Michele Bombardieri

Queen Mary, University of London | QMUL · Faculty of Medicine and Dentistry

Background In Sjögren Disease (SD) salivary gland epithelial cells (SGEC) sustain inflammation due to their acquired capacity to express/secrete adhesion/pro-inflammatory molecules. However, the mechanisms responsible for SGECs activation remain undetermined. The link between immune cells’ function and cells’ metabolic reprogramming is known under...

Background Digital image analysis (DIA) is increasingly utilized for evaluating salivary gland (SG) histopathology in Sjögren’s disease (SD) [1,2]. DIA, particularly in assessing the area fraction (AF) of lympho-mononuclear cell aggregates, addresses the limitations of the focus score (FS) and minimizes variability between raters and across centers...

Background Rheumatoid Arthritis (RA) is characterized by formation of synovial ectopic lymphoid structures, where we previously showed accumulation of Epstein Barr virus (EBV)-infected B-cells. RA synovial fibroblasts (RA-SFs) can sustain B-cells activation and maturation. In more recent work, we showed that RA-SFs activate Interferon type I signal...

Background In our previous Sjögren’s Disease (SjD) Genome-Wide Association Study (GWAS) in European populations, significant single nucleotide polymorphism (SNP) peaks were identified between PRDM1 and ATG5 [1]. ATG5 is an autophagy-related protein that plays a crucial role in neutrophil extracellular trap (NET) formation, degranulation, and limiti...

Background RNA sequencing (RNA-seq) has emerged as a widely embraced technique for comprehensive gene expression profiling on a large scale. Nonetheless, there is a current absence of accessible and versatile tools that facilitate efficient exploration of RNA-seq datasets from individuals with Sjogren’s disease (SD) for researchers. Objectives Our...

Background To fulfil the energy demands upon activation, lymphocytes undergo a profound metabolic reprogramming (i.e switch towards glycolysis), which sustains their pro-inflammatory function. This concept, which is known under the term “immune-metabolism” [1], has become of great interest in rheumatic diseases; however, little is known in Sjogren...

Background Sjögren’s disease (SjD) is a complex systemic autoimmune disease with substantial morbidity and 21 known genetic associations. The International Sjögren’s Genetics Network (SGENE) is a growing international collaboration focused on understanding how genetic variants influence SjD pathology. As sample sizes increase, we are focusing our e...

Background Sjögren’s syndrome (SS) is the second most common rheumatic autoimmune disorder with a prevalence of 0.5-1% in the adult population. Dryness of salivary (SG) and lacrimal glands is one of the major problems affecting the quality of life of SS patients. To date, the treatments aim to alleviate symptoms without restoring a proper water flu...

Background Sjögren’s disease (SjD) presents an unmet medical challenge as there is currently no cure. Despite advances in understanding the immunopathogenesis of SjD, there is still a pressing need to identify novel biomarkers and therapeutic targets, for better patient stratification and personalized treatment. Objectives To create a fully-detail...

Objective Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren’s syndrome (pSS). Methods In both pSS and non-pSS sicca syndrome p...

Sjögren disease (SD) is a chronic, autoimmune disease of unknown aetiology with significant impact on quality of life. Although dryness (sicca) of the eyes and mouth are the classically described features, dryness of other mucosal surfaces and systemic manifestations are common. The key management aim should be to empower the individual to manage t...

The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease activity, and their topographical expression and longitudinal...

Objective The aim of this study was to assess the relationship between self-reported non-adherence, non-trough drug levels, immunogenicity and conventional synthetic DMARD (csDMARD) co-therapy in TNF inhibitor (TNF-i) drug response in PsA. Methods Serum samples and adherence questionnaires were collected at baseline, 3, 6 and 12 months for PsA pat...

The link between immune cell function and cell metabolic reprogramming is currently known under the term "immunometabolism". Similarly to the Warburg's effect described in cancer cells, in activated immune cells an up-regulation of specific metabolic pathways has been described and seems to be pathogenic in different inflammatory conditions.Sjӧgren...

