Methotrexate reduces circulating Th17 cells and impairs plasmablast and memory B cell expansions following pneumococcal conjugate immunization in RA patients

Per Nived,Bo Settergren,Meliha C Kapetanovic,Göran Jönsson,Lillemor Skattum,Anders A Bengtsson,Åsa Pettersson,Åsa Johansson

doi:10.1038/s41598-021-88491-2

Per Nived, Bo Settergren + Show 6 more

Open Access

https://doi.org/10.1038/s41598-021-88491-2

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Abstract

Methotrexate (MTX) impairs antibody response after pneumococcal vaccination. We aimed to investigate differences in phenotypes of circulating B and T cells after pneumococcal conjugate vaccine (PCV) in rheumatoid arthritis (RA) patients on MTX (MTX group), RA without disease-modifying drugs (0DMARD), and controls (HC). MTX group (n = 11), 0DMARD (n = 12) and HC (n = 13) were studied. Blood samples were collected: before MTX, ≥ 4 weeks on stable MTX dose (prevaccination), and 7 days postvaccination (MTX group), and pre- and 7 days postvaccination (0DMARD and HC). Phenotypes of B- and T cell subsets were determined using flow cytometry. Serotype-specific IgG were quantified using multiplex bead assay, pre- and 4–6 weeks postvaccination. Concentrations of plasmablasts and switched memory B cells increased after PCV in HC (both p = 0.03) and the 0DMARD group (p = 0.01 and p = 0.02), but not in the MTX group. Postimmunization plasmablasts were lower in MTX group, compared to the 0DMARD group and HC (p = 0.002 and p < 0.001). Th17 cells decreased after MTX start (p = 0.02), and increased in HC after immunization (p = 0.01). Postimmunization plasmablasts correlated with mean antibody response ratio in all RA patients (R = 0.57, p = 0.035). Methotrexate reduced Th17 cells and blocked activation of plasmablasts and switched memory B cells following polysaccharide-protein conjugate antigen challenge in RA.

Highlights

Rheumatoid arthritis (RA) is associated with an increased risk of infection[1], and immunizations against vaccinepreventable diseases such as pneumococcal infection is important[2]
B cells have an apparent role in the production of rheumatoid arthritis (RA) associated autoantibodies, such as rheumatoid factor (RF) and anti citrullinated peptide antibodies (ACPA), and B cell depletion therapy using anti-CD20 is efficacious for RA patients including those refractory to tumor necrosis factor (TNF)-blockade[10]
Switched memory B cells might be more abundant in the blood of RA patients, and percentages of circulating total B cells seems to decrease in long-standing disease

Summary

Introduction

Rheumatoid arthritis (RA) is associated with an increased risk of infection[1], and immunizations against vaccinepreventable diseases such as pneumococcal infection is important[2]. B cells have an apparent role in the production of RA associated autoantibodies, such as rheumatoid factor (RF) and anti citrullinated peptide antibodies (ACPA), and B cell depletion therapy using anti-CD20 is efficacious for RA patients including those refractory to TNF-blockade[10]. Using vaccination with PCV as a model for antigen challenge, we aimed to investigate the underlying mechanisms by which MTX exerts its effect on the antibody response. We hypothesized that MTX treatment exerts a negative effect on the formation of germinal center (GC) Tfh cells after protein antigen stimulation, resulting in lower numbers of cmTfh cells after immunization with PCV. We conducted a study to investigate phenotypes of peripheral blood B and T cells, including memory Tfh cell subsets, before and after PCV in RA patients on stabile MTX dose compared to RA without DMARD, and healthy controls and thereby explore the mode of action of MTX in RA

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