CXCL13, CCL21, and CXCL12 expression in salivary glands of patients with Sjogren's syndrome and MALT lymphoma: Association with reactive and malignant areas of lymphoid organization

The chemokines (CKs) CXCL13, CCL21, and CXCL12 are known to play differential roles in the organization of the lymphoid tissues and the development of lymphoid malignancies. We investigated the expression of these CKs and their receptors in the salivary glands of Sjogren's syndrome patients with lymphoepithelial lesions (lymphoepithelial sialadenitis or LESA) and in MALT lymphoma to understand their involvement in salivary gland lymphomagenesis. We demonstrate that within salivary glands with LESA and MALT lymphoma the lymphoid CKs CXCL13 and CCL21 are selectively associated with areas of reactive lymphoid proliferation, whereas no significant expression of these molecules was detected in the malignant lymphoid aggregate. Conversely, CXCL12 was observed predominantly in infiltrated ducts and malignant B cells. Accordingly, CXCL13 and CCL21 transcript levels were significantly increased in LESA samples while CXCL12 levels were increased in MALT lymphoma and isolated tumor cells. Low levels of CK receptors were detected on lymphoma-extracted lymphocytes, suggesting down-regulation in the abundance of ligands. Our findings suggest that in salivary gland MALT lymphoma the lymphoid CKs CXCL13 and CCL21 are directly implicated in the organization of ectopic reactive lymphoid tissue, whereas CXCL12 is associated with the infiltrated epithelium and malignant B cell component and is possibly involved in the regulation of malignant B cell survival

P055 CXCL13 as biomarker for histological involvement in sjogren's syndrome

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Neurocognitive Dysfunction in Systemic Lupus Erythematosus: Association with Antiphospholipid Antibodies, Disease Activity and Chronic Damage

Introduction: Systemic lupus erythematosus (SLE) is characterized by frequent neuropsychiatric involvement, which includes cognitive impairment (CI). We aimed at assessing CI in a cohort of Italian SLE patients by using a wide range of neurocognitive tests specifically designed to evaluate the fronto-subcortical dysfunction. Furthermore, we aimed at testing whether CI in SLE is associated with serum autoantibodies, disease activity and chronic damage. Methods: Fifty-eight consecutive patients were enrolled. Study protocol included data collection, evaluation of serum level

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Phenotypes Determined by Cluster Analysis and Their Survival in the Prospective European Scleroderma Trials and Research Cohort of Patients With Systemic Sclerosis

Objective: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained. / Methods: A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty‐four clinical and serologic variables were used for clustering. / Results: Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement. / Conclusion: Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis

Relationships between fish and benthic macroinvertebrate faunas and habitat types in Broke Inlet, Western Australia

Critical to the understanding of estuarine ecosystems is a rigorous classification of their habitats and an assessment of the extent to which the distribution of key faunal assemblages are related to those habitats. This study relates a fully quantitative abiotic classification of the nearshore habitats within Broke Inlet, a ‘near pristine’ seasonally-open estuary in south-western Australia, to the fish and benthic macroinvertebrate communities present at those habitat types in each season for two years and one year, respectively. The eleven habitat types, which differed in their suite of enduring abiotic variables, including those reflecting the vicinity of marine and freshwater sources, exposure to wave activity and substratum type, were found to contain significantly different fish faunas in seven of the eight seasons sampled. Furthermore, the pattern of relative differences among habitat types, as exhibited by the ichthyofauna, statistically matched that among the suite of enduring abiotic variables used to distinguish those habitats in almost all seasons. However, while the benthic macroinvertebrate faunal composition differed among habitats in all four seasons, those differences were only significantly correlated with those among the abiotic characteristics of habitat types in one of those seasons. These results therefore demonstrate that the enduring abiotic classification scheme produced for Broke Inlet provides a sound basis for predicting the ichthyofauna, but not the benthic macroinvertebrate fauna, likely to be found at any location within the estuary

Place attachment and management preferences of visitors at remote coastal campsites in Western Australia

Coastal recreation visitation levels are increasing within Australia and globally .The challenge for managers of coastal recreational areas is that frequent usage can result in degradation of these natural areas and a decline in the recreational and aesthetic quality that attracted visitors in the first place. Additionally, visitors who exhibit place attachment, an emotional connection to an area, often demonstrate greater concern regarding how an area should be managed. The extent to which the dimensions of attachment are related to management preferences has not been sufficiently investigated, especially in coastal and marine areas. This study examined the relationship between the place attachment of visitors to coastal campsites along the southern Ningaloo coastline, northwestern Australia, and management preferences via an on-site survey. The relationship was investigated using a suite of routines in the non-parametric multivariate statistics package PRIMER v6, providing the first example of the use of these types of statistical approaches in place research. Place attachment was measured using the dimensions of place identity, place dependence and everybody’s happy. Within each dimension, significantly different groups of visitors were identified based on differences in their responses to the place attachment survey items. This was achieved using hierarchical agglomerative cluster analysis in conjunction with a Similarity Profile (SIMPROF) test. Subsequent analysis using the BVSTEP procedure showed that the pattern of differences among visitors in their responses to place attachment items produced significant though weak correlations with that in their level of support for various management actions