Deconstruction of <i>HLA-DRB1*04:01:01</i> and <i>HLA-DRB1*15:01:01</i> class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis

Creary, Lisa E.; Mallempati, Kalyan C.; Gangavarapu, Sridevi; Caillier, Stacy J.; Oksenberg, Jorge R.; Fernández-Viña, Marcelo

doi:10.1177/1352458518770019

Cited by 19 publications

(14 citation statements)

References 38 publications

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“…The most striking result was obtained for DQB1 in non-responders who showed a significant enrichment of DQ8/DQ2 serotypes and mainly carried DQA1 genotypes including DQA1*03 and DQA1*02:01 allelic variants. The enrichment of DQ8 in non-responders is consistent with two recent studies ( 13 , 76 ). In a meta-analysis of HLA allelic variation performed with multiple MS cohorts of European ancestry, DQB1*03:02 , the single allele encoding DQ8, was identified as a dominant risk for MS. DQB1*03:02 was also found to be counteracted by the interaction with DQB1*03:01 (encoding DQ7) in this study ( 13 ).…”

Section: Discussionsupporting

confidence: 92%

“…Using next-generation sequencing, the other study associated two extended haplotypes with MS in European-American patients. The haplotype encoding DR53−DR4−DQ8 serotypes was linked with MS risk, while the other haplotype encoding DR53−DR4−DQ7 serotypes was protective ( 76 ). Hence, DQ8 and DQ7, each encoded by a single allele, appear to influence MS susceptibility in an opposite manner.…”

Section: Discussionmentioning

confidence: 99%

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Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment

et al. 2021

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BackgroundInterferon beta (IFNβ) has been prescribed as a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) for nearly three decades. However, there is still a lack of treatment response markers that correlate with the clinical outcome of patients.AimTo determine a combination of cellular and molecular blood signatures associated with the efficacy of IFNβ treatment using an integrated approach.MethodsThe immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFNβ1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4+ T cells and naïve/memory T cell subsets, by measurement of circulating IFNα/β proteins with digital ELISA (Simoa) and analysis of ~600 immune related genes including 159 interferon-stimulated genes (ISGs) with the Nanostring technology. The potential impact of HLA class II gene variation in treatment responsiveness was investigated by genotyping HLA-DRB1, -DRB3,4,5, -DQA1, and -DQB1, using as a control population the Milieu Interieur cohort of 1,000 French healthy donors.ResultsClinical responders and non-responders displayed similar plasma levels of IFNβ and similar ISG profiles. However, non-responders mainly differed from other subject groups with reduced circulating naïve regulatory T cells, enhanced terminally differentiated effector memory CD4+ TEMRA cells, and altered expression of at least six genes with immunoregulatory function. Moreover, non-responders were enriched for HLA-DQB1 genotypes encoding DQ8 and DQ2 serotypes. Interestingly, these two serotypes are associated with type 1 diabetes and celiac disease. Overall, the immune signatures of non-responders suggest an active disease that is resistant to therapeutic IFNβ, and in which CD4+ T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment

et al. 2021

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“…The DRB3, DRB4 and DRB5 loci are presumed to act as modulators of the DRB1-associated MS risk [ 33 ]. In particular, the strong linkage disequilibrium between HLA-DRB1*15:01 and HLA-DRB5 is well-described [ 34 ] and was also confirmed in our hands, as indicated by the fact that all HLA-DRB5*01:01 carriers were HLA-DRB1*15:01 carriers. It has been hypothesized that HLA-DRB5 acts as a modifier of progression, rather than a factor for MS susceptibility, since HLA-DRB5*null patients are at higher risk for the development of secondary progressive MS [ 35 ].…”

Section: Discussionsupporting

confidence: 88%

HLA Class II Genotype Does Not Affect the Myelin Responsiveness of Multiple Sclerosis Patients

