Published on February 19, 2014
SEMINAR PRESENTATION Mast cells MODERATOR:DR.C.M.KULDEEP
Introduction • Mast cells are primary effector cells in immunoglobulin E (lgE) mediated inflammatory reactions. • They are implicated in:– both acquired and innate immune responses, – wound healing, – fibrosis , – angiogenesis, and – autoimmune diseases
History • First described by Ehrlich in 1871 , who distinguished them from other connective tissues by their ability to stain metachromatically with basic aniline dyes.
Structure and staining • Mast cells are bone marrow-derived cells that occur in the normal dermis in small numbers as oval to spindle-shaped cells with a centrally located round to oval nucleus. • They contain in their cytoplasm numerous granules that do not stain with routine stains like hematoxylin-eosin. • The granules stain with methylene blue, which is present in the Giemsa stain, with toluidine blue, and with Alcian blue.
Mast cell with cytoplasmic granules and villous projections from the cell surface.
Functions • Mast cells are reservoirs of preformed inflammatory mediators and rapidly synthesizes others on activation • Mediators contributes to the changes in anaphylaxis and delayed hypersensitivity reactions • Primes B-cell for antibody formation • They play a role in the defense against parasites; stimulate chemotaxis, activation and proliferation of eosinophils; promote phagocytosis • stimulate connective tissue repair and angiogenesis
Mast cell distribution and identity • Mast cells are widely distributed, long lived cells found predominately in connective and mucosal tissues and often in proximity to blood vessels, nerves, and lymphatic tissues. • Mast cells are abundant in the skin, respiratory tract, gastrointestinal tract, and genitourinary tract. • 7000 mast cells/cubic mm in normal skin.
• All human mast cells contain tryptase , histamine, and proteoglycans , including heparin and chondroitin sulfate E. • Mast cells are classically identified in tissue by toluidine blue or giemsa dye that stains the cytoplasmic granules, and more recently, by immunohistochemistry using an antibody that recognizes mast cell tryptase. • Human mast cells are classically divided into two types.
• Mast cells that contain tryptase and chymase are referred to as TC mast cells .Such cells tend to be located in sub mucosal tissues. Increased numbers of these cells are found in fibrotic disease. • Mast cells that contain tryptase but not chymase are referred to as T mast cells (MCt) and are increased in allergic and parasitic diseases.
Ultra-structure of mast cells • Electron microscopic examination of mast cells reveals numerous large and long villi at their periphery . • The mast cell granules appear as round, oval, or angular-shaped, membrane-bound structures. Mature granules measure up to 0.8 Âµm in diameter. • They contain two components: lamellae and electron-dense, finely granular material .
Development & differentiation • Mast cells arise from a CD34*, KIT+ pleuripotent progenitor stem cell. • Cross linking KIT by stem cell factor (SCF) is essential for these precursor cells to differentiate into mast cell. • Mature mast cells require SCF for survival. • KIT (CD117) expressed on haematopoeitic stem cell, is transmembrane tyrosine kinase receptor for SCF.
• While KIT is down-regulated on other bone marrow derived cells during their differentiation , it remains highly expressed on mast cells and is critical for many mast cell functions such as survival, chemotaxis and enhancement of signalling events .
Other cytokines that regulate SCF-dependent mast cell differentiation and proliferation include interleukin 13 (lL-13), IL-4,5, and interferon-gamma (lFN-y). • IL-3 shares a number of signal transduction pathways with SCF but has minimal direct effects on human mast cell proliferation except in early cultures.
• IL-4 enhances mast cell function when added to mature culture. • In contrast , when IL-4 is added during SCFdependent mast cell differentiation, it inhibits cell division and decreases final mast cell numbers. • In developing mast cells , IFN-y inhibits mast cell proliferation and influences mast cell phenotype and function.
PATHOGENESIS • HISTAMINE causes local increase in permeability of capillaries and venules.
Mast cell Activation • Antigen-dependent aggregation of FceRl bound IgE on the surface of mast cells is a primary mechanism of activation of Mast cells and subsequent release of preformed proinflammatory mediators, as well as of newly synthesized mediators
• Non-IgE-driven signals that activate mast cells include Toll-like receptor ligands such as lipopolysaccharide and nucleic acids, the anaphylatoxins C3a and C5a, and certain chemokines and cytokines.
Mast cell degranulation • Degranulation of mast cells occurs after crosslinking of IgE on the cell surface. • Degranulation generally occurs within minutes of exposure of the cell membrane to the secretagogue, and usually consists of the extrusion of entire granules, but some granules may undergo intracellular disintegration .
• Initial stages of degranulation consist of granule swelling with loss of internal substructure and electron density. • Extrusion of granules takes place through extensive membrane fusion between the plasma membrane and peri granular membranes. • This is associated with formation of conduits resulting from fusion of the membranes of multiple granules.
