Ectopic Germinal Center Formation Research Articles

Chemokines and lymphocyte homing in Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as α4β7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-α, interferon (IFN)-α, IFN-β, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-β receptor pathway, and nuclear factor-κB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS.

MiR-146a in myasthenia gravis thymus: from uncontrolled innate immunity to B cell-mediated autoimmunity

The thymus is the main site of autoimmunity development in myasthenia gravis (MG) associated with anti-acetylcholine receptor (AChR) autoantibodies, a prototypic autoimmune disease affecting neuromuscular junction. Most MG patients with early-onset disease presents follicular hyperplastic changes of the thymus, that are critically implicated in the initiation and perpetuation of the autoimmune response against the AChR. Uncontrolled activation of Toll-like receptor (TLR)-mediated innate immune responses, chronic inflammation and ectopic germinal center (GC) formation are key pathological features of hyperplastic thymus in MG, indicating that a close link between innate immunity and B cell-mediated autoimmunity underlies the intra-thymic pathogenesis of MG.
 MiR-146a, an “immune-miR” acting as key modulator of both innate and adaptive immunity, is a potent inhibitor of TLR signaling pathways, able to prevent and avoid an overstimulation of the inflammatory response by targeting the NF-κB signaling transducers IRAK1 and TRAF6. At the same time, miR-146a modulates the expression of c-REL, ICOS and ICOSL, which are crucial regulators of B cell function and GC response. Dysregulation of miR-146a expression is a common molecular event in several autoimmune disorders. Our recent findings revealed defective expression of miR-146a, associated with over-expression of its TLR- and B cell-related target genes, in follicular hyperplastic MG thymuses, indicating that loss of regulatory functions of this miRNA may significantly contribute to the immunopathological steps leading to MG. Of note, corticosteroids were found to increase the miR-146a expression levels, thus suggesting the miRNA capacity to mediate the effects of these drugs in inducing immunosuppression and autoimmunity control. 
 In this review, we discuss the role of miR-146a as a molecular bridge between innate and adaptive immunity, and summarize the current knowledge on the miRNA contribution to the pathogenesis of MG. Based on our and literature data, we highlight the miR-146a potential as biomarker for therapeutic monitoring, as well as target of future advanced RNA-based therapies to modulate the immune system and counteract the autoimmune response in MG.

Human Parvovirus B19 May Be a Risk Factor in Myasthenia Gravis with Thymoma

Our previous studies have demonstrated that human parvovirus B19 (B19V) is involved in the pathogenesis of thymic hyperplasia-associated myasthenia gravis (MG). However, more cases need to be assessed to further elucidate the relationship between this virus and thymoma-associated MG. The clinicopathological characteristics, presence of B19V DNA, and B19V VP2 capsid protein expression of 708 cases of thymomas were investigated using nested polymerase chain reaction (PCR), TaqMan quantitative (q) PCR, immunohistochemistry, fluorescent multiplex immunohistochemistry, and electron microscopy. Patients with MG or ectopic germinal centers (GCs) were significantly younger than those without MG (P < 0.0001) or GCs (P = 0.0001). Moreover, significantly more GCs were detected in thymomas associated with MG than in those without MG (P < 0.0001). The results of nested PCR and TaqMan qPCR were consistent, and B19V DNA positivity was only associated with presence of GCs (P = 0.011). Immunohistochemically, positive staining was primarily detected in neoplastic thymic epithelial cells (TECs) and ectopic GCs. The positive rate of B19V VP2 was significantly higher in thymoma with MG or GCs than in thymoma without MG (P = 0.004) or GCs (P = 0.006). Electron microscopy showed B19V particles in the nuclei of neoplastic TECs and B cells from GCs. We conclude that the pathogenesis of MG is closely associated with the presence of GCs, and B19V infection is plausibly an essential contributor to formation of ectopic GCs in thymoma. To the best of the authors' knowledge, this is the first study to elucidate the role of B19V in thymoma-associated MG and provide new ideas for exploring the etiopathogenic mechanism of MG.

Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma

Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG frequently develops in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-sequencing, we identify ectopic expression of neuromuscular molecules in MG-type thymoma. These molecules are found within a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we name neuromuscular mTECs (nmTECs). MG-thymoma also exhibits microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell–cell interaction analysis also predicts the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma is further confirmed immunohistochemically and by cellular composition estimation from the MG-thymoma transcriptome. Altogether, this study suggests that nmTECs have a significant function in MG pathogenesis via ectopic expression of neuromuscular molecules.

Does HTLV-1 Infection Show Phenotypes Found in Sjögren's Syndrome?

Viruses are a possible cause for Sjögren’s syndrome (SS) as an environmental factor related to SS onset, which exhibits exocrine gland dysfunction and the emergence of autoantibodies. Although retroviruses may exhibit lymphocytic infiltration into exocrine glands, human T-cell leukemia virus type 1 (HTLV-1) has been postulated to be a causative agent for SS. Transgenic mice with HTLV-1 genes showed sialadenitis resembling SS, but their phenotypic symptoms differed based on the adopted region of HTLV-1 genes. The dominance of tax gene differed in labial salivary glands (LSGs) of SS patients with HTLV 1-associated myelopathy (HAM) and adult T-cell leukemia. Although HTLV-1 was transmitted to salivary gland epithelial cells (SGECs) by a biofilm-like structure, no viral synapse formation was observed. After infection to SGECs derived from SS patients, adhesion molecules and migration factors were time-dependently released from infected SGECs. The frequency of the appearance of autoantibodies including anti-Ro/SS-A, La/SS-B antibodies in SS patients complicated with HAM is unknown; the observation of less frequent ectopic germinal center formation in HTLV-1-seropositive SS patients was a breakthrough. In addition, HTLV-1 infected cells inhibited B-lymphocyte activating factor or C-X-C motif chemokine 13 through direct contact with established follicular dendritic cell-like cells. These findings show that HTLV-1 is directly involved in the pathogenesis of SS.

MO142A SINGLE-CENTER CASE SERIES OF 150 PATIENTS WITH RENAL FANCONI SYNDROME

Abstract Background and Aims Renal Fanconi syndrome (RFS) is characterized by generalized dysfunctions of renal proximal tubular (PT) transport. The causes of FS can be inherited or acquired, the latter of which mostly includes drugs, heavy metals, monoclonal light chains (LC), and primary Sj gren’s syndrome (pSS). We intended to observe the clinico-pathological features of RFS with different etiologies. Method From January 2012 to September 2018, all the patients diagnosed as RFS in our hospital were enrolled. Their clinicopathological records were retrospectively reviewed. The diagnosis of RFS was defined as existence of ≥ 3 of the following five items alone or ≥ 2 items combined with an evidence of PT damages in kidney pathology: (I) normoglycemic glycosuria; (II) generalized aminoaciduria; (III) hypophosphatemia and hyperphosphaturia; (IV) hypouricemia and hyperuricosuria; (V) proximal RTA. Results: 1. Clinical characteristics We identified 150 RFS patients, with an average age of (45.9±14.2) years old and male: female ratio 1.3:1. They presented with different degrees of PT dysfunctions and the most common were hypophosphatemia (83.2%) and aminoaciduria (80.6%). Their mean eGFR levels were 76.3 (4.5-188.6) ml/min/1.73m2 with 73.5% had proteinuria. 2. Renal pathological features 47 RFS patients received kidney biopsy and the most common pathological diagnosis was interstitial nephritis. They all presented with different degrees of proximal tubule atrophy, defective brush border, interstitial edema and fibrosis. 3. Etiology-related clinicopathologic features The most common causes of our RFS were LC (14.0%), drugs (13.3%), and pSS (9.3%). Compared to pSS associated RFS, LC associated RFS patients showed a higher prevalence of bone involvement, more severe proteinuria and less severe hypokalemia (P &amp;lt; 0.05) despite similar eGFR levels. Specific renal pathological features were seen in different etiology groups, including crystalline formation and increased lysosomes in PT cells under electron microscope in LC associated RFS, and CD21 positive ectopic germinal center formation in renal interstitum in parts of the pSS associated RFS. Conclusion We identified 150 RFS with different etiologies and they showed etiology-specific patterns of PT dysfunctions and renal pathologic changes.

