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Medical Specialties / Rheumatology / Chronic Inflammation


T Cell Chemokine Receptor Patterns as Pathogenic Signatures in Autoimmunity

Abstract: Autoimmune diseases arise from aberrant activation of immune cells directed against endogenous autoantigens expressed throughout the human body. While the initiating triggers remain poorly understood, the self-perpetuating phase of these diseases is directly linked to the ongoing recruitment of inflammatory cells that traffic to the affected anatomical sites. T lymphocytes are prominent drivers of many autoimmune diseases and the targeted trafficking of these cells to infiltrate the affected organs is often a common denominator. The regulation of T cell trafficking involves the coordinated expression of specific patterns of chemokines and the reciprocal expression of cognate chemokine receptors on T cell membranes. Thereby, chemokines direct the specific trafficking of a wide array of responsive activated immune cells. Specific patterns of chemokine receptor expression can correlate with disease activity in an autoimmune disease, confirming the importance of further characterizing the T cells that infiltrate specific sites of autoimmunity. Herein, we will review our current understanding of the roles of chemokines in two common autoimmune diseases: rheumatoid arthritis and multiple sclerosis. We also discuss the implications for chemokine receptor signatures in autoimmune pathogenesis, and how these may provide novel targets for therapeutic intervention. ... Read more

Epigenetics in Atherosclerosis: a Clinical Perspective

Abstract: Significant progress has been made in understanding in the pathogenesis of atherosclerosis. Nevertheless, atherosclerosis remains a great threat to human health worldwide. Epigenetic mechanisms, which involve DNA methylation, histone modification, and microRNA, have significantly enhanced our understanding of the pathological process of atherosclerosis. More importantly, epigenetic processes (in contrast to genetic alterations) are reversible and thus provide a potential therapeutic target in atherosclerosis treatment. Both in vitro and in vivo studies using drugs targeting enzymes involved in epigenetic modifications have shown considerable promise in atherosclerosis treatment. This review aims to present an overview of current epigenetic mechanisms involved in the pathogenesis of atherosclerosis, and discuss points in these processes where therapeutic interventions likely bear fruition. ... Read more

Determination of Role of Thromboxane A2 in Rheumatoid Arthritis

Abstract: Introduction: To date, the etiology of rheumatoid arthritis (RA) remains largely unknown, and the therapies are still unsatisfactory. The biosynthesis of thromboxane A2 (TxA2) is increased in RA patients, suggesting a role of TxA2 in RA pathology. Methods: RA patients were divided into two groups, DMARDs and non-DMARDs, according to their use of disease-modifying antirheumatic drugs (DMARDs). Sera from RA patients and healthy controls were extracted and subjected to enzyme immunoassays for measurement of the thromboxane B2 (TxB2) level. The statistical correlations between serum TxB2 levels and disease activity score of 28 joints (DAS28), C-reactive protein (CRP), or erythrocyte sedimentation rate (ESR) were calculated. Moreover, the effects of dual TxA2 modulator BM567 on cell proliferation as well as protein expression of α-actinin and NF-κB2 in RA fibroblast-like synovial (FLS) cells MH7A were determined by MTS assays and Western blot analysis, respectively. The effects of BM567 on mRNA expression of cyclooxygenase (COX)-2, a downstream product of NF-κB2 and an upstream enzyme of TxA2, was examined by real-time quantitative PCR experiments. Results: Serum TxB2 level was significantly higher in RA patients as compared to healthy controls. Both DAS28 score and serum TxB2 levels were slightly lower in the DMARDs group than the non-DMARDs group, without statistical significance, and there was positive correlation between these two factors. BM567 significantly suppressed cell proliferation as well as expression of α-actinin, NF-κB2, p52, and COX-2 in MH7A. Conclusion: TxA2 plays an important role in RA pathology, synovial cell proliferation in particular, through an auto-regulatory feedback loop. Thus, targeting TxA2 may represent a promising add-on therapy in the treatment of RA. ... Read more

