Pathogenesis of juvenile idiopathic arthritis
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Abstract:
Although the term juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of diseases, they all share a common pathological hallmark: inflammation of the synovium. Highly activated T cells, monocytes, and neutrophils are attracted to the joint and secrete mediators that not only perpetuate inflammation, but also may attenuate immune regulation. In the oligoarticular and polyarticular forms of JIA, which are thought to be autoimmune conditions, dysregulated adaptive immunity is a likely factor in disease pathogenesis; the nature of the interactions between T-effector cells (Teffs) and T-regulatory cells (Tregs) is probably a key factor in controlling disease progression. Factors that affect the frequency and function of Tregs and/or the sensitivity of Teffs to mechanisms of immune suppression will therefore impact the disease course. In the systemic form of JIA, however, dysregulation of innate immune pathways appears more central to disease pathogenesis, resulting in augmented levels of interleukins IL-1β, IL-6, and IL-18. In the end, a final common pathological pathway in JIA is the activation of monocytes and neutrophils which are the principal mediators of joint inflammation and damage. This is supported by the fact that the therapies that have targeted innate cytokine pathways have shown greater success in the treatment of JIA.Keywords:
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Atherosclerosis is a chronic inflammatory disease of the arterial wall where both innate and adaptive immune responses contribute to disease initiation and progression. The hygiene hypothesis implies that dysregulation of the immune response has led to increased susceptibility to immuno-inflammatory diseases. Recent studies established that subtypes of T cells, regulatory T cells, actively involved in the maintenance of immunological tolerance, inhibit the development and progression of atherosclerosis. Here, we review the immune regulatory pathways of atherosclerosis and discuss the potential implication of pathogens and their associated molecular patterns in the regulation of the immuno-inflammatory response of atherosclerosis.
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Background:Chronic Kidney Disease (CKD) is one of the most important health challenges faced by the world today with new cases being added at an alarming rate. Controlling traditional risk factors has not been effective in bringing down the incidence of the disease. CKD is associated with inflammation, morbidity, poor quality of life, decreased life-expectancy and death. Chronic inflammation is associated with complications and comorbidities frequently seen in CKD. Toll-like receptors (TLRs) are members of innate immune receptors that regulate inflammatory and immune responses and stimulate both immune and nonimmune cells to express inflammatory cytokines and chemokines. Objective:To evaluate the potential role of TLR-2 and proinflammatory cytokines in the pathogenesis of stage 3-4 CKD which could be used to pave the way for prophylactic or therapeutic procedures. Subjects and methods:This study was carried out on 20 patients with stage 3-4 CKD and 10age and sex matched controls. The percentage of CD14+ monocytes expressing TLR-2 and mean florescence intensity (MFI) of TLR-2 on CD14+ monocytes were detected by flowcytometry, while the serum levels of interleukin-6 (IL-6) and IL-18 were measured by enzyme linked immunosorbent assay (ELISA). Results:There was insignificant difference between the percentage of CD14+ monocytes expressing TLR-2 in both patients and control groups(p > 0.05), while there was a highly significant increase in MFI of TLR-2 on CD14+ monocytes, serum IL-6 and serum IL-18 levels in stage 3-4 CKD patients when compared to controls (p ≤ 0.01). There was a significant positive correlation between MFI of TLR-2 on CD14+ monocytes and serum creatinine level (p≤ 0.05, r=0.538) and a highly significant positive correlation between IL-6 serum level and serum creatinine level in patients group (p ≤ 0.01, r= 0.672). Also there was a highly significant negative correlation between MFI of TLR-2 on CD14+ monocyte and estimated glomerular filtration rate (eGFR) (p ≤ 0.01, r=-0.667), and a significant negative correlation between IL-6 and eGFR in patients group (p ≤ 0.05, r=-0.516). Finally, there was a significant positive correlation between MFI of TLR-2 on CD14+ monocytes and serum IL-6 level in patients group (p≤ 0.05 , r = 0.473), while the correlation between serum IL-18 level and serum creatinine level, eGFR, MFI of TLR-2 on CD14+ monocyte and serum IL-6 level in patients group was insignificant (p> 0.05, r =0.168,-0.196,-0.057,-0.010 respectively). Conclusions:This study demonstrated that the expression of TLR-2 on CD14+ monocytes was up regulated in stage 3-4 CKD patients and was associated with inflammatory response as assessed by increased serum levels of IL-6 and IL-18. These findings indicated that TLR-2, IL-6 and IL-18 played a significant role in pathogenesis of CKD.
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Immune regulation is an important mechanism in controlling the severity and duration of an immune response. Ongoing and destructive inflammation suggests a dysfunction in the immune regulation, while a spontaneous relapse or remission of disease suggests a successful immune-regulatory process. Understanding the regulatory mechanisms that control the balance between immunity and tolerance can provide potential new targets for therapeutic intervention.
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Behçet's disease is a chronic inflammatory disorder of unknown etiology. It has long been postulated that immunological abnormalities, which are possibly induced by microbial pathogens in genetically susceptible individuals, are important in its pathogenesis. Recent findings have both supported the significance of genetic factors and better defined the nature of inflammation in Behçet's disease. Molecular genetic studies have strengthened the primary association of HLA-B51 with Behçet's disease. The exact pathogenic mechanism of the HLA-B51 molecule is still unknown, and its contribution to the overall genetic susceptibility to Behçet's disease is estimated to be less than 20%. Spontaneous and/or induced overexpression of pro-inflammatory cytokines (mainly Th1 type) from various cellular sources seems responsible for the enhanced inflammatory reaction in Behçet's disease, and it may be associated with the genetic susceptibility. An antigen-driven immune response superimposed on this primed-state and induced by heat shock proteins or other peptides from different strains of streptoccocci or other microbial agents has been suggested to trigger manifestations of Behçet's disease. Endothelial activation/injury and the resultant occlusive vasculopathy may also contribute to the tissue damage.
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Rheumatoid arthritis (RA) is a particularly debilitating autoimmune disease, which causes chronic inflammation of the joints especially in the hands and legs. Autoimmune diseases are illnesses, which occur when the body tissues are mistakenly attacked by its own immune system. RA is a systemic disease that not only affects joints but also causes inflammation of the blood vessels, anaemia, nodules, fever, weight loss and fatigue. The tissue around the joints, such as the tendons, ligaments, and muscles as well as other organs in the body can also become inflamed. In some patients with RA, chronic inflammation leads to the destruction of the cartilage, bone and ligaments causing deformity of the joints. The life span of a sufferer can be reduced by up to10 years (Oster and McColl 2001).
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IBD patients are genetically predisposed to a dysregulated interaction between commensal bacteria and the intestinal mucosal immune system. Environmental factors trigger the initial presentation and possibly recurrent episodes of disease. IBD most probably is the result of defective bacterial clearance from the lamina propria of the gut. Proposed defective mechanisms include impairment of the epithelial integrity, defective production of antimicrobial peptides, and flawed intracellular handling of bacterial products. IBD pathogenesis is now thought to be due to these flaws in the innate immune system along with "dysbiosis" of the commensal instestinal flora.
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