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose trans...

Sjӧgren's disease (SjD) is a systemic autoimmune disorder characterized by the chronic inflammation and dysfunction of exocrine glands, mainly salivary glands, causing dryness of the eyes and of the mouth. The disease may affect different organs and tissues with complex and heterogeneous clinical presentation, usually with sicca symptoms, profound...

Background NETosis has been described to play a role in the pathogenesis of APS. IgG and sera of APS patients are known to induce NETosis [1], however the direct role of aβ2GPI on NETosis is not fully known. Objectives The aim of this study is to evaluate the interplay between NETosis and aβ2GPI antibodies. Methods HD neutrophils were stimulated...

Both TLR7 and NF-κB hyperactivity are known to contribute to pathogenesis in Systemic Lupus Erythematosus (SLE), driving a pro-interferon response, autoreactive B cell expansion and autoantibody production. UBE2L3 is an SLE susceptibility gene which drives plasmablast/plasma cell expansion in SLE, but its role in TLR7 signalling has not been elucid...

Background Although biological therapies have transformed the outlook for those with rheumatoid arthritis, there is a lack of any meaningful response in approximately 40% of patients. The role of B cells in rheumatoid arthritis pathogenesis is well recognised and is supported by the clinical efficacy of the B-cell-depleting agent rituximab (MabTher...

Objectives: To analyse how the main components of the disease phenotype (sicca symptoms, diagnostic tests, immunological markers and systemic disease) can be driven by the age at diagnosis of primary Sjögren's syndrome (pSS). Methods: By January 2021, the participant centres had included 12,753 patients from 25 countries that fulfilled the 2002/...

Objectives: B cells play a central role in Sjögren's syndrome (SS) whereby autoreactive B-cells populate ectopic germinal centres (GC) in SS salivary glands (SG) and undergo somatic hypermutation (SHM) and class-switch recombination of the immunoglobulin genes. However, the capacity of specific B cell clones to seed ectopic GC in different SG and...

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA;...

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients an...

Immunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibrob...

Ectopic lymphoid structures (ELS) can develop in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and selection are not well understood. Here, we identify a synovial B cell population characterized by co-expression of a family of orphan nuclear receptors (NR4A1-3), which is highly enriched in RA synovial tiss...

Objective To develop a composite responder index in primary Sjögren’s syndrome (pSS): the Sjögren’s Tool for Assessing Response (STAR). Methods To develop STAR, the NECESSITY (New clinical endpoints in primary Sjögren’s syndrome: an interventional trial based on stratifying patients) consortium used data-driven methods based on nine randomised con...

The pathway of Janus tyrosine kinases (JAKs) has a central role in the pathogenesis of Rheumatoid Arthritis (RA) by regulating multiple immune functions and cytokine production. The JAK inhibitor tofacitinib is effective in RA patients not responding to methotrexate or TNF-inhibitors. Since hyperactive autophagy has been associated with impaired ap...

For many decades, the clinical unmet needs of primary Sjögren’s Syndrome (pSS) have been left unresolved due to the rareness of the disease and the complexity of the underlying pathogenic mechanisms, including the pSS-associated lymphomagenesis process. Here, we present the HarmonicSS cloud-computing exemplar which offers beyond the state-of-the-ar...

Primary Sjögren’s syndrome (pSS) is a highly heterogeneous disease in terms of clinical presentation ranging from a mild disease localised to the salivary and lacrimal glands, to multiorgan complications of various degrees of severity, finishing with the evolution, in around 5% of pSS patients, to B cell lymphomas most commonly arising in the infla...

Neutrophil trafficking is a key component of the inflammatory response. Here, we have investigated the role of the immunomodulatory lectin Galectin‐9 (Gal‐9) on neutrophil recruitment. Our data indicate that Gal‐9 is upregulated in the inflamed vasculature of RA synovial biopsies and report the release of Gal‐9 into the extracellular environment fo...

