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The germinal center (GC) is a hallmark microenvironment for the T-dependent antibody response, in which activated B cells divide, mutate their antigen receptor genes, compete for antigen, and are selected on the basis of high-affinity antigen binding in order to produce protective antibodies. GCs form in the center of the B cell follicle and GC B cells remain both spatially confined to their niche and segregated from naive B cells in the surrounding follicle. In addition, GC size is tightly controlled, and it is not understood whether the spatial organization and physical restrictions play a role in controlling GC B cell growth and homeostasis. We set out to identify cues involved in positioning GC B cells in the center of the follicle and contributing to their confinement within the GC.Sphingosine-1-phosphate receptor-2 (S1P2)-deficient mice develop diffuse large B cell lymphoma. However, the role of S1P2 in normal GC physiology is unknown. Here we show that S1P2-deficient GC B cells outgrow their wild-type counterparts in chronically-established GCs. We find that S1P2-, G12-G13- and p115RhoGEF-mediated antagonism of Akt regulates cell viability and is required for growth control in chronically proliferating GCs. We also find that S1P2 inhibits GC B cell responses to follicular chemoattractants and helps confine cells to the GC. Moreover, S1P2 overexpression promotes centering of activated B cells within the follicle. We suggest that by inhibiting Akt activation and migration, S1P2 helps restrict GC B cell survival and localization to an S1P-low niche at the follicle center.

Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0-10 scale) and comments. Criteria for agreement were a mean score >= 6/10 and 75% of respondents scoring >= 6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus.

Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0-10 scale) and comments. Criteria for agreement were a mean score ≥6/10 and 75% of respondents scoring ≥6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus.

We thank Alunno et al 1 for their comments, as a response to our recent publication2 in which we describe that, in contrast to the prevailing view, germinal centres in diagnostic labial gland biopsies are not predictive for the development of mucosa-associated lymphoid tissue (MALT) lymphoma in parotid salivary glands in patients with (primary) Sjogren’s syndrome (pSS). As we2 and others also noted before,3–6 Alunno et al 1 underpin in their comments the need for standardisation of the detection method of germinal centres in salivary gland biopsies in patients with pSS. Germinal centres are structures that arise in B-cell follicles of secondary lymphoid organs as a response to antigenic stimulation. In these structures, high-affinity memory B-cells are generated, as a consequence of an intimate interplay between B-cells, follicular helper T cells (TFH) and immune-complex presenting follicular dendritic cells (FDCs). Germinal centres can also be found within B-cell areas of ectopic (tertiary) lymphoid tissue that develops in target tissues of various rheumatic autoimmune diseases, including pSS.7 While detection in secondary lymphoid tissue is …

We have read with great interest the letter to the editor by van Roon et al 1 commenting on our paper ‘Towards personalised treatment in primary Sjogren's syndrome: baseline parotid histopathology predicts responsiveness to rituximab treatment’.2 The authors argue that there is a need for standardisation of the histopathological characteristics of salivary gland tissue of patients with primary Sjogren's syndrome (pSS), in general, and of the presence of germinal centres (GCs), in particular. We fully agree with van Roon et al 1 and other authors about the need for consensus guidelines to standardise the histopathological evaluation of salivary gland biopsies in patients with pSS.3 A standardised scoring system may facilitate prognostication and stratification of patients with pSS and is needed for a valid evaluation of various clinical trials.3 In particular, histological definition of GCs in salivary gland tissue is warranted, since these structures can be difficult to detect in diagnostic H&E-stained tissue sections. Detection of GCs in the periductal lymphoid infiltrates of the salivary glands is clinically relevant, because the presence of these structures is associated with more severe disease.4 Importantly, the presence of GCs in minor salivary gland biopsies has been postulated to be a predictor of patients who are at risk of lymphoma development.5 …

Lymphotoxin beta (LTbeta), a member of the tumor necrosis factor family, plays an important role in lymphoid organogenesis. In order to determine whether LTbeta is involved in cellular immunity, we investigated the antiviral immune response of LTbeta-deficient (LTbeta -/-) mice to lymphocytic choriomeningitis virus (LCMV). Cytotoxic T lymphocyte (CTL) responses to LCMV were severely diminished, leading to viral persistence in brain and kidney. However, major functions of LTbeta-deficient T lymphocytes and dendritic cells were intact. Reconstitution of irradiated LTbeta +/+ mice with LTbeta -/- bone marrow induced a disorganized splenic structure, accompanied by impairment of the LCMV-specific CTL response. These data indicate that the absence of LTbeta does not affect the intrinsic function of T lymphocytes or of dendritic cells but that the structural integrity of the spleen is strongly associated with generation of antiviral immunity.

Histopathological assessment of salivary gland biopsies is an important element of the diagnostic work-up of Sjögren's syndrome (SS) (Fox, 2017; Kroese et al., 2018). Microscopic evaluation of salivary glands of primary SS (pSS) patients reveals characteristic periductal lymphocytic infiltrates (foci), which mainly consist of T- and B-lymphocytes, as well as a variety of non-lymphoid cells, including dendritic cells and macrophages. Over time, these infiltrates may become organised to ectopic lymphoid tissue with T/B cell compartmentalisation, presence of CD21+ follicular dendritic cell (FDC) networks and high endothelial venules (Fisher et al., 2017; Kroese et al., 2014; Kroese et al., 2018; Salomonsson et al., 2003).