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

Abstract : Background Interferon beta (IFN β ) 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. Aim To determine a combination of cellular and molecular blood signatures associated with the efficacy of IFN β treatment using an integrated approach. Methods The immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFN β 1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4 + T cells and naïve/memory T cell subsets, by measurement of circulating IFN α / 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. Results Clinical responders and non-responders displayed similar plasma levels of IFN β 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 + T EMRA 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 IFN β , and in which CD4 + T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities.
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Submitted on : Monday, June 7, 2021 - 1:20:39 PM
Last modification on : Friday, August 5, 2022 - 3:36:53 AM


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Priyanka Devi-Marulkar, Carolina Moraes-Cabe, Pascal Campagne, Béatrice Corre, Aida Meghraoui-Kheddar, et al.. Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment. Frontiers in Immunology, 2021, 12, ⟨10.3389/fimmu.2021.628375⟩. ⟨pasteur-03251859⟩



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