Objectives: To develop and evaluate the Clinical Trials EULAR Sjögren's Syndrome Disease Activity Index (ClinTrialsESSDAI), consisting of frequently active clinical domains of the ESSDAI, using two randomised controlled trials in primary Sjögren's syndrome (pSS). Methods: The ASAP-III trial in abatacept (80 pSS patients) and TRACTISS trial in ri...

Since the beginning of the COVID-19 disease pandemic caused by the new coronavirus SARS-CoV-2, the disease has claimed over 205M cases (205,338,159) and 4,333,094 deaths (WHO dashboard - accessed 15/08/2021). In addition to the overwhelming impact on healthcare systems treating acutely ill patients, the pandemic has had an impact on all other aspec...

Objectives: Sjögren's syndrome (SS) is a chronic autoimmune disease characterised by lymphocytic infiltration into the salivary glands (SG) and, in a subset of patients, formation of ectopic lymphoid structures (ELS) in the glands. However, the mechanisms of how ELS form ectopically are not fully elucidated. Here we used a viral inducible murine m...

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease resulting from the inflammatory infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to secretory dysfunction and serious complications including debilitating fatigue, systemic autoimmunity, and lymphoma. Like other autoimmune disorders, a strong interferon (I...

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease. It is the second most common rheumatic autoimmune disorder, affecting 0.7% of European Americans and up to 1% of people globally. pSS is characterized by the impaired secretory function of exocrine glands, including salivary and lachrymal glands. A lymphocytic infiltration...

Background Several large randomised controlled trials (RCTs) in primary Sjögren’s syndrome (pSS) failed to demonstrate drug efficacy. ¹⁻⁴ Many of these trials used ESSDAI as primary endpoint, showing large but similar response rates in active treatment and placebo groups. 1,3,4 Given the heterogeneous nature of pSS, there is need for a composite en...

Background The pathogenic role of B-cells in primary Sjögren’s Syndrome (pSS) is well established and B cell abnormalities. Because of the substantial role of B-cells, rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, has been considered as a potential biologic disease modifying drug to reduce disease activity in pSS. To date, the TRial fo...

Background The study of synovial tissue in patients with Rheumatoid Arthritis (RA) has led to the identification of synovial patterns of immune cell infiltration and specific cellular subsets associated that have been disease activity and clinical outcomes( 1 – 3 ). However, the relationship of circulating and synovial immune cell sub-sets with his...

Ectopic lymphoid structures (ELS) can develop in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and selection are not well understood. Here, we identified a unique B cell population in the synovium characterized by co-expression of a family of orphan nuclear receptors, NR4A1 (also known as NUR77), NR4A2 (NU...

Background Recent randomised controlled trials (RCTs) in primary Sjögren's syndrome used the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) as their primary endpoint. Given the heterogeneous and complex nature of primary Sjögren's syndrome, it might be more appropriate to also assess other clinically r...

BACKGROUND Autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. The functional features of cardiac autoimmunity in humans remain undefined because of the challenge of studying immune responses in situ. We previously described a subset of c-mesenchymal epithelial transition factor (c-Met)–expressing (c-Met ⁺...

Programmed death cell receptor 1 (PD-1) is expressed on T cells upon T cell receptor (TCR) stimulation. PD-1 ligand 1 (PD-L1) is expressed in most tumor environments, and its binding to PD-1 on T cells drives them to apoptosis or into a regulatory phenotype. The fact that PD-L1 itself is also expressed on T cells upon activation has been largely ne...

Objective To evaluate the effects of targeting Ikaros and Aiolos by cereblon modulator iberdomide on the activation and differentiation of B-cells from patients with systemic lupus erythematosus (SLE). Methods CD19 ⁺ B-cells isolated from the peripheral blood of patients with SLE (n=41) were cultured with TLR7 ligand resiquimod ±IFNα together with...