• This results in extensive labyrinthine channels in the cell through which swollen, less electrondense granules, all of which have lost their individual surrounding membranes, are released into the extracellular space. • Concomitant with their release into the extracellular space, the granules release their preformed and stored mediators histamine, heparin, serine proteinases, and certain cytokines.
Immunological and non –immunological stimuli lead to activation of intracellular kinases and increase in intracellular Ca2+ Degranulation of mast cells Release of preformed mediators hiatamine, tryptase, chymase
All these lead to rapid onset of local increase in permeability of submucosal or subcutaneous capillaries and post capillary veneules Local plasma extravasation Swellings
Mast cell mediators
PRE-F0RMED SECRET0RY MEDIAT0RS • Pre –formed secretory granular mediators are released In response to aggregation Of the high-affinity IgE receptor activation through complement receptors , or activation by cytokine. • Mast cell tryptase is released upon activation of mast cells, along with histamine, heparin, chymase ,and carboxypeptidase A.
Tryptase • Most abundant human mast cell protein and exists in two forms that show 90 percent homology, alpha and Beta tryptases. • The biologic function of tryptase has not been completely defined, but it appears to activate protein cascade systems, enhance vasopermeability , and alter airway smooth muscle reactivity.
• Tryptase has the capability to Cleave fibronectin , vasoactive intestinal peptide, and kininogens. • Also a growth factor for epithelial cells and fibroblast. • The total tryptase level in Blood is used as an indirect parameter of mast cell burden and mast cell activation.
• Baseline tryptase levels are generally elevated in patients with systemic mastocytosis (SM). • Increased serum tryptase levels are also observed within 15minutes of onset of anaphylaxis with a peak level seen at 1 to 2 hours, although this is not consistent.
Chymase • The mast cell protease chymase converts angiotensin I to angiotensin II. • The vasoactive properties produced by angiotensin II may contribute to transient hypertension in some individuals during mast cell activation reactions . • Carboxypeptidase A similarly converts Angiotensin I to angiotensin II.
Histamine • Histamine is stored in all mast cells, as well as basophils and released with cell activation. • The biological effects of histamine are mediated through activation of H1,H2, H3, and H4 receptors.
• H1 receptors are located on epithelial cells as well as vascular and perivascular cells and mediate vascular permeability and instability. • H2 receptors are present on epithelial Cells in the gastrointestinal tract and are associated with gastric hypersecretion. • H3 receptors are found in the brain and gastrointestinal tract and may be associated with certain neurologic effects such as headache. • H4 receptors are present on eosinophils and mast cells but their significance Is still unknown.
• Heparin stabilizes and regulate secretory granule proteases. • In addition, it binds to antithrombin III, inhibiting activation of the clotting cascade. • Heparin binding also regulates and stabilizes cytokines and growth factor. • Heparin mediated effects include bleeding diathesis , osteopenia and osteoporosis.
NEWLY SYNTHESIZED MEDIAT0RS Newly formed ,membrane-derived Lipid mediators ,produced by mast cell activation, include prostaglandinD (PGD2) ,cysteinyl Leukotrienes and platlet-activating factor (PAI). These mediators have profound effects in both the immediate and late allergic reactions.
• Receptors for PGD2, are present on vascular and perivascular cells and mediate effects including bronchospasm ,vasodilation vasopermeability and inhibition of platelet aggregation. • flushing in response to niacin is mediated by PGD2.
• Cysteinyl Leukotrienes increase vascular Permeability and cause bronchoconstriction. • These mediators also are Responsible for the long-lasting wheal and flare in responseto injection of antigen in human skin. • Leukotrienes are believed to contribute to abdominal Symptoms in patients with SM.
• PAF is a potent inducer of bronchoconstriction mediated through microvascular leakage in the airways and the subsequent development of submucosal edema. • Various cells synthesize PAF including endothelial cells, neutrophils and macrophages. • Functions as a chemotactic agents for eosinophils , neutrophils and mast cells.
• Mast cells similarly produce and release a number of cytokines viz. • Tumor necrosis factor causes cachexia and vascular instability. • Transforming growth factor-Beta contributes to tissue fibrosis, abnormal bone remodeling ,osteopenia and eosinophilia. • IL -4 is implicated in IgE synthesis and the development of a T helper2 phenotype.
• IL-5 is instrumental in the recruitment and survival of eosinophils that contribute to tissued damage. • IL -6 has been linked to the Pathogenesis of osteoporosis and is elevated in the plasma of patients with SM.
• Mast cell products may both induce an immediate reaction with in minutes of Fc epsilon receptor I cross linking and its consequence are referred to as immediate HSR. • Whereas late phase reaction peaks 6-12 hours following antigen challenge and are associated with cytokine and chemokine from eosinophils, neutrophils and basophils that have been secondarily recruited.
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