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- Pejler, Gunnar, et al.
(författare)
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Mast cell proteases
- 2007
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Ingår i: Advances in Immunology. - 0065-2776 .- 1557-8445. ; 95, s. 167-255
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells (MCs) are traditionally thought of as a nuisance for its host, for example, by causing many of the symptoms associated with allergic reactions. In addition, recent research has put focus on MCs for displaying harmful effects during various autoimmune disorders. On the other hand, MCs can also be beneficial for its host, for example, by contributing to the defense against insults such as bacteria, parasites, and snake venom toxins. When the MC is challenged by an external stimulus, it may respond by degranulation. In this process, a number of powerful preformed inflammatory “mediators” are released, including cytokines, histamine, serglycin proteoglycans, and several MC-specific proteases: chymases, tryptases, and carboxypeptidase A. Although the exact effector mechanism(s) by which MCs carry out their either beneficial or harmful effects in vivo are in large parts unknown, it is reasonable to assume that these mediators may contribute in profound ways. Among the various MC mediators, the exact biological function of the MC proteases has for a long time been relatively obscure. However, recent progress involving successful genetic targeting of several MC protease genes has generated powerful tools, which will enable us to unravel the role of the MC proteases both in normal physiology as well as in pathological settings. This chapter summarizes the current knowledge of the biology of the MC proteases.
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| 2. |
- Uibo, Raivo, et al.
(författare)
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GAD65 Autoimmunity-Clinical Studies
- 2008
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Ingår i: Advances in Immunology. - 0065-2776. ; 100, s. 39-78
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Forskningsöversikt (refereegranskat)abstract
- Type 1 diabetes (TID) in children and particularly in teenagers and adults is strongly associated with autoreactivity to the Mr 65,000 isoform of glutamic acid decarboxylase (GAD65). Autoantibodies to GAD65 are common at the time of clinical diagnosis and may be present for years prior to the onset of hyperglycemia. GAD65 autoantibodies predict conversion to insulin dependence when present in patients classified with type 2 diabetes nowadays more often referred to as patients with latent autoimmune diabetes in the adult (LADA) or type 1,5 diabetes. Analyses of T cells with HLA DRB1*0401-tetramers with GAD65-specific peptides as well as of anti-idiotypic GAD65 autoantibodies suggest that GAD6S auto-reactivity is common. The immunological balance is disturbed and the appearance of GAD65 autoantibodies represents markers of autoreactive loss of pancreatic beta cells. Extensive experimental animal research. in particular of the Non-obese diabetic (NOD) mouse, showed that GAD65 therapies reduce insulitis and prevent spontaneous diabetes. Recombinant human GAD65 produced by current Good Manufacturing Practice (cGMP) and formulated with alum was found to be safe in Phase I and 11 placebo-controlled, double-blind, randomized clinical trials. The approach to modulate GAD65 autoreactivity with subcutaneous immunotherapy (SCIT) showed promise as alum-formulated GAD65 induced a dose-dependent reduction in the disappearance rate of endogenous residual C-peptide production. Additional controlled clinical trials are needed to uncover the mechanisms by which subcutaneous injections of recombinant human GAD65 may alter GAD6S autoreactivity.
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