Background Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells—the target for rituximab—in the main disease tiss...

Ectopic lymphoid structures (ELS) can develop in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and selection are not well understood. Here, we identify a synovial B cell population characterized by co-expression of a family of orphan nuclear receptors (NR4A1-3), which is highly enriched in RA synovial tiss...

The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol (1). This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence (NICE) accreditation.

Autoimmune diseases (AIDs) share similar serological, clinical, and radiological findings, but, behind these common features, there are different pathogenic mechanisms, immune cells dysfunctions, and targeted organs. In this context, multiple lines of evidence suggest the application of precision medicine principles to AIDs to reduce the treatment...

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 collec...

Objective Ectopic lymphoid structures (ELS) develop at sites of infection, autoimmunity, and cancer. In patients with Sjögren's syndrome (SS), ELS support autoreactive B cell activation and lymphomagenesis. Interleukin‐27 (IL‐27) is a key regulator of adaptive immunity and limits Th17 cell–driven pathology. We undertook this study to elucidate the...

The pathogenesis of primary Sjögren's syndrome (pSS) remains poorly understood. However, important efforts have been made during the last few months. In this review, following the others of this series we will summarise the most recent literature on pSS pathogenesis focusing in particular on new insights into pSS animal models, genetics and epigene...

Objectives: To assess whether the use of digital image analysis (DIA) in primary Sjögren's syndrome (pSS) for the calculation of the total area of the salivary gland (SG), focus score (FS) and SG area occupied by the inflammatory infiltrate (area fraction, AF), was able to generate reproducible readings among different raters, reducing disagreemen...

There is accumulating evidence that patients with primary Sjögren's syndrome (pSS) display aberrant CD4+ T cell responses, both in the peripheral compartment and in the inflamed salivary glands. CD4+ T cell abnormalities are also critically associated with B cell hyper activation, one of the hallmarks of disease, which is linked with disease severi...

Background Despite substantial improvements in long-term clinical outcomes, a significant proportion of rheumatoid arthritis (RA) patients still fail to respond to treatment adequately, and early prognostic biomarkers of response are missing. Single-cell transcriptomic studies on RA synovial tissue (ST) have shown that MerTK is highly expressed in...

Objectives: To assess whether the histopathological features of the synovium before starting treatment with the TNFi certolizumab-pegol could predict clinical outcome and examine the modulation of histopathology by treatment. Methods: Thirty-seven RA patients fulfilling UK NICE guidelines for biologic therapy were enrolled at Barts Health NHS trust...

Background Psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are clinically distinct autoimmune joint disorders both marked by the chronic infiltration of the synovial tissue (ST) by inflammatory cells. It has been proposed that a more prominent thickening of the lining layer and a higher number of T/B-cells within the sublining characterised...

Background Biologic therapies have transformed the outlook for RA but the significant health economic impact of these therapies has highlighted the need to define predictive markers of response. Rituximab (RTX) is licensed for use following failure of csDMARDs and TNF inhibitor (TNFi) therapy. However, in this increasing therapeutically resistant c...

Background A third of Sjögren’s syndrome (SS) patients develop ectopic lymphoid structures (ELS) in their salivary glands (SG). ELS play an active role in autoimmunity and contribute to the development of MALT lymphoma. Interleukin 27 (IL-27) exerts key immunomodulatory actions on numerous immune cells but its role in the formation and regulation o...

We previously showed that anti-neutrophil extracellular trap (NET) rheumatoid arthritis (RA)-rmAbs derived from CD19+ B cells within RA human synovial tissues frequently react against NETs. In this study, we aimed to characterize the importance of affinity maturation via somatic hypermutation (SHM) within the Ig variable H (VH) and variable L (VL)...

Objective To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA). Methods Synovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patient...