An imbalance between blood CD4+CXCR5+Foxp3+ Tfr cells and CD4+CXCR5+Tfh cells may contribute to the immunopathogenesis of rheumatoid arthritis

BackgroundFollicular helper T (Tfh) cells are a subgroup of activated CD4+ T cells which can assist the formation and maintenance of germinal centers. Follicular regulatory T (Tfr) cells are a new class of regulatory T cells which play a major role in suppressing cells in humoral immunity. In contrast to the role of Tfh cells, Tfr cells can inhibit the function of Tfh cells and B cells. Imbalance of blood Tfr/Tfh ratio resulted in the expansion of auto-reactive B cells and auto-antibody production (). However, the effect of Tfr cells and Tfh cells in the pathogenesis of RA (rheumatoid arthritis) is unclear. The purpose of this study was to investigate the function of Tfr cells and Tfh cells in the pathogenesis of RA. MethodsWe recruited 20 patients fulfilled the the American College of Rheumatology diagnosis criteria and 20 healthy controls (HCs). The number of CD4+CXCR5+Foxp3+ Tfr cells and CD4+CXCR5+ Tfh cells in 20 RA patients were measured by flow cytometry analysis. Furthermore, the correlations between the Tfr/Tfh ratio and the characteristic clinical parameters were assessed. The serum levels of IL-21(interleukin-21), CXCL13 (chemokine (C-X-C motif) ligand 13) and TGF-β (Transforming growth factor-β) were measured by ELISA. The formation of ectopic germinal center (GC) of synovial membrane was examined by H&E staining. The transcriptional levels of CXCR5 (C-X-C chemokine receptor type 5), CXCL13, ICOS (inducible co-stimulater) and TGF-β mRNA were also analyzed. In addition, the expression of Bcl-6 (B-cell lymphoma 6), CXCR5, CXCL13 and ICOS in synovial membrane were examined by immunohistochemistry. ResultsRA patients had more Tfh cells in peripheral blood, conversely, the frequency of blood Tfr cells (p < 0.05) and the ratio of Tfr/Tfh were significantly decreased compared to healthy controls (p < 0.05, p < 0.01). Furthermore, the ratio of Tfr/Tfh was negatively correlated with values of ESR (r=-0.57, p < 0.05), RF (r=-0.5275, p < 0.001), CRP (r=-0.4486, p < 0.001), IgG (r=-0.4631, p < 0.05), DAS28 scores (r=-0.5645, p < 0.01), as well as the levels of IL-21(r=-0.7398, p < 0.01), CXCL13 (r=-0.4832, p < 0.05). However, the ratio of Tfr/Tfh was positively with the serum level of TGF-β (r=0.5115, p < 0.05). Higher mRNA expression of CXCR5, CXCL13, ICOS and lower TGF-β mRNA expression were observed in RA patients. The serum expression level of IL-21, CXCL13 was significantly increased and expression of TGF-β was significantly decreased in RA patients. Furthermore, ectopic germinal center formation and higher expression of Bcl-6, CXCR5, ICOS, CXCL13 in the synovial membrane of the joints in RA patients were observed. ConclusionsThe decreased blood CD4+CXCR5+Foxp3+ Tfr cells/CD4+CXCR5+ Tfhcells may be responsible for the immunopathogenesis of RA.