Enterovirus Persistence as a Mechanism in the Pathogenesis of Type 1 Diabetes

Abstract: Beyond acute clinical conditions, the role of enteroviruses (EVs) in chronic human diseases has been described. Although they are considered as highly cytolytic viruses, EVs can persist in various tissues. The persistence is believed to play a major role in the pathogenesis of EV related chronic diseases such as type 1 diabetes (T1D). T1D is characterized by an autoimmune destruction of pancreatic beta cells, and results from interplay between a genetic predisposition, the immune system, and environmental factors. EVs and especially group B coxsackieviruses (CVB) have been the most incriminated as exogenous agents involved in the development of T1D. Enteroviral persistence is the result of a virus-host coevolution combining a cell resistance to lysis through mutations or down-regulation of viral receptor, and a decrease of the viral replication by genomic modifications or the production of a stable double-stranded RNA form. CVB can persist in pancreatic cells and therefore could trigger, in genetically predisposed individuals, the autoimmune destruction of beta cells mainly through an activation of inflammation. The persistence of the virus in other tissues such as intestine, blood cells, and thymus has been described, and could also contribute to some extent to the enteroviral pathogenesis of T1D. The molecular and cellular mechanisms of CVB persistence and the link with the development of T1D should be investigated further. ... Read more

Mechanisms of Autoimmune Liver Disease

Abstract: The immune system of the liver is characterized by a predominant innate component. Several innate immune cell populations have been implicated in the pathogenesis of immune-mediated hepatic diseases, which are frequently associated with systemic symptoms or with co-morbidities affecting other organ systems. Thus, next to tissue-specific factors, general tolerance mechanisms are affected in devastating hepatic disorders like primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), or primary biliary cirrhosis (PBC). The innate immune cell populations abundantly detected within the liver and endowed with potent immunomodulatory capacities include innate lymphoid cells (ILCs) and natural killer T (NKT) cells. While both ILCs and NKT cells can be activated by different cytokines and/or chemokines, NKT cells also respond to (glyco-) lipid antigens engaging their canonical, semi-invariant TCR. Once activated, ILCs and NKT cells release copious amounts of Th1, Th2, and/or Th17 cytokines that shape subsequent innate and adaptive immune responses. Those immunomodulatory features as well as the recently described antigen-presenting capacity of ILCs and/or the bi-directional functional role of NKT cells might not only underlie the pathogenic mechanisms in the respective disorders, but also provide promising targets for clinical intervention. We will discuss these novel aspects as well as the role of alarmin-like cytokines such as IL-33 in the context of ILC and NKT cell activation and the consequences for the induction and progress of hepatic tissue damage and fibrosis. ... Read more

Advances in Pathogenesis and Treatment of ANCA-associated Vasculitis

Abstract: Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed to proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA) are sensitive and specific markers for their associated diseases, granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) and microscopic polyangiitis (MPA), respectively. Clinical observations suggest but do not prove that ANCA are involved in the pathogenesis of GPA and MPA. In vivo and in vitro experimental data strongly suggest if not prove that MPO-ANCA underlie the pathological lesions seen in MPO-ANCA associated MPA. This is less clear for PR3-ANCA associated GPA in which, besides small-vessel vasculitis, granulomatous inflammation is apparent. Here, cellular immunity appears to play an additional role. Insight into the pathogenetic events involved in these diseases has resulted in new ways of treatment that target the specific pathways that underlie the development of the lesions. ... Read more

Advances in the Etiology and Mechanisms of Type 1 Diabetes

Abstract: Type 1 diabetes (T1D) is an insulin-dependent form of diabetes resulting from the autoimmune destruction of pancreatic beta cells. The past few decades have seen tremendous progress in our understanding of the molecular basis of the disease, with the identification of susceptibility genes and autoantigens, the demonstration of several abnormalities affecting various cell types and functions, and the development of improved assays to detect and monitor autoimmunity and beta cell function. New findings about the disease pathology and pathogenesis are emerging from extensive studies of organ donors with T1D promoted by the JDRF nPOD (Network for the Pancreatic Organ Donor with Diabetes). Furthermore, the establishment of extensive collaborative projects including longitudinal follow-up studies in relatives and clinical trials are setting the stage for a greater understanding of the role of environmental factors, the natural history of the disease, and the discovery of novel biomarkers for improved prediction, which will positively impact future clinical trials. Recent studies have highlighted the chronicity of islet autoimmunity and the persistence of some beta cell function for years after diagnosis, which could be exploited to expand therapeutic options and the time window during which a clinical benefit can be achieved. ... Read more