Background Primary Sjögren's syndrome is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands. To our knowledge, no systemic therapies for primary Sjögren's syndrome have shown efficacy. CD40–CD154-mediated T cell–B cell interactions in primary Sjögren's syndrome contribute to aberrant lympho...

Objective: To characterize the systemic phenotype of primary Sjögren's syndrome at diagnosis by analysing the EULAR-SS disease activity index (ESSDAI) scores. Methods: The Sjögren Big Data Consortium is an international, multicentre registry based on worldwide data-sharing cooperative merging of pre-existing databases from leading centres in cli...

Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4+ T cel...

Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4+ T cel...

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune rheumatic disease with symptoms including dryness, fatigue, and pain. The previous work by our group has suggested that certain proinflammatory cytokines are inversely related to patient-reported levels of fatigue. To date, these findings have not been validated. This study aims to validate t...

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response.

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster ana...

Background: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. / Methods: We did hierarchical cluster...

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren’s syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster...

There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein we report a comprehensive RNA-sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood R...

Objectives: SS is an autoimmune condition characterized by systemic B-cell activation, autoantibody production and ectopic germinal centres' formation within the salivary gland (SG). The extent of SG infiltrate has been proposed as a biomarker of disease severity. Plasma levels of CXCL13 correlate with germinal centres' activity in animal models a...

Objectives: To analyse the phenotype of patients with primary Sjogren syndrome (SjS) in whom a lymphoproliferative disease is diagnosed concomitantly. Methods: By January 2019, The Big Data Sjögren Project included 11,420 consecutive patients with primary SjS recruited from 24 countries of the five continents. Results: 117 (1%) patients were diagno...

Background Saliva and tear flow rates and minor salivary gland biopsy are typically used to assess gland function and disease activity in primary Sjögren’s syndrome (pSS); however, these have limitations. Imaging methods can directly visualize and generate quantitative values in individual glands. ¹⁸F-FDG-PET/CT (¹⁸F-FDG) measures glucose metabolis...

Background Despite early intervention with disease modifying therapy a high percentage of patients (∼30%) fail to respond and require escalation to advanced therapies such as TNFi, with no available biomarkers to predict response. Whether synovial signatures predicting subsequent response to TNFi therapy can be identified at disease onset remains a...

Background Approximately 30% of Sjögren’s Syndrome (SS) patients develop Ectopic Lymphoid Structures (ELS) in their salivary glands (SG). ELS play an active role in autoimmunity and contribute to the development of MALT lymphoma. Interleukin 27 (IL-27) exerts key immunomodulatory actions on CD4 T cells with both pro and anti-inflammatory roles but...

Background Primary Sjögren’s syndrome (pSS) is a systemic progressive autoimmune disease characterised by formation of lymphoid structures and germinal centres within glandular tissue. Iscalimab (CFZ533) is a novel monoclonal antibody that potently and selectively blocks CD40, a co-stimulatory pathway receptor important for germinal centre reaction...

Background Psoriatic Arthritis (PsA) and Rheumatoid Arthritis (RA) are autoimmune joint diseases characterised by chronic inflammation of the synovial tissue (ST). It has been previously suggested that PsA-ST has less marked hyperplasia of the synovial lining and fewer infiltrating T/B cells in comparison with RA. However, several confounders such...

Objectives To analyse how the age at diagnosis modifies the phenotype of primary Sjögren syndrome (SS) Methods The Big Data Sjögren Project was formed in 2014 to take a “high-definition” picture of the main features of primary SS at diagnosis by merging international SS databases. By January 2019, the database included 11,420 patients from 24 coun...

Objectives To analyze the clinical phenotype of primary Sjögren syndrome (SjS) with focal lymphocytic sialadenitis (FLS) without Ro autoantibodies (FLS+/Ro-). Methods The International Big Data Sjögren Project was designed in 2014 to take a “high-definition” picture of the primary SjS at diagnosis (2002 criteria) by merging international databases...

