The Imbalance of Circulating Follicular T Helper Cell Subsets in Primary Sjögren's Syndrome Associates With Serological Alterations and Abnormal B-Cell Distribution.

Krisztina Szabó,Tünde Tarr,Gábor Papp,Ildikó Fanny Horváth,Ilona Jámbor,Antónia Szántó,Peter Szodoray,Britt Nakken

doi:10.3389/fimmu.2021.639975

Krisztina Szabó, Tünde Tarr + Show 6 more

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https://doi.org/10.3389/fimmu.2021.639975

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Abstract

Since B-cell hyperactivity and pathologic antibody response are key features in the immunopathogenesis of primary Sjögren’s syndrome (pSS), the role of follicular T helper (TFH) cells as efficient helpers in the survival and differentiation of B cells has emerged. Our aim was to investigate whether a change in the balance of circulating (c)TFH subsets and follicular regulatory T (TFR) cells could affect the distribution of B cells in pSS. Peripheral blood of 38 pSS patients and 27 healthy controls was assessed for the frequencies of cTFH cell subsets, TFR cells, and certain B cell subpopulations by multicolor flow cytometry. Serological parameters, including anti-SSA, anti-SSB autoantibodies, immunoglobulin, and immune complex titers were determined as part of the routine diagnostic evaluation. Patients with pSS showed a significant increase in activated cTFH cell proportions, which was associated with serological results. Frequencies of cTFH subsets were unchanged in pSS patients compared to healthy controls. The percentages and number of cTFR cells exhibited a significant increase in autoantibody positive patients compared to patients with seronegative pSS. The proportions of transitional and naïve B cells were significantly increased, whereas subsets of memory B cells were significantly decreased and correlated with autoantibody production. Functional analysis revealed that the simultaneous blockade of cTFH and B cell interaction with anti-IL-21 and anti-CD40 antibodies decreased the production of IgM and IgG. Imbalance in TFH subsets and TFR cells indicates an ongoing over-activated humoral immune response, which contributes to the characteristic serological manifestations and the pathogenesis of pSS.

Highlights

Primary Sjögren’s syndrome is a chronic autoimmune disease displaying slow progression and affecting primarily middle-aged women nine-times more frequently than men
We investigated the distribution of recently described subtypes of cTFH cells in a relatively large number of Primary Sjögren’s syndrome (pSS) patients
The ratio of these cells did not differ significantly in pSS patients compared to healthy controls, the percentages of TFH1 cells tended to increase within the CD4+CXCR5+ cTFH pool

Summary

Introduction

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease displaying slow progression and affecting primarily middle-aged women nine-times more frequently than men. The clinical manifestations in pSS are not homogenous, besides glandular symptoms; the disease can involve any organ system and present with a wide variety of extraglandular manifestations affecting skin, genitourinary tract, kidneys, cardiovascular, nervous or musculoskeletal systems [1]. The development of pSS is still unclear; recent lines of evidence support a complex network between salivary gland epithelial cells and the innate and acquired immune systems. Type I interferon production by plasmacytoid dendritic cells induces infiltrating leukocytes and epithelial cells to secrete B-cell activating factor (BAFF), which promotes B-cell survival and contributes to B-cell hyperactivity, and acts as a mediator between innate and adaptive immunity [2, 3]. Local accumulation and sustained survival of autoreactive B cells promote the development of ectopic germinal centers (GCs), which establish the perfect niche for autoantibody production or lymphomagenesis [4, 5]

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