Bimodal Plasma Metabolomics Strategy Identifies Novel Inflammatory Metabolites in Inflammatory Bowel Diseases

Abstract: Introduction: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by variable phenotypes. Metabolites are signatures of biochemical activity that can reveal unknown pathogenic pathways. We employed untargeted mass spectrometry (MS) based metabolomics to identify novel inflammatory mechanisms in IBD and a targeted assay to quantify metabolites of the auto-immunomodulating kynurenine pathway (KP) in IBDs and health. Materials and Methods: Metabolome analysis of CD, UC, and control plasmas was performed on a Liquid Chromatography (LC)-MS/MS system. KP metabolites quinolinic acid (QA) and picolinic acid (PA) were quantified by gas chromatography/MS. Results: Nineteen UC, 25 CD, and 9 control plasmas were analyzed: 34 metabolites exhibited abundance profiles associated with CD by global metabolome analysis (P≤0.05, false discovery rate q≤0.01). Notably, inflammatory-implicated metabolites angiotensin IV (P=0.049, q<0.001), diphthamide (P=0.018, q<0.001), and GM3 gangliosides (P<0.001, q<0.001) were increased in CD. By targeted kynurenine metabolites assay, QA (73.53 ng/mL ± 23.40 SD) and combined kynurenine metabolites (CKM) were increased in CD (120.19 ± 39.71) compared to controls (QA  50.14 ± 15.04; P<0.01; CKM 92.73 ± 26.30; P<0.01). CD QA positively correlated with CDAI (r=0.85; P<0.01), CRP (r=0.46; P=0.01), and ESR (r=0.42; P=0.03), while CKMs correlated with CDAI (r=0.615; P<0.01) and CRP (r=0.615; P=0.02). Conclusions: Associations of angiotensin IV, diphthamide, and GM3 gangliosides with CD implicate novel pathways in activating a Th1/Th17 inflammatory profile. Increased QA concentrations in CD may indicate a defective auto-immunomodulation mechanism. ... Read more

Targeting VEGF/VEGFR in the Treatment of Psoriasis

Abstract: Psoriasis is a common chronic skin disorder characterized by cutaneous inflammation and keratinocyte hyperproliferation. In the past decade, a number of novel effective biological agents have been developed to treat moderate-to-severe psoriasis. However, these drugs have potential serious side effects, particularly the development of infectious diseases. Therefore there is still a need for new therapies with better efficacy and less adverse effects. Angiogenesis is implicated in various pathological conditions including psoriasis. Direct targeting of angiogenesis becomes a new therapeutic strategy for the treatment of psoriasis. Vascular endothelial growth factor (VEGF), the most critical angiogenic factor, is thought to play important roles during the pathogenesis of psoriasis and may be a promising target for treating psoriasis. Therefore, we proposed that targeting VEGF/VEGFRs could lead to new treatments for psoriasis. ... Read more

Axonal Pathology and Demyelination in Viral Models of Multiple Sclerosis

Abstract: Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system (CNS). Monozygotic twin studies suggest that while there is a genetic contribution, genetics alone cannot be the sole determining factor in the development of MS. As the rates of MS are increasing, particularly among women, environmental factors such as viral infections are coming to the foreground as potential agents in triggering disease in genetically susceptible individuals. This review highlights pathological aspects related to two pre-clinical viral models for MS; data are consistent between these two models as experimental infection of susceptible mice can induce axonal degeneration associated with demyelination. These data are consistent with observations in MS that axonal damage or Wallerian degeneration is occurring within the CNS contributing to the disability and disease severity. Such early damage, where axonal damage is primary to secondary demyelination, could set the stage for more extensive immune mediated demyelination arising later. ... Read more

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