Background The pathway of Janus tyrosine kinases (JAKs) has a central role in the pathogenesis of rheumatoid arthritis (RA) by regulating multiple immune functions and cytokine production. The orally available JAK inhibitor CP-690,550, named tofacitinib, is able to inhibit Jak1, Jak2 and Jak3 and it showed a great clinical efficacy in RA patients n...

Background The transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos), essential for the maturation, differentiation and survival of B cells, have been linked to Systemic Lupus Erythematosus (SLE). The cereblon modulator Iberdomide, which induces degradation of IKZF1 and IKZF3, is undergoing clinical trials in SLE. However, the role of IKZF1 and I...

Background Polymorphisms of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for the maturation, differentiation and survival of B cells, have been linked to systemic autoimmunity. The Cereblon modulator iberdomide, known to induce their degradation, is being explored as a therapeutic option in Systemic Lupus Erythematosus (SLE)....

Background B/T cell aggregates in the salivary glands (SG) of Sjögren’s syndrome (SS) can form ectopic lymphoid structures (ELS) with germinal centers (GC), which are linked to MALT lymphoma (MALT-L) development. T follicular-helper cells (Tfh), main producers of IL21, are crucial for affinity maturation and class-switching of GC B cells, and may b...

Background The role of B cells in the pathogenesis of Rheumatoid Arthritis (RA) is well recognised and has been reinforced by the established efficacy of B cell depleting treatments. However, B cell infiltration in synovia is highly variable and their association with clinical disease activity has been inconsistently reported, with contradicting re...

Despite the well-established role of B cells in the pathogenesis of primary Sjögren's syndrome (pSS), the beneficial role of B-cell depletion therapy with rituximab remains elusive in this condition, contrary to other autoimmune diseases. Although early, small-scale studies showed promising results, two recent large randomised controlled trials did...

Tertiary lymphoid organs named also tertiary lymphoid structures (TLS) often occur at sites of autoimmune inflammation, organ transplantation and cancer. Although the mechanisms for their formation/function are not entirely understood, it is known that TLS can display features of active germinal centres supporting the proliferation and differentiat...

Background Polymorphisms in IKZF1 (Ikaros) and IKZF3 (Aiolos), which are transcriptions factors essential for B cell activation, maturation and differentiation, have been associated with Systemic Lupus Erythematosus (SLE). However the functional role of IKZF1 and IKZF3 in the context of failed B cell checkpoints and aberrant plasmablast development...

Objectives To report on fatigue in patients from the United Kingdom Primary Sjögren’s Syndrome Registry identifying factors associated with fatigue and robust to assignable causes such as comorbidities and medications associated with drowsiness. Methods From our cohort (n=608) we identified those with comorbidities associated with fatigue, and tho...

Objectives To unravel the hierarchy of cellular/molecular pathways in the disease tissue of early, treatment-naïve rheumatoid arthritis (RA) patients and determine their relationship with clinical phenotypes and treatment response/outcomes longitudinally. Methods 144 consecutive treatment-naïve early RA patients (<12 months symptoms duration) unde...

Lymphoma development is the most serious complication of SS and the main factor impacting on mortality rate in patients with this condition. Lymphomas in SS are most commonly extranodal non-Hodgkin B-cell lymphomas of the mucosa-associated lymphoid tissue and frequently arise in salivary glands that are the target of a chronic inflammatory autoimmu...

Career situation of first and presenting author Post-doctoral fellow. Introduction Sjogren’s syndrome (SS) is an autoimmune condition characterised by systemic B cell activation, autoantibody production and ectopic germinal centers (GC) formation within salivary gland (SG). The extent of SG infiltrate has been proposed as biomarker of disease seve...

Objective We aimed to understand the role of the tyrosine phosphatase PTPN14—which in cancer cells modulates the Hippo pathway by retaining YAP in the cytosol—in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). Methods Gene/protein expression levels were measured by quantitative PCR and/or Western blotting. Gene kno...