HLA alleles as biomarkers of high-titre neutralising antibodies to interferon-β therapy in multiple sclerosis

Núñez, Concepción; Cénit, M. Carmen; Álvarez‐Lafuente, Roberto; Río, Jordi; Fernández‐Arquero, Miguel; Arroyo, Rafael; Montalbán, Xavier; Fernández, Óscar; Oliver-Martos, Begoña; Leyva, Laura; Comabella, Manuel; Urcelay, Elena

doi:10.1136/jmedgenet-2014-102348

Cited by 18 publications

(12 citation statements)

References 37 publications

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“…Notably, part of the side effect could be explained by the higher production of neutralizing antibodies against drugs (or their metabolites) in the HLA-DRB1*07 : 01 and/or DQA1*02 carriers [59, 60]. Although drug-specific antibodies are undesirable in therapies involving biological proteins, these findings reinforce our results of a much higher frequency and persistence of DBPII neutralizing antibodies in individuals harboring those alleles HLA class II.…”

Section: Discussionsupporting

confidence: 81%

The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants

et al. 2016

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BackgroundThe human malaria parasite Plasmodium vivax infects red blood cells through a key pathway that requires interaction between Duffy binding protein II (DBPII) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). A high proportion of P. vivax-exposed individuals fail to develop antibodies that inhibit DBPII-DARC interaction, and genetic factors that modulate this humoral immune response are poorly characterized. Here, we investigate if DBPII responsiveness could be HLA class II-linked.Methodology/Principal FindingsA community-based open cohort study was carried out in an agricultural settlement of the Brazilian Amazon, in which 336 unrelated volunteers were genotyped for HLA class II (DRB1, DQA1 and DQB1 loci), and their DBPII immune responses were monitored over time (baseline, 6 and 12 months) by conventional serology (DBPII IgG ELISA-detected) and functional assays (inhibition of DBPII–erythrocyte binding). The results demonstrated an increased susceptibility of the DRB1*13:01 carriers to develop and sustain an anti-DBPII IgG response, while individuals with the haplotype DRB1*14:02-DQA1*05:03-DQB1*03:01 were persistent non-responders. HLA class II gene polymorphisms also influenced the functional properties of DBPII antibodies (BIAbs, binding inhibitory antibodies), with three alleles (DRB1*07:01, DQA1*02:01 and DQB1*02:02) comprising a single haplotype linked with the presence and persistence of the BIAbs response. Modelling the structural effects of the HLA-DRB1 variants revealed a number of differences in the peptide-binding groove, which is likely to lead to altered antigen binding and presentation profiles, and hence may explain the differences in subject responses.Conclusions/SignificanceThe current study confirms the heritability of the DBPII antibody response, with genetic variation in HLA class II genes influencing both the development and persistence of IgG antibody responses. Cellular studies to increase knowledge of the binding affinities of DBPII peptides for class II molecules linked with good or poor antibody responses might lead to the development of strategies for controlling the type of helper T cells activated in response to DBPII.

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Section: Discussionsupporting

confidence: 81%

The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants

et al. 2016

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“…In addition, an association of HLA-DRB1*07:01 with ADAs was described for 39 American patients 17 . A study conducted on 610 Spanish patients reported an increased risk of developing NAbs for the combined presence of the haplotype HLA-DRB1*07:01 with the HLA class I alleles HLA-A*26 and HLA-B* 14 and replicated the association of DRB1*04:01 18 . In a Swedish analysis, the HLA-DRB1*15 and HLA-DQA1*05 alleles were associated with an increased risk for developing NAbs in patients treated with interferon β-1a 19 , while HLA-DRB1*04 was nominally associated in patients receiving interferon β-1b.…”

Section: Introductionmentioning

confidence: 85%

“…Although the immunogenicity of biopharmaceuticals is a known critical phenomenon, reasons for the large inter-individual variation in the occurrence of ADA are still poorly understood. In previous studies, nine HLA-DRB1 alleles and two SNPs have been proposed to either influence the risk to develop antiinterferon β antibodies or to be associated with ADA titers [15][16][17][18][19][20] . Six of these markers are assumed to increase the risk for ADA development, the remaining five are candidates for protection from ADA.…”

Section: Discussionmentioning

confidence: 99%

Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

et al. 2018

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“… 13 – 15 Smoking is a risk factor for the development of multiple sclerosis (MS), and the risk is greater if smoking is combined with well-known HLA associations. It is also a risk factor for the development of ADAs in IFN-β- and natalizumab-treated MS patients, 16 , 17 as well as for the development of RA by means of a mechanism of citrullination.…”

Section: Discussionmentioning

confidence: 99%

Correlation between HLA haplotypes and the development of antidrug antibodies in a cohort of patients with rheumatic diseases

Benucci¹,

Damiani²,

Gobbi³

et al. 2018

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IntroductionThe aim of this study was to investigate the correlation between human leukocyte antigen (HLA) haplotypes and the development of antidrug antibodies (ADAs) in a cohort of patients with rheumatic diseases.Patients and methodsWe evaluated the presence of ADAs in 248 patients with inflammatory rheumatic diseases after 6 months of treatment with anti-TNF drugs: 26 patients were treated with infliximab (IFX; three with rheumatoid arthritis [RA], 13 with ankylosing spondylitis [AS], 10 with psoriatic arthritis [PsA]); 83 treated with adalimumab (ADA; 24 with RA, 36 with AS, 23 with PsA); 88 treated with etanercept (ETA; 35 with RA, 27 with AS, 26 with PsA); 32 treated with certolizumab (CERT; 25 with RA, two with AS, five with PsA); and 19 treated with golimumab (GOL; three with RA, seven with AS, nine with PsA). Serum drug and ADA levels were determined using Lisa-Tracker Duo, the ADA-positive samples underwent an inhibition test, and the true-positive samples underwent genetic HLA typing. To have a homogeneous control population, we also performed genetic HLA typing of 11 ADA-negative patients.ResultsAfter inhibition test, the frequency of ADAs was 2/26 patients treated with IFX (7.69%), 4/83 treated with ADA (4.81%), 0/88 treated with ETA (0%), 4/32 treated with CERT (12.5%), and 1/19 treated with GOL (5.26%). The frequency of HLA alleles in the examined patients was HLA-DRβ-11 0.636, HLA-DQ-03 0.636, and HLA-DQ-05 0.727. The estimated relative risks between the ADA-positive patients and the ADA-negative patients were HLA-DRβ-11 2.528 (95% CI 0.336–19.036), HLA-DQ-03 1.750 (95% CI 0.289–10.581), and HLA-DQ-05 2.424 (95% CI 0.308–15.449).ConclusionThis is the first study that shows an association between HLA and genetic factors associated with the occurrence of ADAs in patients with rheumatic diseases, but the number of samples is too small to draw any definite conclusion.

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HLA alleles as biomarkers of high-titre neutralising antibodies to interferon-β therapy in multiple sclerosis

Abstract: 50% of the studied MS patients carried some of the five independently associated HLA allele/allele combinations described in this work. This relevant percentage of patients could benefit a therapeutic decision.

Cited by 18 publications

References 37 publications

The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants

The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants

Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

Correlation between HLA haplotypes and the development of antidrug antibodies in a cohort of patients with rheumatic diseases

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