Catalpol ameliorates Sjögren’s Syndrome by modulating interplay of T and B cells

Catalpol is an active ingredient of Rehmanniae Radix, a medical herb used frequently in treating primary Sjogren’s Syndrome (pSS). However, no study has assessed the therapeutic effects of catalpol in treating Sjogren’s Syndrome. This study aimed to investigate the therapeutic effects of catalpol for pSS by evaluating the water consumption, stimulated salivary flow rates, sialadenitis, T cell subsets and related cytokine levels. Catalpol treated mice had improved stimulated salivary flow rates and water consumption compared to mice from the control group. Catalpol also reduced the lymphocytic infiltration and prevented the formation of ectopic germinal centers. These effects, especially in the catalpol high dose group, were associated with elevated CD4+ CXC-R5+ PD-1+ Foxp3+ T follicular regulatory (Tfr) cells (1.572 % vs 1.118 %, P = 0.0005) and a higher ratio of Tfr cells to T follicular helper (Tfh) cells (2.137 vs 1.541, P = 0.0007). Downregulated levels of IFN-γ and BAFF in serum and submandibular glands were also noted in catalpol treated groups. Our work indicated that catalpol might be a potential drug for treating pSS by regulating the interplay between T and B cells.

Therapies for multiple sclerosis targeting B cells

Increasing evidence suggests that B cells contribute both to the regulation of normal autoimmunity and to the pathogenesis of immune mediated diseases, including multiple sclerosis (MS). B cells in MS are skewed toward a pro-inflammatory profile, and contribute to MS pathogenesis by antibody production, antigen presentation, T cells stimulation and activation, driving autoproliferation of brain-homing autoreactive CD4+ T cells, production of pro-inflammatory cytokines, and formation of ectopic meningeal germinal centers that drive cortical pathology and contribute to neurological disability. The recent interest in the key role of B cells in MS has been evoked by the profound anti-inflammatory effects of rituximab, a chimeric monoclonal antibody (mAb) targeting the B cell surface marker CD20, observed in relapsing-remitting MS. This has been reaffirmed by clinical trials with less immunogenic and more potent B cell-depleting mAbs targeting CD20 – ocrelizumab, ofatumumab and ublituximab. Ocrelizumab is also the first disease-modifying drug that has shown efficacy in primary-progressive MS, and is currently approved for both indications. Another promising approach is the inhibition of Bruton's tyrosine kinase, a key enzyme that mediates B cell activation and survival, by agents such as evobrutinib. On the other hand, targeting B cell cytokines with the fusion protein atacicept increased MS activity, highlighting the complex and not fully understood role of B cells and humoral immunity in MS. Finally, all other approved therapies for MS, some of which have been designed to target T cells, have some effects on the frequency, phenotype, or homing of B cells, which may contribute to their therapeutic activity.

Type I interferon induces CXCL13 to support ectopic germinal center formation.

Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection-induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation.

Novel Anti-CD40 Monoclonal Antibody CFZ533 in Patients with Primary Sjogren Syndrome: A Phase Iia Double-Blind, Placebo–Controlled Randomized Trial

Objectives: Primary Sjogren syndrome (pSS) is a progressive autoimmune disease characterized by formation of ectopic germinal centers in exocrine glands and secretory gland dysfunction with subset of patients developing extraglandular manifestations. CFZ533 is a novel monoclonal antibody that selectively blocks CD40, a co-stimulatory pathway receptor essential for germinal center reactions and other immune-mediated functions implicated in pSS pathogenesis. We conducted a randomized, double-blind, placebo-controlled, multicentric, partial crossover, Phase IIa Proof of Concept (PoC) study to evaluate the safety, tolerability and efficacy of CFZ533 in patients with pSS.

Dietary Docosahexaenoic Acid Prevents Silica-Induced Development of Pulmonary Ectopic Germinal Centers and Glomerulonephritis in the Lupus-Prone NZBWF1 Mouse.

Ectopic lymphoid structures (ELS) consist of B-cell and T-cell aggregates that are initiated de novo in inflamed tissues outside of secondary lymphoid organs. When organized within follicular dendritic cell (FDC) networks, ELS contain functional germinal centers that can yield autoantibody-secreting plasma cells and promote autoimmune disease. Intranasal instillation of lupus-prone mice with crystalline silica (cSiO2), a respirable particle linked to human lupus, triggers ELS formation in the lung, systemic autoantibodies, and early onset of glomerulonephritis. Here we tested the hypothesis that consumption of docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid with anti-inflammatory properties, influences the temporal profile of cSiO2-induced pulmonary ectopic germinal center formation and development of glomerulonephritis. Female NZBWF1 mice (6-wk old) were fed purified isocaloric diets supplemented with 0, 4, or 10 g/kg DHA - calorically equivalent to 0, 2, or 5 g DHA per day consumption by humans, respectively. Beginning at age 8 wk, mice were intranasally instilled with 1 mg cSiO2, or saline vehicle alone, once per wk, for 4 wk. Cohorts were sacrificed 1, 5, 9, or 13 wk post-instillation (PI) of the last cSiO2 dose, and lung and kidney lesions were investigated by histopathology. Tissue fatty acid analyses confirmed uniform dose-dependent DHA incorporation across all cohorts. As early as 1 wk PI, inflammation comprising of B (CD45R+) and T (CD3+) cell accumulation was observed in lungs of cSiO2-treated mice compared to vehicle controls; these responses intensified over time. Marked follicular dendritic cell (FDC; CD21+/CD35+) networking appeared at 9 and 13 wk PI. IgG+ plasma cells suggestive of mature germinal centers were evident at 13 wk. DHA supplementation dramatically suppressed cSiO2-triggered B-cell, T-cell, FDC, and IgG+ plasma cell appearance in the lungs as well as anti-dsDNA IgG in bronchial lavage fluid and plasma over the course of the experiment. cSiO2 induced glomerulonephritis with concomitant B-cell accumulation in the renal cortex at 13 wk PI but this response was abrogated by DHA feeding. Taken together, realistic dietary DHA supplementation prevented initiation and/or progression of ectopic lymphoid neogenesis, germinal center development, systemic autoantibody elevation, and resultant glomerulonephritis in this unique preclinical model of environment-triggered lupus.

Aberrant Humoral Immune Responses in Neurosyphilis: CXCL13/CXCR5 Play a Pivotal Role for B-Cell Recruitment to the Cerebrospinal Fluid.

Previous studies documented that humoral immune responses participated in neurological damage in neurosyphilis patients. However, the mechanisms that trigger and maintain humoral immunity involved in neurosyphilis remain unknown. Using flow cytometry, expression of B cells was measured in neurosyphilis and non-neurosyphilis. Expression of immunoglobulin indices and chemokine ligand CXCL13 was detected by enzyme-linked immunosorbent assay. The migration and inhibition assays were evaluated by modified chamber assays. The presence of CXCL13+ cells, cluster of differentiation (CD)20+ B cells, CD3+ T cells, CD138+ plasma cells and CD35+ follicular dendritic cells was studied by immunohistochemistry. Enrichment of B cells was observed and activated in the cerebrospinal fluid (CSF) of neurosyphilis patients. Immunoglobulin indices were increased and associated with the progress to neurosyphilis. High expression of CSF CXCL13 mediated B cell migration both in vitro and in vivo. There was a positive correlation among the CSF B cells, immunoglobulin indices, and CSF CXCL13 levels. Ectopic germinal centers (EGCs), important structures for humoral immunity, were observed in the intracranial syphilitic gumma. CXCL13/CXCR5 mediated the aggregation of B cells, that directed the aberrant humoral immune responses via the formation of EGCs, which suggests a molecular mechanism of neurological damage in neurosyphilis.

Ectopic germinal center and megalin defect in primary Sjogren syndrome with renal Fanconi syndrome

BackgroundThis study reports the clinical and pathological features of 12 cases of primary Sjogren syndrome (pSS) with renal involvement presenting with proximal tubular dysfunction in a single center, and investigates the possible correlation of ectopic germinal center formation and megalin/cubilin down-expression.MethodClinical and pathological records were reviewed. Immunohistochemistry was carried out to detect megalin, cubilin, CD21 and IL-17 expression.ResultsPatients presented with different degrees of proximal renal tubule lesion and decreased estimated glomerular filtration rate (eGFR). Renal biopsy revealed tubulointerstitial nephritis, with tubular epithelial cell degeneration, tubular atrophy, interstitial inflammation and focal fibrosis. Immunohistochemistry revealed decreased expression of megalin and cubilin, two important multiligand protein receptors on the brush border of proximal tubular epithelial cells. IL-17 secreted by Th17 subtype effector T cells was diffusely detected in the renal proximal tubule, with a negative correlation of IL-17 and megalin expression. In addition, ectopic germinal centers characterized by CD21+ follicular dendritic cells were present in the renal interstitium. In patients with a decreased eGFR, treatment with 4 weeks of glucocorticoid therapy resulted in an improved eGFR in 75% of patients.ConclusionWe report 12 cases of pSS characterized by Fanconi syndrome. The decreased megalin and cubilin expression may contribute to the proximal tubular reabsorption defect, possibly secondary to Th17 infiltration and formation of ectopic germinal centers.

Mechanisms and New Strategies for Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, mainly salivary and lacrimal, resulting in oral and ocular dryness, although virtually any organ system can be affected. SS-related systemic manifestations are classified as either related to the presence of periepithelial infiltrates in exocrine and parenchymal organs or resulting from immunocomplex deposition due to B cell hyperactivity with increased risk for B cell lymphoma development. Activation of both innate and adaptive immune pathways contributes to disease pathogenesis, with prominent interferon (IFN) signatures identified in both peripheral blood and affected salivary gland tissues. Recently, LINE-1 genomic repeat elements have been proposed as potential triggers of type I IFN pathway activation in SS through activation of Toll-like receptor-dependent and -independent pathways. In view of the increasingly appreciated variability of SS, elucidation of distinct operating pathways in relation to diverse clinical phenotypes and selection of the optimal therapeutic intervention remain major challenges. Inhibition of cathepsin S molecules, blockade of costimulation through administration of abatacept and inhibitors of B7-related molecules and CD40, blockade of B cell function and B cell survival factors, and disruption of the formation of ectopic germinal centers are considered the main therapeutic targets. Well-controlled multicenter clinical trials are ongoing and data are awaited.

Characteristics of germinal center-like structures in patients with Sjögren's syndrome.

To analyze the relationship between ectopic germinal centers (GCs) in the salivary glands and the clinical/laboratory characteristics of patients with Sjögren's syndrome (SS). Retrospectively, 126 patients with primary SS (pSS) and 16 patients with secondary SS (sSS) were analyzed. Minor salivary gland biopsies were evaluated for the presence of GC-like morphology by hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining for CD21. Clinical and serological data were obtained from medical records. GC-like structures were observed in 36/126 (28.6%) pSS patients and 4/16 (25.0%) sSS patients. The mean inflammatory focus score of the gland was significantly higher in GC-positive samples than in GC-negative ones in both pSS and sSS patients (P = 0.007 and 0.024, respectively). In pSS, significantly elevated titers of rheumatoid factor (RF)-IgM (P = 0.023) and antinuclear antibodies (ANA) (P = 0.036), increased levels of IgA (P = 0.012) and IgG (P = 0.017) were encountered in GC-positive patients. The GC-positive group also presented higher prevalence of anti-SSA antibodies, lower levels of white blood cells, higher levels of erythrocyte sedimentation rate and γ-globulin, although not statistically significant. In sSS patients with ectopic GC formation, ANA titers were remarkably elevated. The anticyclic citrullinated peptide (anti-CCP)-IgG titers and the prevalence of antikeratin antibody (AKA)-IgG, antiperinuclear factor (APF)-IgG were also increased, yet not significantly. GCs were found to be associated with antibody and immunoglobulin production. This study indicates that SS patients with ectopic GCs have distinct features. Ectopic GC structures were particularly noted in patients with higher focus scores, and might play an essential role in sustaining antibody production as well as B cell activation.

