In the last decade, the understanding of the molecular mechanisms of regulation of the inflammatory process in chronic inflammatory diseases has moved remarkably forward. Recent evidence in various fields has consistently indicated that T-cells play a key role in initiating and perpetuating inflammation, not only via the production of soluble mediators but also via cell/cell contact interactions with a variety of cell types through membrane receptors and their ligands. Signalling through CD40 and CD40 ligand is a versatile pathway that is potently involved in all these processes. In this article, we review how T-cells become activated by dendritic cells or inflammatory cytokines, and how these T-cells activate, in turn, monocytes/macrophages, endothelial cells, smooth muscle cells and fibroblasts to produce pro-inflammatory cytokines (tumour necrosis factor alpha, interleukin-6), chemokines (interleukin-8, monocyte chemotactic protein-1), tissue factor, the main initiator of the coagulation cascade in vivo, and finally matrix metalloproteinases, responsible for tissue destruction. Moreover, we discuss how CD40 ligand at inflammatory sites stimulates fibroblasts and tissue monocyte/macrophage production of VEGF, leading to angiogenesis, which promotes and maintains the chronic inflammatory process. This cascade of events is discussed in the context of disease initiation/progression, with particular reference to atherosclerosis and rheumatoid arthritis, and to potential novel therapeutic targets for their treatment.
Purpose: To investigate the function and expression of Toll-like receptors (TLR) in bone marrow cells of myelodysplastic syndrome (MDS) patients and to examine their involvement in the apoptotic phenomenon characterizing MDS hematopoiesis. Experimental Design: TLR mRNA and protein expression was investigated in bone marrow cell populations of MDS patients and controls. TLR-4 ability to recognize lipopolysaccharide and up-regulate self mRNA and protein expression was examined. Tumor necrosis factor involvement in the constitutive and lipopolysaccharide (LPS)-induced TLR expression was also evaluated. Possible correlation between TLR-4 overexpression and apoptosis was investigated by simultaneous staining with Annexin V and TLR-4. Results: TLR-2 and TLR-4 are expressed in almost all bone marrow cell lineages including megakaryocytes, erythroid cells, myeloid precursors, monocytes, and B lymphocytes and are up-regulated in MDS patients compared with controls. In hematopoietic CD34+ cells, TLR-4 is also expressed and significantly up-regulated at both the mRNA and protein levels. Treatment with an anti–tumor necrosis factor antibody reduces both constitutive and LPS-induced TLR-4 levels. Increased TLR-4 expression correlates with increased apoptosis as TLR-4 is almost exclusively found in apoptotic bone marrow mononuclear and CD34+ cells. The addition of the TLR-4 ligand LPS further enhances the apoptosis of these cells. Conclusions: TLR-4 and other TLRs are significantly up-regulated in MDS patients whereas TLR-4 is involved in promoting apoptosis, possibly contributing to MDS cytopenia.
Our studies demonstrate for the first time in vivo the pathogenic consequences of deregulated Activin-A expression in the lung, document novel aspects of Activin-A biology that provide mechanistic explanation for the observed phenotype, link Activin-A to ALI/ARDS pathophysiology, and provide the rationale for therapeutic targeting of Activin-A in these disorders.
Over the last decade it has become apparent that common pathogenic mechanisms are shared between many human chronic inflammatory diseases of unrelated pathology and manifestation. These mechanisms include common inflammatory networks that control tissue destructive and repair processes and their study is of major therapeutic potential as recently demonstrated for TNFalpha. Thus, early studies in rheumatoid arthritis defined TNFalpha as a major therapeutic target, the blockade of which was subsequently proved to be of great efficacy in the clinic. This paved the way for the successful blockade of TNFalpha in various other diseases including Crohn's disease, psoriasis, spondyloarthropathies and juvenile arthritis, although no similar networks with anti-TNFalpha at their apex had previously been demonstrated. In this article, we review the current knowledge of the pathogenic mechanisms involved in rheumatoid arthritis and chronic obstructive pulmonary disease with particular emphasis on the role of inflammatory cytokines, chemokines, and tissue degrading enzymes as revealed by studies in the laboratory and the clinic. Direct comparison of these mechanisms may provide clues for a future therapy for these painful and incurable diseases.
Chapter summaryThe elucidation of the signalling pathways involved in inflammatory diseases, such as rheumatoid arthritis, could provide long sought after targets for therapeutic intervention. Gene regulation is complex and varies depending on the cell type, as well as the signal eliciting gene activation. However, cells from certain lineages, such as macrophages, are specialised to degrade exogenous material and consequently do not easily transfect. Methods for high-efficiency gene transfer into primary cells of various lineages and disease states are desirable, as they remove the uncertainties associated with using transformed cell lines. Significant research has been undertaken into the development of nonviral and viral vectors for basic research, and as vehicles for gene therapy. We briefly review the current methods of gene delivery and the difficulties associated with each system. Adenoviruses have been used extensively to examine the role of various cytokines and signal transduction molecules in the pathogenesis of rheumatoid arthritis. This review will focus on the involvement of different signalling molecules in the production of tumour necrosis factor alpha by macrophages and in rheumatoid synovium. While the NF-κB pathway has proven to be a major mediator of tumour necrosis factor alpha production, it is not exclusive and work evaluating the involvement of other pathways is ongoing.
COVID-19 vaccines are safe and effective at preventing severe disease. Among the rare complications that may compromise vaccine acceptance are allergic reactions. [1][2][3] Recently we demonstrated that anaphylaxis rates associated with COVID-19 vaccines are comparable to those of traditional vaccines. 4 Herein, we aimed to comparatively assess the incidence and potential underlying causes of the most common allergic reactions post COVID-19 vaccination in Europe and the United States (US).Allergic reactions data following COVID-19 vaccination reported from week 52/2020 to week 39/2021 were collected from EudraVigilance for the European Economic Area (EEA) and from Vaccine Adverse Event Reporting System (VAERS) for the US and analyzed for all licensed vaccines. These included mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech), AD26.COV2.S (Janssen/Johnson & Johnson), and the not yet licensed in the US ChAdOx1-S (Oxford/AstraZeneca). Incidence rates were calculated using the corresponding administered vaccine doses as denominators. Vaccine composition was examined to identify potential allergic triggers.The most common allergic reactions after COVID-19 vaccination were anaphylactic reactions, with an overall incidence of 9.91/million doses (EEA: 13.69/million/US: 4.44/million, Fig. 1). Anaphylactic shock followed, with much lower rates (overall incidence: 1.36/million, EEA: 2.01/million/US: 0.41/million).The incidence of anaphylactic reactions reported in EudraVigilance varied considerably by vaccine and was 3to 4-fold higher for BNT162b2 or mRNA-1273 compared to VAERS. AD26.COV2.S-associated anaphylaxis did not differ between databases. The very low incidence of anaphylactic shock also varied by vaccine, particularly as captured in EudraVigilance.Considering vaccine platforms, the incidence of anaphylactic reactions post adenovirus-vectored vaccination was higher compared to mRNA-based vaccines (EudraVigilance: 15.62/ vs . 13.36/million, VAERS: 6.79/vs . 4.34/million doses). Anaphylactic shock incidence rates were also higher for vectored compared to mRNA vaccines (EudraVigilance: 3.14/ vs . 1.81/million, VAERS: 1.20/ vs . 0.38).Detailed demographic data and outcomes of anaphylactic reaction and anaphylactic shock cases post-COVID-19 vaccination are presented in Tables S1 and S2, respectively. The vast majority of cases affected females
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.