Objectives To explore the relevance of T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph) in promoting ectopic lymphoid structures (ELS) and B-cell mucosa-associated lymphoid tissue (MALT) lymphomas (MALT-L) in Sjögren’s syndrome (SS) patients. Methods Salivary gland (SG) biopsies with matched peripheral blood were collected from four centres across the European Union. Transcriptomic (microarray and quantitative PCR) analysis, FACS T-cell immunophenotyping with intracellular cytokine detection, multicolor immune-fluorescence microscopy and in situ hybridisation were performed to characterise lesional and circulating Tfh and Tph-cells. SG-organ cultures were used to investigate functionally the blockade of T-cell costimulatory pathways on key proinflammatory cytokine production. Results Transcriptomic analysis in SG identified Tfh-signature, interleukin-21 (IL-21) and the inducible T-cell co-stimulator (ICOS) costimulatory pathway as the most upregulated genes in ELS+SS patients, with parotid MALT-L displaying a 400-folds increase in IL-21 mRNA. Peripheral CD4⁺CXC-motif chemokine receptor 5 (CXCR5)⁺programmed cell death protein 1 (PD1)⁺ICOS⁺ Tfh-like cells were significantly expanded in ELS+SS patients, were the main producers of IL-21, and closely correlated with circulating IgG and reduced complement C4. In the SG, lesional CD4⁺CD45RO⁺ICOS⁺PD1⁺ cells selectively infiltrated ELS+ tissues and were aberrantly expanded in parotid MALT-L. In ELS+SG and MALT-L parotids, conventional CXCR5⁺CD4⁺PD1⁺ICOS⁺Foxp3^- Tfh-cells and a uniquely expanded population of CXCR5^-CD4⁺PD1^hiICOS⁺Foxp3^- Tph-cells displayed frequent IL-21/interferon-γ double-production but poor IL-17 expression. Finally, ICOS blockade in ex vivo SG-organ cultures significantly reduced the production of IL-21 and inflammatory cytokines IL-6, IL-8 and tumour necrosis factor-α (TNF-α). Conclusions Overall, these findings highlight Tfh and Tph-cells, IL-21 and the ICOS costimulatory pathway as key pathogenic players in SS immunopathology and exploitable therapeutic targets in SS.

The significance of the oral manifestations of HIV has been widely recognised since the start of the epidemic. It is estimated that more than 38 million people are living with HIV currently, with more than a third presenting with oral manifestations. Access to optimum clinical management and effective treatment in resource‐rich countries has led to a remarkable decrease in some of the oral manifestations in the HIV population but this is not mirrored in developing countries, where most HIV‐positive patients reside. In this paper, a review of the literature since the start of the HIV infection in different parts of the world is presented to highlight the current significance of the oral conditions in this population. Oral candidiasis was repeatedly reported as the most encountered oral manifestation of HIV in different countries, including in studies on groups on anti‐retroviral therapy. Over time salivary gland disease was reported less in developed countries but was encountered more in developing countries. There is evidence to show that the prevalence of oral warts increased with the establishment of anti‐retroviral therapy. A review of the worldwide prevalence of HIV‐related oral conditions indicates that except for oral hairy leucoplakia, the prevalence of all other nine commonly reported oral conditions remained the same or increased over time. Oral opportunistic infections in HIV‐infected patients are an ongoing clinical burden mainly in developing countries. Maintaining research in the subject and improving access to HIV treatment will help address the oral health inequalities around the world.

Immune reconstitution inflammatory syndrome (IRIS) is a phenomenon observed in patients recovering from immunodeficiency. The clinical presentation of IRIS involves the unmasking of covert infections or the worsening of overt conditions. Several causes and pathways have been suggested, most recognizing an inflammatory flare component occurring in the context of rapid immune reconstitution. In HIV-infected patients, IRIS inadvertently occurs as the consequence of successful antiretroviral therapy, and it is affiliated with improvement of the immune function, complicating the course of the disease and presenting treatment challenges to clinicians. The pathogenesis of IRIS is poorly understood, but in recovering HIV patients, its initiation and progression seem to be primarily linked to an increase in CD4+ T-helper and CD8+ T-suppressor cell count and a reduction in T-regulatory cells, all endorsed by exaggerated cytokine release and activity. The clinical presentation of IRIS is usually atypical. The manifestations depend on the trigger antigen, which can be an infective agent (viable or nonviable), a host antigen, or a tumor antigen. Most IRIS cases are self-limiting, but a few cases can be overwhelming and life-threatening; hence, early recognition is important. In most cases, there is no need to discontinue the antiretroviral therapy, although in the more severe cases, other clinical intervention may be necessary.

Objective: This study aimed to identify peripheral and salivary gland (SG) biomarkers of response/resistance to B cell depletion based on the novel concise Composite of Relevant Endpoints for Sjögren Syndrome (cCRESS) and candidate Sjögren Tool for Assessing Response (STAR) composite endpoints.Methods: Longitudinal analysis of peripheral blood and SG biopsies was performed pre‐ and post‐treatment from the Trial of Anti–B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS) combining flow cytometry immunophenotyping, serum cytokines, and SG bulk RNA sequencing.Results: Rituximab treatment prevented the worsening of SG inflammation observed in the placebo arm, by inhibiting the accumulation of class‐switched memory B cells within the SG. Furthermore, rituximab significantly down‐regulated genes involved in immune‐cell recruitment, lymphoid organization alongside antigen presentation, and T cell co‐stimulatory pathways. In the peripheral compartment, rituximab down‐regulated immunoglobulins and auto‐antibodies together with pro‐inflammatory cytokines and chemokines. Interestingly, patients classified as responders according to STAR displayed significantly higher baseline levels of C‐X‐C motif chemokine ligand‐13 (CXCL13), interleukin (IL)‐22, IL‐17A, IL‐17F, and tumor necrosis factor‐α (TNF‐α), whereas a longitudinal analysis of serum T cell–related cytokines showed a selective reduction in both STAR and cCRESS responder patients. Conversely, cCRESS response was better associated with biomarkers of SG immunopathology, with cCRESS‐responders showing a significant decrease in SG B cell infiltration and reduced expression of transcriptional gene modules related to T cell costimulation, complement activation, and Fcγ‐receptor engagement. Finally, cCRESS and STAR response were associated with a significant improvement in SG exocrine function linked to transcriptional evidence of SG epithelial and metabolic restoration.Conclusion: Rituximab modulates both peripheral and SG inflammation, preventing the deterioration of exocrine function with functional and metabolic restoration of the glandular epithelium. Response assessed by newly developed cCRESS and STAR criteria was associated with differential modulation of peripheral and SG biomarkers, emerging as novel tools for patient stratification. image