Increasingly, inflammatory mediators are considered crucial to the onset and perpetuation of tendinopathy. We sought evidence of interleukin 17A (IL-17A) expression in early human tendinopathy and thereafter, explored mechanisms whereby IL-17A mediated inflammation and tissue remodeling in human tenocytes. Torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing ‘early pathology’) along with control biopsies were collected from patients undergoing shoulder surgery. Markers of inflammation and IL-17A were quantified by RT-PCR and immunohistochemistry. Human tendon cells were derived from hamstring tendon obtained during ACL reconstruction. In vitro effects of IL-17A upon tenocytes were measured using RT-PCR, multiplex cytokine assays, apoptotic proteomic profiling, immunohistochemistry and annexin V FACS staining. Increased expression of IL-17A was detected in ‘early tendinopathy’ compared to both matched samples and non-matched control samples (p < 0.01) by RT-PCR and immunostaining. Double immunofluoresence staining revealed IL-17A expression in leukocyte subsets including mast cells, macrophages and T cells. IL-17A treated tenocytes exhibited increased production of proinflammatory cytokines (p < 0.001), altered matrix regulation (p < 0.01) with increased Collagen type III and increased expression of several apoptosis related factors. We propose IL-17A as an inflammatory mediator within the early tendinopathy processes thus providing novel therapeutic approaches in the management of tendon disorders.
BackgroundSmall studies suggest an association between ANCA-associated vasculitis (AAV) incidence and rurality, seasonality and socioeconomic deprivation. We examined the incidence of kidney biopsy-proven AAV and its relationship with these factors in the adult Scottish population.MethodsUsing the Scottish Renal Biopsy Registry, all adult native kidney biopsies performed between 2014 and 2018 with a diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) were identified. The Scottish Government Urban Rural Classification was used for rurality analysis. Seasons were defined as autumn (September–November), winter (December–February), spring (March–May) and summer (June–August). Patients were separated into quintiles of socioeconomic deprivation using the validated Scottish Index of Multiple Deprivation and incidence standardised to age. Estimated glomerular filtration rate and urine protein:creatinine ratio at time of biopsy were used to assess disease severity.Results339 cases of renal AAV were identified, of which 62% had MPA and 38% had GPA diagnosis. AAV incidence was 15.1 per million population per year (pmp/year). Mean age was 66 years and 54% were female. Incidence of GPA (but not MPA) was positively associated with rurality (5.2, 8.4 and 9.1 pmp/year in ‘urban’, ‘accessible remote’ and ‘rural remote’ areas, respectively; p=0.04). The age-standardised incidence ratio was similar across all quintiles of deprivation (p=ns).ConclusionsSeasonality and disease severity did not vary across AAV study groups. In this complete national cohort study, we observed a positive association between kidney biopsy-proven GPA and rurality.
ObjectivesMacrophage subsets, activated by T cells, are increasingly recognised to play a central role in rheumatoid arthritis (RA) pathogenesis. Janus kinase (JAK) inhibitors have proven beneficial clinical effects in RA. In this study, we investigated the effect of JAK inhibitors on the generation of cytokine-activated T (Tck) cells and the production of cytokines and chemokines induced by Tck cell/macrophage interactions.MethodsCD14+monocytes and CD4+T cells were purified from peripheral blood mononuclear cells from buffy coats of healthy donors. As representative JAK inhibitors, tofacitinib or ruxolitinib were added during Tck cell differentiation. Previously validated protocols were used to generate macrophages and Tck cells from monocytes and CD4+T cells, respectively. Cytokine and chemokine including TNF, IL-6, IL-15, IL-RA, IL-10, MIP1α, MIP1β and IP10 were measured by ELISA.ResultsJAK inhibitors prevented cytokine-induced maturation of Tck cells and decreased the production of proinflammatory cytokines TNF, IL-6, IL-15, IL-1RA and the chemokines IL-10, MIP1α, MIP1β, IP10 by Tck cell-activated macrophages in vitro (p<0.05).ConclusionsOur findings show that JAK inhibition disrupts T cell-induced macrophage activation and reduces downstream proinflammatory cytokine and chemokine responses, suggesting that suppressing the T cell-macrophage interaction contributes to the therapeutic effect of JAK inhibitors.
Background and Aims Individuals living in areas of multiple socioeconomic deprivation have reduced life expectancy and experience health inequalities. Chronic kidney disease is more common in areas of social deprivation and these patients are more likely to develop end stage kidney disease. Vasculitis is a rare but significant cause of kidney disease. The impact of socioeconomic status on disease activity or outcomes in patients with ANCA Associated Vasculitis (AAV) is yet to be fully explored. The aim of this study was to establish whether there is an association between the incidence of biopsy-proven renal vasculitis and socioeconomic status, as measured by the Scottish Index of Multiple Deprivation (SIMD). Method Using the Scottish renal biopsy registry, we identified all adult native renal biopsies performed across Scotland between 2014 and 2018 with a diagnosis of AAV. Patient’s postcode and SIMD (2016) rank were recorded. Patients were separated into quintiles of SIMD rank. Baseline demographics were recorded. We derived the denominator population from the 2016 SIMD census. Data were calculated per million population (PMP) served. Results 339 biopsy proven cases of AAV were identified. 6 cases were excluded as postcode was unavailable. Overall, mean age was 65.9 (±13.0) years and 45% of patients were male. At time of diagnosis, mean estimated glomerular filtration rate (eGFR) was 61.7 (±25.7) ml/min/1.73m2 and median urinary protein creatinine ratio (uPCR) was 134mg/mmol (IQR 64-21). Microscopic Polyangiits n=205(65%) was more common than Granulomatosis with Polyangiits n=128(35%). The incidences of kidney biopsy proven AAV were similar across all quintiles of deprivation. In the most deprived 20% of population, incidence rate of kidney biopsy proven AAV was 11.2 per million person-years vs 13.0 per million person-years in least deprived 20% of population. Patients in areas of greatest relative deprivation were younger (64.0 (±12.3) vs. 68.1 (±12.7) years) and had slightly less proteinuria at diagnosis (99mg/mmol (IQR 35-211) vs. 138mg/mmol (IQR 78-281)) when compared to patients living in least deprived areas. However, there was no difference in level of renal function at diagnosis (33.8 (±29.6) ml/min/1.73m2 vs 31.5 (±23.2) ml/min/1.73m2). Conclusion Our complete national dataset shows that there is no significant difference in incidence of renal AAV across the spectrum of socioeconomic deprivation. The analysis of renal function at presentation suggests no evidence of an association between deprivation and delay in diagnosis in a healthcare system free at the point of access.
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