 ]. Nevertheless, the CEH compositions, which account for this population structure, vary markedly between different regions [ 26 – 29 ]. Thus, in the predominantly European WTCCC, the most frequent 250 CEHs accounted for 57% of all CEHs present [ 29 ] and, in an African population [ 28 ], the most frequent 250 CEHs accounted for 31% of all CEHs present reflecting greater haplotypic diversity.…”

Section: Introductionmentioning

confidence: 99%

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Genetic susceptibility to multiple sclerosis in African Americans

et al. 2021

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Objective To explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans. Background Recently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocompatibility complex (MHC) have been known for decades. For example, the haplotypes HLA-DRB1*15:01~HLA-DQB1*06:02, and HLA-DRB1*03:01~ HLA-DQB1*02:01 have odds ratios (ORs) for an MS-association orders of magnitude stronger than many of these newly-discovered associations. Nevertheless, all these haplotypes are part of much larger conserved extended haplotypes (CEHs), which span both the Class I and Class II MHC regions. African-Americans are at greater risk of developing MS compared to a native Africans but at lesser risk compared to Europeans. It is the purpose of this manuscript to explore the relationship between MS-susceptibility and the CEH make-up of our African-American cohort. Design/methods The African-American (AA) cohort consisted of 1,305 patients with MS and 1,155 controls, who self-identified as being African-American. For comparison, we used the 18,492 controls and 11,144 MS-cases from the predominantly European Wellcome Trust Case Control Consortium (WTCCC) and the 28,557 phased native Africans from the multinational “Be the Match” registry. The WTCCC and the African-Americans were phased at each of five HLA loci (HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1) and the at 11 SNPs (10 of which were in non-coding regions) surrounding the Class II region of the DRB1 gene using previously-published probabilistic phasing algorithms. Results Of the 32 most frequent CEHs, 18 (56%) occurred either more frequently or exclusively in Africans) whereas 9 (28%) occurred more frequently or exclusively in Europeans. The remaining 5 CEHs occurred in neither control group although, likely, these were African in origin. Eight of these CEHs carried the DRB1*15:03~DQB1*06:02~a36 haplotype and three carried the DRB1*15:01~DQB1*06:02~a1 haplotype. In African Americans, a single-copy of the European CEH (03:01_07:02_07:02_15:01_06:02_a1) was associated with considerable MS-risk (OR = 3.30; p = 0.0001)–similar to that observed in the WTCCC (OR = 3.25; p<10−168). By contrast, the MS-risk for the European CEH (02:01_07:02_07:02_15:01_06:02_a1) was less (OR = 1.49; ns)–again, similar to the WTCCC (OR = 2.2; p<10−38). Moreover, four African haplotypes were “protective” relative to a neutral reference, to three European CEHs, and also to the five other African CEHs. Conclusions The common CEHs in African Americans are divisible into those that are either African or European in origin, which are derived without modification from their source population. European CEHs, linked to MS-risk, in general, had similar impacts in African-Americans as they did in Europeans. By contrast, African CEHs had mixed MS-risks. For a few, the MS-risk exceeded that in a neutral-reference group whereas, for many others, these CEHs were “protective”–perhaps providing a partial rationale for the lower MS-risk in African-Americans compared to European-Americans.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic susceptibility to multiple sclerosis in African Americans

et al. 2021

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“…EBV infection and altered immune responses during IM have now been strongly associated with an increased risk of developing MS [55,[80][81][82]. It is less clear, however, if this results from an uncontrolled reservoir of B cells, activated by EBV infection, that stimulates autoreactive T cells, possibly even in the CNS, or if the infection primes crossreactive T cell responses that recognize both EBV and myelin antigens.…”

Section: Discussionmentioning

confidence: 99%

Epstein Barr Virus Exploits Genetic Susceptibility to Increase Multiple Sclerosis Risk

Läderach

Münz

2021

Microorganisms

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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) for which both genetic and environmental risk factors have been identified. The strongest synergy among them exists between the MHC class II haplotype and infection with the Epstein Barr virus (EBV), especially symptomatic primary EBV infection (infectious mononucleosis) and elevated EBV-specific antibodies. In this review, we will summarize the epidemiological evidence that EBV infection is a prerequisite for MS development, describe altered EBV specific immune responses in MS patients, and speculate about possible pathogenic mechanisms for the synergy between EBV infection and the MS-associated MHC class II haplotype. We will also discuss how at least one of these mechanisms might explain the recent success of B cell-depleting therapies for MS. While a better mechanistic understanding of the role of EBV infection and its immune control during MS pathogenesis is required and calls for the development of innovative experimental systems to test the proposed mechanisms, therapies targeting EBV-infected B cells are already starting to be explored in MS patients.

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HLA Associations of Intrathecal IgG Production against Specific Viruses in Multiple Sclerosis

Neidhart,

Vlad,

Hilty

et al. 2024

Annals of Neurology

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ObjectiveSpecific human leucocyte antigen (HLA) alleles are not only associated with higher risk to develop multiple sclerosis (MS) and other autoimmune diseases, but also with the severity of various viral and bacterial infections. Here, we analyzed the most specific biomarker for MS, that is, the polyspecific intrathecal IgG antibody production against measles, rubella, and varicella zoster virus (MRZ reaction), for possible HLA associations in MS.MethodsWe assessed MRZ reaction from 184 Swiss patients with MS and clinically isolated syndrome (CIS) and 89 Swiss non‐MS/non‐CIS control patients, and performed HLA sequence‐based typing, to check for associations of positive MRZ reaction with the most prevalent HLA alleles. We used a cohort of 176 Swedish MS/CIS patients to replicate significant findings.ResultsWhereas positive MRZ reaction showed a prevalence of 38.0% in MS/CIS patients, it was highly specific (97.7%) for MS/CIS. We identified HLA‐DRB1*15:01 and other tightly linked alleles of the HLA‐DR15 haplotype as the strongest HLA‐encoded risk factors for a positive MRZ reaction in Swiss MS/CIS (odds ratio [OR], 3.90, 95% confidence interval [CI] 2.05–7.46, padjusted = 0.0004) and replicated these findings in Swedish MS/CIS patients (OR 2.18, 95%‐CI 1.16–4.02, padjusted = 0.028). In addition, female MS/CIS patients had a significantly higher probability for a positive MRZ reaction than male patients in both cohorts combined (padjusted <0.005).InterpretationHLA‐DRB1*15:01, the strongest genetic risk factor for MS, and female sex, 1 of the most prominent demographic risk factors for developing MS, predispose in MS/CIS patients for a positive MRZ reaction, the most specific CSF biomarker for MS. ANN NEUROL 2024

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Multiple sclerosis: doubling down on MHC

Cited by 30 publications

References 84 publications

Genetic susceptibility to multiple sclerosis in African Americans

Genetic susceptibility to multiple sclerosis in African Americans

Epstein Barr Virus Exploits Genetic Susceptibility to Increase Multiple Sclerosis Risk

HLA Associations of Intrathecal IgG Production against Specific Viruses in Multiple Sclerosis

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