Autoimmune disorders

Cure Arthritis Naturally

Cure Arthritis Naturally

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Several autoimmune responses result in the generation of autoantibodies, which can promote cell and tissue destruction and chronic inflammatory responses via Fc receptor activation on leukocytes [17]. Autoantibodies against antigens on the cell surface of blood cells, for example, can result in the rapid destruction of these cells by macrophages localized in the reticuloendothelial system of the spleen and liver. Immune thrombocytopenia purpura (ITP) and autoimmune hemolytic anemia (AIHA) are caused in large part by self-reactive antibodies against platelet antigens (e.g., GPIIb-IIIa, GPIb-IX, GPIb, GPIIIa) and erythrocyte antigens (e.g., Band 3) [30]. Experimental mouse models of ITP and AIHA are dependent on FcgR-signaling, which in turn depends on Syk kinase activity for activation of phagocytes. Indeed, treatment with a Syk kinase inhibitor reduces platelet loss in an experimental murine model of ITP [31].

Other examples of organ-specific pathogenic self-antigens are the a3 domain of basement membrane collagen type IV, causing glomerulonephritis in Goodpasture's syndrome and desmoglein in pemphigus vulgaris, a blistering skin disease. A direct correlation between anti-desmoglein IgG4 levels and disease activity was recently reported, strengthening the idea that the autoantibody is the causative agent for tissue damage [32]. In this case, monocytes, neutrophils and mast cells activated via their Fcg receptors are the likely triggers and mediators of tissue damage. Syk inhibitors should block these responses and thus potentially ameliorate clinical symptoms.

4.2.1 Rheumatoid arthritis (RA), multiple sclerosis (MS) and systemic lupus erythematosus (SLE)

The pathogenesis of RA is still incompletely understood but has been associated with rheumatoid factors, recognizing Fc portions of IgGs, and a battery of autoantibodies directed against joint-antigens, including type II collagen and several citrullinated proteins [6]. Syk was detected in the synovial intimal lining in the synovial tissue from RA patients, and significantly greater amounts of phospho-Syk expression were observed in RA synovial tissue as compared with osteoarthritis synovial tissue [33]. Moreover, Syk and FcgR-signaling play critical roles in the activation of immune cells elicited by these autoantibodies and their immune complexes (ICs) [3]. Syk inhibition blocks activation of mast cells, macrophages, dendritic cells, neutrophils and B cells via B cell receptors. Overall, Syk inhibitors can attenuate vascular leakage, leukocyte infiltration, disease propagation, release of reactive oxygen intermediates, nitric oxide, proteases and pro-inflammatory cytokines that cause adjacent tissue damage and osteoclast activation leading to bone destruction. These salutary effects, observed in Syk-deficient and/or FcRg-deficient mice, have been phenocopied using a small molecule inhibitor of Syk [34]. In a rat model of RA, Syk inhibitor treatment drastically reduced bone erosions, as well as the influx of inflammatory cells into the synovium [35].

MS is a neurological chronic and progressive disease likely caused by an autoimmune response to various antigens present in the myelin sheath. MS is characterized by focal demyelination and lymphocytic infiltration in the central nervous system and the brain [36]. The involvement of autoantibodies is not clear as reflected by the fact that induction of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, can occur in B-cell deficient animals. Remarkably, despite the apparent lack of participation by autoantibodies and immune complexes, FcRg-deficient mice are resistant to EAE suggesting that the FcRg signaling chain is coupling to receptors other than antibody-Fc receptors. In fact, FcRg-deficiency actually protects mice from the neuropath-ogenic effects of adoptively transferred anti-myelin specific lymphocytes [37]. Other possible receptors linking to murine FcRg, and by extension Syk, include NKR-P1 in NK cells, Pir-A (LILRA family of proteins in humans) on dendritic cells, mast cells, macrophages and platelets, and possibly the T cell receptor (TCR) complex in y8 T cells [37]. Thus, Syk inhibitors may also be able to dampen, directly or indirectly, the inflammatory action of autoantigen-specific effector T lymphocytes.

SLE is a chronic relapse and remitting autoimmune disease that affects multiple organ systems including the skin, joints, kidneys and nervous system. It initially manifests as fever, malaise, joint pains, myalgias and fatigue, and is virtually always accompanied by the presence of a diverse but characteristic set of autoantibodies [38]. In addition to organ-specific damage mediated by IC-triggered macrophage and neutrophil activation, Syk can potentially affect SLE pathophysiology in several other ways. The genetic contributions to disease susceptibility and severity are complex and involve multiple traits that implicate abnormalities of both the innate and adaptive immune systems [38]. Microarray studies with peripheral blood leukocytes from SLE patients have helped identify ''gene signatures'' typically found as a result of the action of type I interferons (IFNs) [39,40]. Interestingly, ICs containing nucleic acids, which are commonly found in SLE affected blood, were shown to be potent stimuli of IFNa production by plasmacytoid dendritic cells (pDCs) [41]. As expected, this IFNa production required intact FcgRIIa, which is known to signal through Syk. The importance of Syk function in SLE is further substantiated in the literature including reported affects on ITAM-bearing ezrin/radixin/moesin (ERM) signal transduction in T cell tissue invasion, and FcgRIIIa alleles predictive of progression to end-stage renal disease [38,42-44]. Treatment with 4 an oral small molecule inhibitor of Syk demonstrated delays in disease progression and improvements in survival in NZB/W lupus prone mice [45].

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Treating Rheumatoid Arthritis With Herbs Spices Roots

Treating Rheumatoid Arthritis With Herbs Spices Roots

Did You Know That Herbs and Spices Have Been Used to Treat Rheumatoid Arthritis Successfully for Thousands of Years Do you suffer with rheumatoid arthritis Would you like to know which herbs and spices naturally reduce inflammation and pain 'Treating Rheumatoid Arthritis with Herbs, Spices and Roots' is a short report which shows you where to start.

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