Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atopic disorders are on the increase in the Western world and are due, at least in part, to an overactive mast cell response. A better understanding of the intracellular signalling pathways that regulate both mast cell degranulation and the secretion of arachidonic acid metabolites and inflammatory cytokines could help in the treatment of these disorders. The src homology 2-containing inositol-polyphosphate 5'-phosphatase, SHIP, has been shown to be a key 'gatekeeper' of mast cell degranulation. SHIP prevents degranulation from occuring when IgE alone binds to the high-affinity receptor for IgE (FcvarepsilonR1), SHIP restrains it when IgE-bound FcvarepsilonR1 are engaged by multivalent allergens, and SHIP inhibits it when an IgG against the same allergen co-clusters the inhibitory low-affinity receptor for IgG (FcgammaRIIB) with the IgE receptor. SHIP acts as a negative regulator of degranulation by hydrolyzing phosphatidylinositol-3,4,5-trisphosphate, a second messenger generated in activated cells by phosphatidylinositol 3-kinase. Our finding that binding of only IgE to the FcvarepsilonR1 of SHIP-deficient mast cells results in massive degranulation, led us to investigate the signalling pathways that are triggered in normal murine bone marrow-derived mast cells by monomeric IgE. We report here that monomeric IgE activates signalling pathways resulting in mast cell survival, without stimulating degranulation or proliferation. These studies demonstrate that mast cell sensitization by IgE is an active rather than a passive process.
 ...
PMID:The role of SHIP in mast cell degranulation and IgE-induced mast cell survival. 1200 29

Atopic disorders such as allergic rhinitis, asthma and atopic dermatitis are associated with skewing of immune responses towards a TH2 phenotype, resulting in eosinophilic inflammation. TH2 cytokines promote eosinophil growth, migration and activation, mast cell differentiation, and IgE production, and are candidate mediators of pathologic abnormalities in asthma and other atopic diseases. There has been a significant increase in the prevalence of allergic disorders over the past several decades. Recent epidemiological studies suggest that reduced early-life exposure to strong TH1 stimuli in industrialized counties has skewed the TH1/TH2 balance towards TH2 responses. Improved hygiene, vaccination, and use of antibiotics may contribute to this imbalance. In the last half of the twentieth century we have seen the use of multiple agents to treat atopic disorders, ranging from antihistamines, steroids and leukotriene modifiers to anti-IgE antibodies. All these agents can block symptoms but do not significantly modify the course of the disease. Recent attempts to restore TH1/TH2 balance by blocking TH2 cytokines or inducing TH1 cytokines, have not only failed to alter the outcome of atopic diseases but, in some cases, have caused significant adverse effects. An alternate method of suppressing TH2 responses takes advantage of the innate immune response to bacterial DNA. Oligodeoxynucleotides (ODN) containing sequence motifs centered on unmethylated CG dinucleotides (CpG ODN) resemble bacterial DNA, and like bacterial DNA are immunostimulatory; we and others have shown that CpG ODN can suppress TH2-mediated atopic inflammation without requiring the induction of TH1-type cytokines. These agents may represent a novel therapeutic approach toward restoring immune tolerance in atopic individuals.
 ...
PMID:CpG oligodeoxynucleotides: a novel therapeutic approach for atopic disorders. 1456 Nov 54

Atopic disorders include a range of conditions such as allergic asthma, -rhinitis, -conjunctivitis, -dermatitis, food and drug allergies and anaphylaxis. Induction of T helper (Th)-2 immune response with consequent IgE dependent eosinophil, basophil and mast cell mediated tissue damage is the characteristic feature of allergies. The mechanism underlying this unique and long appreciated feature of allergy is being elucidated at the molecular level with advances in our knowledge of the chemokine system. Thus, chemokines that target CCR3 in concert with Th2 cytokines appear to play a pathogenic role in allergy. In contrast, chemokines that target CXCR3 in concert with Th1 cytokine appear to play a beneficial role. Accordingly, inhibiting CCR3/Th2 pathway using CCR3 antagonists is viewed as a potentially useful strategy for anti-allergy drug development. In contrast, the idea of using CXCR3 agonists to inhibiting allergic response by promoting CXCR3/Th1 pathway faces serious concerns of their potential pro-inflammatory activities in vivo. In this article we have critically evaluated the literature examining the principle and potential of this anti-allergy drug development strategy including a summary of various compounds that are under investigation.
 ...
PMID:CCR3 and CXCR3 as drug targets for allergy: principles and potential. 1456 Nov 76