Abatacept treatment in patients with primary SS reduces circulating Tfh cell numbers and expression of the activation marker ICOS on T cells. Lower numbers of activated circulating Tfh cells contribute to attenuated Tfh cell-dependent B cell hyperactivity and may underlie the efficacy of abatacept.

In primary Sjögren syndrome (pSS), the function of the salivary glands is often considerably reduced. Multiple innate immune pathways are likely dysregulated in the salivary gland epithelium in pSS, including the nuclear factor-κB pathway, the inflammasome and interferon signalling. The ductal cells of the salivary gland in pSS are characteristically surrounded by a CD4 + T cell-rich and B cell-rich infiltrate, implying a degree of communication between epithelial cells and immune cells. B cell infiltrates within the ducts can initiate the development of lymphoepithelial lesions, including basal ductal cell hyperplasia. Vice versa, the epithelium provides chronic activation signals to the glandular B cell fraction. This continuous stimulation might ultimately drive the development of mucosa-associated lymphoid tissue lymphoma. This Review discusses changes in the cells of the salivary gland epithelium in pSS (including acinar, ductal and progenitor cells), and the proposed interplay of these cells with environmental stimuli and the immune system. Current therapeutic options are insufficient to address both lymphocytic infiltration and salivary gland dysfunction. Successful rescue of salivary gland function in pSS will probably demand a multimodal therapeutic approach and an appreciation of the complicity of the salivary gland epithelium in the development of pSS.

Th17 cells play an important physiological role at mucosal barriers, and are involved in inflammatory responses to pathogens. Th17 cells and their signature cytokine IL-17 are also present in salivary gland lesions of primary Sjögren's syndrome (pSS) patients and can be elevated in their peripheral blood. In pSS patients, clear correlations between increased Th17 cell activity and symptoms of the disease have not been found, but Th17 cells may contribute to disease progression, for example by supporting autoreactive B cell responses. In mouse models of pSS, Th17 cells play an important role in pathogenesis, particularly at disease onset, when there is a disturbed balance between T effector and T regulatory cells. Studying the pathogenicity of Th17 cells in humans is complicated due to the plasticity of this cell subset, allowing them to obtain different effector functions depending on the local environment. Th17 cells can develop towards Th17.1 cells, producing both IL-17 and IFN-γ, or even towards Th1-like cells producing IFN-γ in the absence of IL-17. These effector subsets may be more pathogenic than bona fide Th17 cells. Co-expression of IFN-γ by Th17 cells has been shown to promote chronic inflammation in several autoimmune diseases and may also contribute to pSS pathogenesis. In line with the noticeable role of IL-17 in pSS mouse models, interference with Th17 cell generation, recruitment or effector functions (e.g. IL-17 inhibition) can prevent or ameliorate disease in these models. Therapies targeting Th17 cells or IL-17 have not been tested so far in pSS patients, although treatment with rituximab seems to lower local and systemic IL-17 protein levels, and to a lesser extent also chemokine receptor-defined Th17 cells. In this review we discuss current knowledge of pathogenicity and plasticity of Th17 cells in human pSS and murine models of pSS. We postulate that plasticity towards Th17.1 cells in pSS may enhance pathogenicity of Th17 cells at the main target sites of the disease, i.e. salivary and lacrimal glands.

These data indicate that autoimmune disease in humans is characterized by enhanced BTK activity, which is linked not only to autoantibody formation but also to T cell activity.

This study represents the first characterization of SGSCs in pSS, and also the first linkage between an autoimmune disease and a parenchymal premature ageing phenotype. The knowledge garnered in this study argues that disease modifying anti-rheumatic drugs used to treat pSS are not likely to restore saliva production, but should be supplemented with fresh SGSCs to recover saliva production. This article is protected by copyright. All rights reserved.

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.

B cell depletion therapy in patients with pSS results in normalization of the elevated levels of circulating TFH cells. This reduction is associated with improved objective clinical disease activity measures. Our observations illustrate the pivotal role of the crosstalk between B cells and TFH cells in the pathogenesis of pSS.

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