T cells in primary Sjögren's syndrome: targets for early intervention

Abstract

A histologic hallmark of primary SS (pSS) is lymphocytic infiltration of the salivary and lacrimal glands, in particular by CD4+ T and B cells. In the early stages of the disease, infiltrates are dominated by CD4+ T cells, while B cell accumulation occurs at later stages. Activated T cells contribute to pathogenesis by producing pro-inflammatory cytokines and by inducing B cell activation, which results in the establishment of a positive feedback loop. In the inflamed glandular tissues, many different CD4+ effector subsets are present, including IFN-γ-producing Th1 cells, IL-17-producing Th17 cells and IL-21-producing T follicular helper cells. In blood from pSS patients, frequently observed abnormalities of the T cell compartment are CD4+ T cell lymphopenia and enrichment of circulating follicular helper T (Tfh) cells. Tfh cells are critical mediators of T cell-dependent B cell hyperactivity and these cells can be targeted by immunotherapy. Inhibition of T cell activation, preferably early in the disease process, can mitigate B cell activity and may be a promising treatment approach in this disease.

Keywords: SS; T cells; biologic therapies; biomarkers; cytokines; histopathology; immunotherapy; lymphocytes.

Fig. 1

Proposed role of CD4⁺ T cells in primary Sjögren’s syndrome (pSS) pathogenesis Antigen is presented to CD4⁺ T cells via MHC class II (HLA) molecules, resulting in CD4⁺ T cell activation. Risk loci in HLA-DR and HLA-DQ regions, associated with pSS, may be involved in a loss of tolerance to self-antigens. Depending on the type of antigen and additional environmental cues, differentiation of naïve cells into Th1 cells, Th17 cells and Tfh cells is induced. IL-12A and STAT4 risk variants may contribute to enhanced Th1 cell differentiation. A second, local hit may induce migration of effector CD4⁺ T cells to salivary and/or lacrimal gland tissues. This stage is clinically reflected in features suggestive of pSS, without the presence of focal periductal infiltrates and without evident signs of B cell hyperactivity. A third hit is probably required to establish a positive feedback loop between T cells and B cells, resulting in T cell–dependent B cell hyperactivity. In this stage, typical features associated with pSS become evident.

Fig. 2

Characteristic features of pSS in the tissue and blood involve Tfh cells and IL-21 (A) Immunofluorescent staining of IL-21 protein in inflamed parotid gland tissue of a pSS patient. 4′,6-diamidino-2-phenylindole was used to image the nuclei. *Excretory duct. **Striated duct. (B) A representative example of a flow cytometric analysis of circulating T cells illustrates the increase in Tfh cells, defined as CD4⁺CD45RA⁻FoxP3⁻ CXCR5⁺PD-1⁺ cells, in pSS patients compared with non-SS sicca patients.