Derdelinckx

Nkansah

Ooms

et al. 2020

Cells

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Background: When aiming to restore myelin tolerance using antigen-specific treatment approaches in MS, the wide variety of myelin-derived antigens towards which immune responses are targeted in multiple sclerosis (MS) patients needs to be taken into account. Uncertainty remains as to whether the myelin reactivity pattern of a specific MS patient can be predicted based upon the human leukocyte antigen (HLA) class II haplotype of the patient. Methods: In this study, we analyzed the reactivity towards myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP) and proteolipid protein (PLP) peptides using direct interferon (IFN)-γ enzyme-linked immune absorbent spot (ELISPOT). Next, the HLA class II haplotype profile was determined by next-generation sequencing. In doing so, we aimed to evaluate the possible association between the precursor frequency of myelin-reactive T cells and the HLA haplotype. Results: Reactivity towards any of the analyzed peptides could be demonstrated in 65.0% (13/20) of MS patients and in 60.0% (6/10) of healthy controls. At least one of the MS risk alleles HLA-DRB1*15:01, HLA-DQA1*01:02 and HLA-DQB1*06:02 was found in 70.0% (14/20) of patients and in 20.0% (2/10) of healthy controls. No difference in the presence of a myelin-specific response, nor in the frequency of myelin peptide-reactive precursor cells could be detected among carriers and non-carriers of these risk alleles. Conclusion: No association between HLA haplotype and myelin reactivity profile was present in our study population. This complicates the development of antigen-specific treatment approaches and implies the need for multi-epitope targeting in an HLA-unrestricted manner to fully address the wide variation in myelin responses and HLA profiles in a heterogeneous group of MS patients.

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“…The Ugandan, Egyptian and Spanish populations have been previously examined for KIR gene content [40–42]. Similarly, the European American sample was described in a recent HLA study [43]. The Papuan sample consists of individuals from both the highland and lowland regions, as described [44].…”

Section: Methodsmentioning

confidence: 99%

Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop

et al. 2018

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The goals of the KIR component of the 17th International HLA and Immunogenetics Workshop (IHIW) were to encourage and educate researchers to begin analyzing KIR at allelic resolution, and to survey the nature and extent of KIR allelic diversity across human populations. To represent worldwide diversity, we analyzed 1269 individuals from ten populations, focusing on the most polymorphic KIR genes, which express receptors having three immunoglobulin (Ig)-like domains (KIR3DL1/S1, KIR3DL2 and KIR3DL3). We identified 13 novel alleles of KIR3DL1/S1, 13 of KIR3DL2 and 18 of KIR3DL3. Previously identified alleles, corresponding to 33 alleles of KIR3DL1/S1, 38 of KIR3DL2, and 43 of KIR3DL3, represented over 90% of the observed allele frequencies for these genes. In total we observed 37 KIR3DL1/S1 allotypes, 40 for KIR3DL2 and 44 for KIR3DL3. As KIR allotype diversity can affect NK cell function, this demonstrates potential for high functional diversity worldwide. Allelic variation further diversifies KIR haplotypes. We determined KIR3DL3~KIR3DL1/S1~KIR3DL2 haplotypes from five of the studied populations, and observed multiple population-specific haplotypes in each. This included 234 distinct haplotypes in European Americans, 191 in Ugandans, 35 in Papuans, 95 in Egyptians and 86 in Spanish populations. For another 35 populations, encompassing 642,105 individuals we focused on KIR3DL2 and identified another 375 novel alleles, with approximately half of them observed in more than one individual. The KIR allelic level data gathered from this project represents the most comprehensive summary of global KIR allelic diversity to date, and continued analysis will improve understanding of KIR allelic polymorphism in global populations. Further, the wealth of new data gathered in the course of this workshop component highlights the value of collaborative, community-based efforts in immunogenetics research, exemplified by the IHIW.

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Deconstruction of HLA-DRB104:01:01* and HLA-DRB115:01:01* class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis

Abstract: HLA-DR15 haplotypes, including genomic variants of HLA-DRB5, and HLA-DR4 haplotypes affect MS risk.

Cited by 19 publications

References 38 publications

Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment

Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment

HLA Class II Genotype Does Not Affect the Myelin Responsiveness of Multiple Sclerosis Patients

Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop

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Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis

Abstract: HLA-DR15 haplotypes, including genomic variants of HLA-DRB5, and HLA-DR4 haplotypes affect MS risk.

Cited by 19 publications

References 38 publications

Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment

Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment

HLA Class II Genotype Does Not Affect the Myelin Responsiveness of Multiple Sclerosis Patients

Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop

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Deconstruction of HLA-DRB104:01:01* and HLA-DRB115:01:01* class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis