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    ABSTRACT: One of the hallmarks of rheumatoid arthritis (RA) is the development of humoral autoimmunity resulting in circulating autoantibodies. The clinical efficacy of B cell-depleting biologic treatments highlighted a key role for autoreactive B cell activation in the pathogenesis of RA. In this review, we discuss the key mechanisms leading to breach of B cell self-tolerance in the peripheral compartment. We also highlight the contribution of synovial ectopic lymphoid structures (ELS) in the development of functional niches of autoreactive B cells promoting humoral autoimmunity in the inflamed RA joints over and above secondary lymphoid organs (SLO).
    Drug discovery today. 05/2014;
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    ABSTRACT: TLS, characterized by the formation of ectopic B/T cell follicles with FDCs supporting an ectopic GC response, have been described in the target organs of several autoimmune diseases, including MS, RA, SS, and autoimmune thyroiditis. These structures represent functional niches, whereby autoreactive B cells undergo in situ affinity maturation and differentiation to autoantibody-producing cells, thus contributing to the progression and persistence of autoimmunity. Increasing evidence demonstrates that TLS can also develop in the context of cancer, as well as chronic infections. In this review, we collect recent evidences that highlights the relationship between persistent viral infection and the development of ectopic lymphoid structures in animal models and patients. Furthermore, we shall discuss the concept that whereas in physiological conditions, inducible TLS are critical for viral clearance and the establishment of protective immunity, but in the context of susceptible individuals, persistent viral infections may contribute, directly or indirectly, to the development of breach of tolerance against self-antigens and the development of autoimmunity through the formation of TLS.
    Journal of leukocyte biology 06/2013;
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    ABSTRACT: Nuclear factor (NF)-κB plays a pivotal role in sepsis. Activation of NF-κB is initiated by the signal-induced ubiquitination and subsequent degradation of inhibitors of kappa B (IκBs) primarily via activation of the IκB kinase (IKK). This study was designed to investigate the effects of IKK inhibition on sepsis-associated multiple organ dysfunction/injury (MOD) and to elucidate underlying signaling mechanisms in two different in vivo models: Male C57BL/6 mice were subjected to either bacterial cell wall components [lipopolysaccharide (LPS)/peptidoglycan (PepG)] or underwent cecal ligation and puncture (CLP) to induce sepsis-associated MOD. One hour after LPS/PepG or CLP mice were treated with the IKK inhibitor IKK 16 (1 mg/kg). At 24 hours parameters of organ dysfunction/injury were assessed in both models. Mice developed a significant impairment in systolic contractility (echocardiography), a significant increase in serum creatinine, alanine aminotransferase as well as lung myeloperoxidase activity, and, thus, cardiac dysfunction, renal dysfunction and hepatocellular injury as well as lung inflammation, respectively. Treatment with IKK 16 attenuated the impairment in systolic contractility, renal dysfunction, hepatocellular injury and lung inflammation in LPS/PepG induced multiple organ dysfunction/injury and in polymicrobial sepsis. Compared with mice that were injected with LPS/PepG or underwent CLP, immunoblot analyzes of heart and liver tissues from mice that were injected with LPS/PepG or underwent CLP and treated with IKK 16 revealed a significant attenuation of the i) increased phosphorylation of IκBα; ii) increased nuclear translocation of the NF-κB subunit p65; iii) significant increase in inducible nitric oxide synthase (iNOS) expression; and iv) revealed a significant increase in the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). Here, we report for the first time that delayed IKK inhibition reduces MOD in experimental sepsis. We suggest that this protective effect is (at least in part) attributable to inhibition of inflammation through NF-κB, the subsequent decreased iNOS expression and the activation of the Akt/eNOS survival pathway.
    Disease Models and Mechanisms 05/2013;
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    ABSTRACT: The β-common receptor (βcR) plays a pivotal role in the nonhematopoietic tissue-protective effects of erythropoietin (EPO). Here we determined whether EPO reduces the acute kidney injury (AKI) caused by sepsis and whether this effect is mediated by the βcR. In young (2 months old) C57BL/6 wild-type and βcR knockout mice, lipopolysaccharide caused a significant increase in serum urea and creatinine, hence AKI. This AKI was not associated with any overt morphological alterations in the kidney and was attenuated by EPO given 1 h after lipopolysaccharide in wild-type but not in βcR knockout mice. In the kidneys of endotoxemic wild-type mice, EPO enhanced the phosphorylation of Akt, glycogen synthase kinase-3β, and endothelial nitric oxide synthase, and inhibited the activation of nuclear factor-κB. All these effects of EPO were lost in βcR knockout mice. Since sepsis is more severe in older animals or patients, we tested whether EPO was renoprotective in 8-month-old wild-type and βcR knockout mice that underwent cecal ligation and puncture. These older mice developed AKI at 24 h, which was attenuated by EPO treatment 1 h post cecal ligation and puncture in wild-type mice but not in βcR knockout mice. Thus, activation of the βcR by EPO is essential for the observed reduction in AKI in either endotoxemic young mice or older mice with polymicrobial sepsis, and for the activation of well-known signaling pathways by EPO.Kidney International advance online publication, 17 April 2013; doi:10.1038/ki.2013.118.
    Kidney International 04/2013;
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    ABSTRACT: There is limited evidence that the tissue-protective effects of erythropoietin are mediated by a heterocomplex of the erythropoietin-receptor and the β-common receptor ('tissue-protective receptor'), which is pharmacologically distinct from the 'classical' erythropoietin-receptor homodimer responsible for erythropoiesis. However, the role of the β-common receptor and/or erythropoietin in sepsis-induced cardiac dysfunction (a well known, serious complication of sepsis) is unknown. Here we report for the first time that the β-common receptor is essential for the improvements in the impaired systolic contractility afforded by erythropoietin in experimental sepsis. Cardiac function was assessed in vivo (echocardiography) and ex vivo (Langendorff-perfused heart) in wild-type and β-common receptor knock-out mice, that were subjected to lipopolysaccharide (9 mg/kg; young mice) for 16-18 h or cecal ligation and puncture (aged mice) for 24 h. Mice received erythropoietin (1000 IU/kg) 1 h after lipopolysaccharide or cecal ligation and puncture. Erythropoietin reduced the impaired systolic contractility (in vivo and ex vivo) caused by endotoxemia/sepsis in young as well as old wild-type mice in a β-common receptor-dependent fashion. Activation by erythropoietin of the β-common receptor also resulted in the activation of well-known survival pathways (Akt and endothelial nitric oxide synthase) and inhibition of pro-inflammatory pathways (glycogen synthase kinase-3β, nuclear factor-κB and interleukin-1β). All the above pleiotropic effects of erythropoietin were lost in β-common receptor knock-out mice. Erythropoietin attenuates the impaired systolic contractility associated with sepsis by activation of the β-common receptor, which in turn, results in activation of survival pathways and inhibition of inflammation.
    Disease Models and Mechanisms 03/2013;
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    ABSTRACT: PURPOSE OF REVIEW: To critically appraise the literature related to the pathophysiology of rheumatoid arthritis (RA) focusing on the contribution of synovial tissue pathology (synovitis) in determining diverse clinical outcome/therapeutic response. RECENT FINDINGS: RA synovitis is highly heterogeneous with diverse cellular and molecular signatures (pathotypes) emerging as potential taxonomic classifiers of disease phenotypes.The challenge is to understand mechanistically the sophisticated interplay between systemic disease 'initiators' and joint-specific 'localizing/perpetuating' factors leading to disparate coupling of inflammation/tissue-destructive pathways and disease outcome. Synovial tissue analysis has been instrumental in enhancing understanding of R0A pathogenesis and developing targeted DMARD-biologic therapies. The next step is to elucidate the relationship of different synovial pathotypes/molecular signatures with therapeutic response/resistance in randomized clinical trials in order to develop effective therapies for 'resistant' patients. The development of ultrasound-guided synovial biopsy as a rapid, safe and well tolerated procedure that enables synovial tissue collection from most joints/patients will facilitate such studies. SUMMARY: RA is a heterogeneous clinical and pathobiological entity. Specific pathways within synovial tissues are emerging as associated with diverse clinical evolution and therapeutic response/resistance that, if confirmed in randomized clinical trials, may lead to the development of synovial tissue analysis as a potential clinical tool for patient stratification.
    Current opinion in rheumatology 03/2013;
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    ABSTRACT: Objective Syndecan 4, a heparan sulfate proteoglycan, has been associated with osteoarthritis. The present study was undertaken to analyze the functional role of syndecan 4 in endochondral ossification of mouse embryos and in adult fracture repair, which, like osteoarthritis, involves an inflammatory component. Methods Sdc4 promoter activity was analyzed in Sdc4−/− lacZ-knockin mice, using β-galactosidase staining. Endochondral ossification in embryos from embryonic day 16.5 was assessed by histologic and immunohistologic staining. Bone fracture repair was analyzed in femora of adult mice on days 7 and 14 postfracture. To evaluate Sdc2 and Sdc4 gene expression with and without tumor necrosis factor α (TNFα) and Wnt-3a stimulation, quantitative real-time polymerase chain reaction was performed. ResultsIn Sdc4−/− lacZ-knockin animals, syndecan 4 promoter activity was detectable at all stages of chondrocyte differentiation, and Sdc4 deficiency inhibited chondrocyte proliferation. Aggrecan turnover in the uncalcified cartilage of the epiphysis was decreased transiently in vivo, but this did not lead to a growth phenotype at birth. In contrast, among adult mice, fracture healing was markedly delayed in Sdc4−/− animals and was accompanied by increased callus formation. Blocking of inflammation via anti-TNFα treatment during fracture healing reduced these changes in Sdc4−/− mice to levels observed in wild-type controls. We analyzed the differences between the mild embryonic and the severe adult phenotype, and found a compensatory up-regulation of syndecan 2 in the developing cartilage of Sdc4−/− mice that was absent in adult tissue. Stimulation of chondrocytes with Wnt-3a in vitro led to increased expression of syndecan 2, while stimulation with TNFα resulted in up-regulation of syndecan 4 but decreased expression of syndecan 2. TNFα stimulation reduced syndecan 2 expression and increased syndecan 4 expression even in the presence of Wnt-3a, suggesting that inflammation has a strong effect on the regulation of syndecan expression. Conclusion Our results demonstrate that syndecan 4 is functionally involved in endochondral ossification and that its loss impairs fracture healing, due to inhibition of compensatory mechanisms under inflammatory conditions.
    Arthritis & Rheumatology 03/2013; 65(3).
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    ABSTRACT: OBJECTIVES: Rheumatoid arthritis (RA) is associated with an increased Epstein-Barr virus (EBV) blood DNA load, a robust immune response to EBV and cross-reactive circulating antibodies to viral and self-antigens. However, the role of EBV in RA pathogenesis remains elusive. Here, we investigated the relationship between synovial EBV infection, ectopic lymphoid structures (ELS) and immunity to citrullinated self and EBV proteins. METHODS: Latent and lytic EBV infection was investigated in 43 RA synovial tissues characterised for presence/absence of ELS and in 11 control osteoarthritis synovia using RT-PCR, in situ hybridisation and immunohistochemistry. Synovial production of anti-citrullinated protein (ACPA) and anti-citrullinated EBV peptide (VCP1/VCP2) antibodies was investigated in situ and in vivo in the severe combined immunodeficiency (SCID)/RA chimeric model. RESULTS: EBV dysregulation was observed exclusively in ELS+ RA but not osteoarthritis (OA) synovia, as revealed by presence of EBV latent (LMP2A, EBV-encoded small RNA (EBER)) transcripts, EBER+ cells and immunoreactivity for EBV latent (LMP1, LMP2A) and lytic (BFRF1) antigens in ELS-associated B cells and plasma cells, respectively. Importantly, a large proportion of ACPA-producing plasma cells surrounding synovial germinal centres were infected with EBV. Furthermore, ELS-containing RA synovia transplanted into SCID mice supported production of ACPA and anti-VCP1/VCP2 antibodies. Analysis of CD4+ and CD8+ T-cell localisation and granzyme B expression suggests that EBV persistence in ELS-containing synovia may be favoured by exclusion of CD8+ T cells from B-cell follicles and impaired CD8-mediated cytotoxicity. CONCLUSIONS: We demonstrated active EBV infection within ELS in the RA synovium in association with local differentiation of ACPA-reactive B cells.
    Annals of the rheumatic diseases 12/2012;
  • European journal of cancer (Oxford, England: 1990) 11/2012;
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    ABSTRACT: Salivary glands in patients with Sjögren's syndrome (SS) develop ectopic lymphoid structures (ELS) characterized by B/T cell compartmentalization, the formation of high endothelial venules, follicular dendritic cell networks, functional B cell activation with expression of activation-induced cytidine deaminase, as well as local differentiation of autoreactive plasma cells. The mechanisms that trigger ELS formation, autoimmunity, and exocrine dysfunction in SS are largely unknown. In this article, we present a novel model of inducible ectopic lymphoid tissue formation, breach of humoral self-tolerance, and salivary hypofunction after delivery of a replication-deficient adenovirus-5 in submandibular glands of C57BL/6 mice through retrograde excretory duct cannulation. In this model, inflammation rapidly and consistently evolves from diffuse infiltration toward the development of SS-like periductal lymphoid aggregates within 2 wk from AdV delivery. These infiltrates progressively acquire ELS features and support functional GL7(+)/activation-induced cytidine deaminase(+) germinal centers. Formation of ELS is preceded by ectopic expression of lymphoid chemokines CXCL13, CCL19, and lymphotoxin-β, and is associated with development of anti-nuclear Abs in up to 75% of mice. Finally, reduction in salivary flow was observed over 3 wk post-AdV infection, consistent with exocrine gland dysfunction as a consequence of the inflammatory response. This novel model has the potential to unravel the cellular and molecular mechanisms that regulate ELS formation and their role in exocrine dysfunction and autoimmunity in SS.
    The Journal of Immunology 08/2012; 189(7):3767-76.
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