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eosinophils and mast cells

eosinophils and mast cells. eosinophil. Eosinophil : introduction. bone marrow derived granulocytes Myeloid lineage Paul Ehrlich 1879 red, eosinophilic basic granules nucleus divided into two tear-shaped lobes non-dividing - approx 13 hr in circulation usually less than 4% of WBC

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eosinophils and mast cells

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  1. eosinophils and mast cells

  2. eosinophil

  3. Eosinophil : introduction • bone marrow derived granulocytes • Myeloid lineage • Paul Ehrlich 1879 red, eosinophilic basic granules • nucleus divided into two tear-shaped lobes • non-dividing - approx 13 hr in circulation • usually less than 4% of WBC • secretory function

  4. Eosinophil : function • increase (eosinophilia) associated with • parasite infections eg. helminths • allergy eg. Aspergillus fumigatus • some poorly understood immunological conditions eg. Churg-Strauss syndrome, Loeffler’s syndrome, endomyocardial fibrosis • increase in : - blood, bronchial tissue, skin, nasal polyps and gut tissue

  5. Eosinophil : IL-5 • IL-5 eosinophil recruitment, proliferation, maturation, maintenance and activation factor • Bone marrow cultures with IL-3 and GM-CSF produce very few eosinophil colonies. T-cell derived IL-5 is required. • IL-5 is a heterogeneous glycoprotein 32 - 62kDa. Gene on the long arm of chromosome 5, along with the other haematopoetic growth factors GM-CSF, IL-3, IL-4. • IL-5 enhances phagocytic activity, stimulates superoxide production, upregulates IgG and IgE Fc and complement receptors, delays apoptosis - prolongs eosinophil survival • Humanised monoclonal anti-IL-5 decreases circulating eosinophils

  6. Eosinophil : selective traffic Eosinophils need to move to sites of inflammation and adhere to and cross pulmonary vascular epithelial cells. This involves : Eosinophil chemotactic factors eosinophil chemotactic factor of anaphylaxis (ECF-A) from mast cells Val-Gly-Ser-Glu and Ala-Gly-Ser-Glu N-formyl peptides (f-Met-Leu-Phe) bacteria C5a complement activation ecalectin T cell derived, 36-kDa protein eotaxin CCR3 chemokine from lung and skin stromal cells MIP-1, RANTES, MCP-3 monos,T cells, platelets, basophils

  7. eotaxin • CCR-3 receptor-specific, eosinophil-selective chemokine. • 8.4 kDa, 74 amino acid polypeptide • mast cell and macrophage-produced TNF-a and IL-1a act on adjacent epithelium, endothelium, lymphocytes, macrophages and eosinophils to produce eotaxin. • receptor is a 355 aa residue seven transmembrane domain, G-linked protein exclusively on eosinophils. • is unique among known C-C chemokines in that it binds to only one receptor, CCR-3 (Kd=0.1-1.5 nM). • has no known activity on neutrophils, macs or lymphocytes. • induces the production of ROS • synergises with IL-5 • eosinophils also produce IL-4, IL-5 and Eotaxin

  8. Eosinophil : selective traffic Adhesion : • the alpha-4 integrin (very late activation antigen) VLA-4 on eosinophils binds to the adhesion molecule VCAM-1 on vascular endothelium. Transmigration : • the beta-2 integrin p-selectin on eosinophils binds to its ligand ICAM-1 on vascular endothelium

  9. eosinophil life cycle

  10. Eosinophil : receptors and degranulation • CD4, HLA-DR, CD25, IL-5R, CCR3R etc. • CD23, low affinity IgE receptor Fc epsilon R11 - selective for EPO, MBP but not ECP. • CD32, high affinity IgG receptor Fc gamma R11 - selective for ECP not EPO. • CD35, type 1 high-affinity complement receptor CR1 binds C3b / C3d and C4b. • synergy with IL-3, IL-5, GM-CSF, TNF, IFN-beta, PAF.

  11. Eosinophil : mediators • Preformed : • stored in cytoplasmic granules • Produced on activation : • lipid mediators • cytokines

  12. Eosinophil : preformed mediators The cytoplasmic granules are membrane bound and contain a crystalloid protein core. The granule and cell membranes fuse on triggering and release the granule contents. The granules contain four highly toxic arginine-rich proteins with a high isoelectric point pH > 11.0 • major basic protein (MBP), • eosinophil cationic protein (ECP), • eosinophil peroxidase (EPO), • eosinophil-derived neurotoxin (EDN). These bind the negatively charged surfaces of parasites.

  13. Eosinophil : basic proteins 1 ECP 21 kDa • kills certain parasites • potent neurotoxin • induce histamine release from mast cells • down-regulate T-cell proliferation • shortens clotting time • alters the GAG production by fibroblasts • Controlled by binding of heparin and -2 macroglobulin. EDN 18kDa (70% homology with ECP) • kills parasites • potent neurotoxin • potent ribonuclease

  14. Eosinophil : basic proteins 2 EPO 74 kDa • peroxidase activity - ie. generation of cytotoxic free radicals • degranulates mast cells • platelet aggregation • Controlled by uptake and neutralisation by neutrophils MBP 14 kDa • Toxic to certain parasites, tumour cells and mammalian cells • degranulates mast cells • neutralises heparin • platelet aggregation • cytotoxic for bronchial epithelium - leading to airways hyper-reactivity.

  15. Eosinophil : newly synthesised mediators Lipids • Leukotrienes LTC4, D4, E4. These prolong broncho-constriction, mucus secretion, increased vascular permeability. Cytokines • IL-3, IL-5, IL-13, GM-CSF. Content increased in allergic patients Reactive oxygen metabolites • oxidative burst Regulatory enzymes • histaminase histamine • phospholipase PAF • arysulphatase B leukotrienes • collagenases basement membrane

  16. Eosinophil : protective role against parasites Eosinophils kill the schistosomula (egg) stage of Schistosoma mansoni Degree of protection against nematodes in guinea pigs and sheep correlates with eosinophilia. Genetic determination - strain-dependent differences in eosinophilia following parasitic infection in mice. Possibly related to IL-5 or eotaxin polymorphism. Mice infected with Trichonella spiralis treated with anti-eosinophil antibody cannot eliminate the worms and have more muscle cysts.

  17. Eosinophil : pathogenic role in allergy • Eosinophils abundant in allergic sites • ECP / MBP cause damage and denudation of bronchial epithelium, and can cause impairment of ciliary beating. Seen in biopsy of asthma • Serum and bronchial lavage / sputum ECP levels raised in : • asthmatics • seasonal hay fever • experimental asthma challenge • IL-5 KO mice lack bronchial hyper-reactivity.

  18. Eosinophil : resolution of inflammation • Apoptosis - eosinophils retain granules but lose the ability to secrete them. Apoptotic eosinophils are ingested and digested by macrophages in a non-inflammatory process. • Steroid treatment - very effective for eosinophil-mediated diseases. • prevents transcription of eosinophil cytokines • accelerates eosinophil apoptosis • downregulates VCAM-1

  19. eosinophil : summary • recruited from bone marrow • chemotaxis, attachment and diapedesis • functions with other factors / cells • non-specific recognition • secretion of toxic mediators • effective against extra-cellular parasites • resolution of inflammation

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