ObjectivesTo investigate whether monocytes contribute to matrix deposition in systemic sclerosis (SSc) by production of tissue-inhibitor of metalloproteinase-1 (TIMP-1).MethodsMatrix metalloproteinase-1 (MMP-1) and TIMP-1 expression and secretion were measured by qRT-PCR and ELISA in circulating monocytes from patients with SSc, patients with rheumatoid arthritis (RA) and healthy controls (HC) and in healthy monocytes cultured in the presence of SSc or HC serum samples. Production of TIMP-1 was determined in response to a panel of Toll-like receptor (TLR) agonists and MyD88 inhibitory peptide. The functional effect of conditioned media from SSc and HC serum samples or TLR8-stimulated monocytes was studied in an MMP-1 activity assay.ResultsTIMP-1 production by monocytes was upregulated in patients with SSc compared with patients with RA and HC. Incubation of HC monocytes with SSc serum samples resulted in functionally active TIMP-1 production. However, pretreatment with MyD88 inhibitor, but not control peptide, decreased TIMP-1 secretion. TIMP-1 production was significantly stronger when SSc and HC monocytes were stimulated with TLR8 (ssRNA) agonist, but the response was more pronounced in SSc monocytes. TIMP-1 production after TLR stimulation was also strongly reduced in the presence of MyD88 inhibitory peptide or in the monocytes isolated from a patient with a genetic TLR signalling defect. MMP-1 activity was significantly inhibited in media from serum samples or TLR8-stimulated monocytes indicative of functional TIMP activity.ConclusionsThis study demonstrates profibrotic properties of circulating monocytes from patients with SSc and a key role for TLR signalling, particularly TLR8, in TIMP-1 secretion and matrix remodelling.
Background Medical doctors with postgraduate training in Global Health and Tropical Medicine (MDGHTM) from the Netherlands, a high-income country with a relatively low caesarean section rate, assist associate clinicians in low-income countries regarding decision-making during labour. Objective of this study was to assess impact of the presence of MDGHTMs in a rural Malawian hospital on caesarean section rate and indications. Methods This retrospective pre- and post-implementation study was conducted in a rural hospital in Malawi, where MDGHTMs were employed from April 2015. Indications for caesarean section were audited against national protocols and defined as supported or unsupported by these protocols. Caesarean section rates and numbers of unsupported indications for the years 2015 and 2016 per quarter for different staff cadres were assessed by linear regression. Results Six hundred forty-five women gave birth by caesarean section in the study period. The caesarean rate dropped from 20.1 to 12.8% (p < 0.05, R2 = 0.53, y = − 0.0086x + 0.2295). Overall 132 of 501 (26.3%) auditable indications were not supported by documentation in medical records. The proportion of unsupported indications dropped significantly over time from 47.0 to 4.4% (p < 0.01, R2 = 0.71, y = − 0.0481x + 0.4759). Stratified analysis for associate clinicians only (excluding caesarean sections performed by medical doctors) showed a similar decrease from 48.3 to 6.5% (p < 0.05, R2 = 0.55, y = − 0.0442x + 0.4805). Conclusions Our results indicate that presence of MDGHTMs was accompanied by considerable decreases in caesarean section rate and proportion of unsupported indications for caesarean section in this facility. Their presence is likely to have influenced decision-making by associate clinicians.
Abstract:There is increasing evidence that B cells can play important roles in the pathogenesis of various autoimmune diseases, either by autoantibody secretion, production of proinflammatory cytokines or autoantigen presentation. An increasing number of B cell directed therapies are in development as a possible treatment strategy of rheumatic autoimmune diseases, such as Rituximab which targets the B cell specific CD20 surface marker. This article provides an overview of the principal understandings of B cell immunology in autoimmunity and selected rheumatic autoimmune diseases.
Systemic sclerosis (SSc) is an autoimmune disease of unknown origin. The clinical hallmarks are progressive fibrosis of skin and internal organs and vasculopathic changes in the form of digital ulcers and pulmonary arterial hypertension. The chronicity and heterogeneity of the disease has hampered research in SSc in the past, but new research tools and animal models have contributed to a greater understanding of the pathogenesis of SSc and resulted in new findings in the fields of genomics, cytokine expression, autoantibodies and abnormalities of blood progenitor or effector cells. As a consequence, targeted therapeutic compounds such as imatinib are currently under clinical investigation. Whilst the search for an effective "targeted therapy" is still ongoing, autologous stem cell transplantation represents a "multitarget" approach aiming at "resetting" the immune system. This review gives an overview of the translation from pathogenic findings into therapeutical application.
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