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

Front Immunol. 2021 May 25:12:628375. doi: 10.3389/fimmu.2021.628375. eCollection 2021.

Abstract

Background: Interferon 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.

Aim: To determine a combination of cellular and molecular blood signatures associated with the efficacy of IFNβ treatment using an integrated approach.

Methods: The 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.

Results: Clinical 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.

Keywords: HLA class II genes; T cells; blood biomarkers; immune phenotypes; interferon-stimulated genes; multiple sclerosis; type I interferon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Case-Control Studies
  • Female
  • Genetic Variation*
  • HLA-DQ beta-Chains / genetics*
  • HLA-DQ beta-Chains / immunology
  • Humans
  • Immunologic Factors / therapeutic use*
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Interferon beta-1a / therapeutic use*
  • Male
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting / blood
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy*
  • Multiple Sclerosis, Relapsing-Remitting / genetics
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Phenotype
  • Treatment Failure
  • Young Adult

Substances

  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • Immunologic Factors
  • Interferon Regulatory Factors
  • Interferon beta-1a