Basophils mechanism

There are also other immimological mechanisms, especially via IgG or IgM antibodies with immune complex formation, which can lead to similar clinical conditions [20, 34, 42] as has been shown in dextran anaphylaxis (table 1). Triggering of mast cells and basophils leads to release of various vasoactive mediators, among which histamine was the first recognized in 1908 (fig. 3,4) [6]. 

This chapter highlights the mechanisms responsible for mast cell activation during anaphylactic responses to environmental substances. In addition to discussing in detail the activation of mast cells and basophils by IgE and antigen, we also will describe how mouse models have been used to analyze the importance of various proteins, cells, mediators and activation mechanisms in the expression of anaphylaxis in that species. 

Interleukin-1 (IL-1) produced by monocytes and several other cell types [70, 146] has a wide array of biological properties, including T cell activation and inflammatory interactions with muscle, liver, fibroblasts, brain and bone [70, 146], IL-1, both natural and recombinant, has been shown to release histamine from human basophils and from human adenoidal mast cells [70,146,151] and this release was abolished by an IL-1 antibody. However, the average release produced by 10 units of IL-1 was less than 20% and there was considerable variability between populations of basophils in the extent of histamine release. Moreover, the secretory response elicited was quite slow (within 15 min) compared with that of other peptides [151]. Desensitization of the basophils by anti-IgE serum had no effect on the subsequent IL-1 response, suggesting different mechanisms of action [ 151], as has been the case with other peptides. Interestingly, the portion of the IL-1 molecule that is responsible for its immu-nostimulatory activity appears to be separate from that portion responsible for its proinflammatory effects [152]. However, that portion of the molecule responsible for eliciting basophil and mast-cell histamine release has not as yet been defined. 

To obtain tissue preparations whose constituents were maintained as closely as possible to their state in vivo, the material had to be fixed, i.e. the enzymes inactivated so that cell structures were instantaneously preserved, an almost unattainable ideal. Formalin was the favored fixative, but others (e.g. picric acid), were also employed. Different methods of fixation caused sections to have different appearances. Further artifacts were introduced because of the need to dehydrate the preparations so that they could be stained by dyes, many of which were lipid-soluble organic molecules. Paraffin wax was used to impregnate the fixed, dehydrated material. The block of tissue was then sectioned, originally by hand with a cut-throat razor, and later by a mechanical microtome. The sections were stained and mounted in balsam for examination. Hematoxylin (basophilic) and eosin (acidophilic) (H and E staining) were the commonest stains, giving blue nuclei and pink cytoplasm. Eosinophils in the blood were recognized in this way. 

Mechanism of Action A monoclonal antibody that selectively binds to human immunoglobulin E (IgE) preventing it from binding to the surface of mast cells and basophils. Therapeutic Effect Prevents or reduces the number of asthmatic attacks. Pharmacokinetics Absorbed slowly after subcutaneous administration, with peak concentration in 7-8 days. Excreted in the liver, reticuloendothelial system, and endothelial cells. Half-life 26 days. 

Most anaphylactoid reactions are due to a direct or chemical release of histamine, and other mediators, from mast cells and basophils. Immune-mediated hypersensitivity reactions have been classified as types I-IV. Type I, involving IgE or IgG antibodies, is the main mechanism involved in most anaphylactic or immediate hypersensitivity reactions to anaesthetic drugs. Type II, also known as antibody-dependent hypersensitivity or cytotoxic reactions are, for example, responsible for ABO-incompatible blood transfusion reactions. Type III, immune complex reactions, include classic serum sickness. Type IV, cellular responses mediated by sensitised lymphocytes, may account for as much as 80% of allergic reactions to local anaesthetic. 

By a negative feedback control mechanism mediated by H2 receptors, histamine appears to modulate its own release and that of other mediators from sensitized mast cells in some tissues. In humans, mast cells in skin and basophils show this negative feedback mechanism lung mast cells do not. Thus, histamine may act to limit the intensity of the allergic reaction in the skin and blood. 

Mechanism of type I hypersensitivity. Initial exposure to allergen (sensitization phase) leads to production of IgE by plasma cells differentiated from allergen-specific cells (not shown). The secreted IgE binds IgE-specific receptors (FcsR) on blood basophils and... 

IL-18 also induces IL-4, IL-10 and IL-13 production, increases IgE expression on B cells and in association with IL-2, it enhances stimulus-induced IL-4 production from TH2 cells. Bone marrow-derived basophils produce IL-4 and IL-13 in response to a stimulus from IL-18 and IL-3. IL-18 in combination with IL-12 induces IFN-y from dendritic cells and bone marrow-derived macrophages. Adhesion molecules, ICAM-1 and VCAM-1, are induced by this cytokine on synovial fibroblasts and endothelial cells. It inhibits osteoclast formation via its induction of GM-CSF from T cells. The receptors ofIL-18, IL-18Ra and IL-18R(3, share their signaling mechanisms via the IL-1R family. Toll-like receptors also share the downstream signaling pathway of IL-18 and are known to regulate IL-18 expression. 

Regarding human tissues, the few data available are contradictory, since according to some authors (Tedeschi et al., 1991) histamine release from basophils is not modified by H3 receptor ligands. In other studies (Bent et al., 1991), it was found that thioperamide could increase histamine release from adenoidal mast cells, but apparently (R)a-methylhistamine was totally inactive. In any case the concentrations of thioperamide are much higher than those necessary to block H3 receptors, thus suggesting that other mechanisms might be involved. Raible et al., (1994) hypothesized by the use of thioperamide, the presence of H3 receptors on human eosinophils which mediate histamine-induced increase in cytosolic calcium mobilization. However, the low efficacy of the known H3 receptor agonists, -as stimuli for eosinophils... 

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