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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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eosinophil introduction
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
eosinophil function
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
eosinophil il 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
eosinophil selective traffic
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

eotaxin
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
eosinophil selective traffic1
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
eosinophil receptors and degranulation
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.
eosinophil mediators
Eosinophil : mediators
  • Preformed :
    • stored in cytoplasmic granules
  • Produced on activation :
    • lipid mediators
    • cytokines
eosinophil preformed mediators
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.

eosinophil basic proteins 1
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
eosinophil basic proteins 2
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.
eosinophil newly synthesised mediators
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
eosinophil protective role against parasites
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.

eosinophil pathogenic role in allergy
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.
eosinophil resolution of inflammation
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
eosinophil summary
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