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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.

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