Treatment of primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is a progressive autoimmune disease characterized by sicca and systemic manifestations. In this Review, we summarize the available data on topical and systemic medications, according to clinical signs and disease activity, and we describe the ongoing studies using biologic drugs in the treatment of pSS. Expanding knowledge about the epidemiology, classification criteria, systemic activity scoring (ESSDAI) and patient-reported outcomes (ESSPRI) is driving active research. Treatment decisions are based on the evaluation of symptoms and extraglandular manifestations. Symptomatic treatment is usually appropriate, whereas systemic treatment is reserved for systemic manifestations. Sicca is managed by education, environment modification, elimination of contingent offending drugs, artificial tears, secretagogues and treatments for complications. Mild systemic signs such as fatigue are treated by exercise. Pain can require short-term moderate-dose glucocorticoid therapy and, in some cases, disease-modifying drugs. Severe and acute systemic manifestations indicate treatment with glucocorticoids and/or immunosuppressant drugs. The role for biologic agents is promising, but no double-blind randomized controlled trials (RCTs) proving the efficacy of these drugs are available. Targets for new treatments directed against the immunopathological mechanisms of pSS include epithelial cells, T cells, B-cell overactivity, the interferon signature, proinflammatory cytokines, ectopic germinal centre formation, chemokines involved in lymphoid cell homing, and epigenetic modifications.

BAFF overexpression increases lymphocytic infiltration in Sjögren's target tissue, but only inefficiently promotes ectopic B-cell differentiation

B-cell activating factor (BAFF) levels are increased in rheumatoid arthritis, lupus and primary Sjögren's syndrome (pSS). However, BAFF contribution to pathogenesis is not completely understood. In pSS, immune infiltration of the salivary and lacrimal glands leads to xerostomia and xerophtalmia. Glandular B cell hyperactivation, differentiation into germinal center (GC)-like structures and plasma cell accumulation are histopathological hallmarks that were attributed to increased BAFF. Here, we experimentally tested this hypothesis by overexpressing BAFF in a mouse model of pSS. BAFF overexpression enhanced lymphocytic infiltration and MHCII expression on B cells. Increased BAFF also induced B cell differentiation into GC B cells within the autoimmune target tissue. However, even in these conditions, GC B cells only accounted for <1% of glandular B cells, demonstrating that BAFF is not efficiently promoting ectopic GC formation in pSS and warranting further investigation of therapeutics targeting both BAFF and the related TNF-family member APRIL.

New biological therapies in Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by dryness and systemic involvement in more than a third of the patients. Patient management has suffered from the lack of effective treatments. However, progresses made in the understanding of pSS pathogenesis have allowed a move to a more targeted approach to therapeutic intervention. Given the key role of chronic B cell activation, B cell-targeted therapies were the first candidate. New pathways are currently investigated including costimulation and ectopic germinal centre formation. In this review, we have summarized the new tools available in clinical research in the field of pSS, the current evidence regarding B cell-targeted therapies and an overview of the promising drugs in the pipeline.

Antibodies against carbamylated proteins are present in primary Sjögren's syndrome and are associated with disease severity

ObjectivesHerein, we investigate the presence and prognostic value of autoantibodies against carbamylated proteins (anti-CarP) in the serum of patients with primary Sjögren's syndrome (pSS).Patients and methodsSerum levels of anti-CarP antibodies...