Role of Mast Cell in Chronic Pathologies
Chronic infections start as acute infections. Some acute infections resolve while others take a chronic course. The infective agent as well as the immune system plays an active role in the outcome of the disease.
Normally, most infections are resolved, aided by treatment or not, by phagocytosis when the microbes are still in their discrete, planktonic forms. To start with, mast cells degranulate, in the presence of an infective agent, or a solid particle that provides shear strain or stress-- and may eventually lead to allergy if antigenic. Allergens cause the cross-linking of IgE on mast cells and the mechanical shear therefrom causes degranulation.
Mast cell degranulation releases histamine, heparin, prostaglandin D2, leukotriene C4 as well as chymase and tryptase--serine proteases, hydrogen peroxide, oxygen free radicals and NO. This leads to increased capillary permeability, and fleeting hives may form. Leucocyte migration leads to phagocytosis and although this will help clear the infection it is less likely to clear an indigestible or persistent solid particle. A more chronic course leads to increased inter-cell molecular interaction, promoted by the amino-glycan, heparin; eventually forming transient leucoplakia and pyogenic granuloma, and eventually granuloma proper which is a more persistent lesion.
Mast cell degranulation helps establish a granuloma, characterized by inner, epitheloid, renegade macrophages which secrete cytokines but no longer perform the phagocytic function and often called palisade cells. They enclose the offending organism or particle to prevent infection spread and also support ischemic necrosis. However, this prevents access of the infection to antibiotic and active phagocytes. The palisade cells are bordered by other leucocytes, including mast cells with upregulated adhesion molecle and stem cell proliferation factor production which perpetuate the heparin-aided cell-cell bonding in the granuloma and giant cells which contain intracellular agents that could not be broken down. They are all encapsulated in a fibrillar casing.
Persistence of an agent, constant activation of the mast cell as well as eosinophil infiltration into the focus are the root cause of granuloma formation. Oxidation burst is a major aspect of phagocytosis and its failure will likely lead to the persistence of an infection. Persistence of an infection also leads to the switch to the IgE antibody, which further causes more mast cell and eosinophil degranulation, and this helps in the progression and maintenance of the granuloma. Autoimmune diseases which cause damage to cells also promote mast cell degranulation and granuloma formation.
An aspect of chronic infection that complicates the picture is the transition from the planktonic microbial form to the sessile form, living in communities or colonies. This means that phagocytosis is highly impaired and infection persists in the body. The sheer size of the colony promotes mast cell and eosinophil degranulation, instead. These attributes all promote granuloma formation. The mast cell heparin is an aminoglycan, basic, that has a similar structure to amyloid, and is an amyloid-associated protein. Biofilm infections(which have amyloid curlis) will therefore promote the formation of granulomas, damage to the tissue; hypersensitivity and chronic pain, when they flare.
Usually, it is the over-activation of the immune system with the accompanying increased secretion of cytokines and toxic molecules--which is self-damaging to immune cells, rendering them less effective--that breaks open a granuloma, and leads to the rapid growth of microbes(reactivation) with a fatal outcome. Though immunity may have been built, the sheer number of the microbes in the colony means that the aggressive interaction between the two protagonists will be the more devastating to the body.
A persistent allergic reaction will lead to mast cell activation and granuloma formation. Granulomas are encapsulated by fibrous tissue which may be calcified. Histamine causes the weal and flare reactions via H1 and H2 receptors, respectively. It causes pruritis and, as a base, binds protons and promotes the cross-linking of keratin which leads to the formation of melanoidins. The skin becomes leathery and dark; and ages, in the long run.
UV light, trauma, alcohol, NSAIDS, polymixin antibiotic, morphine, cold and heat all cause the release of histamine and eosinophil infiltration. Histamine also promotes the release of neurotrophic factor from neuronal axons, and this leads to lichen planus, lichen sclerosis, and the growth of mast cells as well as other cells. The tissue is prone to cancer. Autoimmunity leads to hair loss, and localized hydrogen peroxide production leads to the bleaching of hair. Paleness in many advanced disease states could be the result of the production of hydrogen peroxide. In the beginning, the production of melanoidins may annul this effect but eventually the melanoids, themselves, will become bleached.
Tryptase from mast cell granules sensitizes neuronal axons. Stress stimulates mast cells to degranulate through the endocrine and neuronal pathways.
Dr. Oliver Verbe Birnso MD.
Normally, most infections are resolved, aided by treatment or not, by phagocytosis when the microbes are still in their discrete, planktonic forms. To start with, mast cells degranulate, in the presence of an infective agent, or a solid particle that provides shear strain or stress-- and may eventually lead to allergy if antigenic. Allergens cause the cross-linking of IgE on mast cells and the mechanical shear therefrom causes degranulation.
Mast cell degranulation releases histamine, heparin, prostaglandin D2, leukotriene C4 as well as chymase and tryptase--serine proteases, hydrogen peroxide, oxygen free radicals and NO. This leads to increased capillary permeability, and fleeting hives may form. Leucocyte migration leads to phagocytosis and although this will help clear the infection it is less likely to clear an indigestible or persistent solid particle. A more chronic course leads to increased inter-cell molecular interaction, promoted by the amino-glycan, heparin; eventually forming transient leucoplakia and pyogenic granuloma, and eventually granuloma proper which is a more persistent lesion.
Mast cell degranulation helps establish a granuloma, characterized by inner, epitheloid, renegade macrophages which secrete cytokines but no longer perform the phagocytic function and often called palisade cells. They enclose the offending organism or particle to prevent infection spread and also support ischemic necrosis. However, this prevents access of the infection to antibiotic and active phagocytes. The palisade cells are bordered by other leucocytes, including mast cells with upregulated adhesion molecle and stem cell proliferation factor production which perpetuate the heparin-aided cell-cell bonding in the granuloma and giant cells which contain intracellular agents that could not be broken down. They are all encapsulated in a fibrillar casing.
Persistence of an agent, constant activation of the mast cell as well as eosinophil infiltration into the focus are the root cause of granuloma formation. Oxidation burst is a major aspect of phagocytosis and its failure will likely lead to the persistence of an infection. Persistence of an infection also leads to the switch to the IgE antibody, which further causes more mast cell and eosinophil degranulation, and this helps in the progression and maintenance of the granuloma. Autoimmune diseases which cause damage to cells also promote mast cell degranulation and granuloma formation.
An aspect of chronic infection that complicates the picture is the transition from the planktonic microbial form to the sessile form, living in communities or colonies. This means that phagocytosis is highly impaired and infection persists in the body. The sheer size of the colony promotes mast cell and eosinophil degranulation, instead. These attributes all promote granuloma formation. The mast cell heparin is an aminoglycan, basic, that has a similar structure to amyloid, and is an amyloid-associated protein. Biofilm infections(which have amyloid curlis) will therefore promote the formation of granulomas, damage to the tissue; hypersensitivity and chronic pain, when they flare.
Usually, it is the over-activation of the immune system with the accompanying increased secretion of cytokines and toxic molecules--which is self-damaging to immune cells, rendering them less effective--that breaks open a granuloma, and leads to the rapid growth of microbes(reactivation) with a fatal outcome. Though immunity may have been built, the sheer number of the microbes in the colony means that the aggressive interaction between the two protagonists will be the more devastating to the body.
A persistent allergic reaction will lead to mast cell activation and granuloma formation. Granulomas are encapsulated by fibrous tissue which may be calcified. Histamine causes the weal and flare reactions via H1 and H2 receptors, respectively. It causes pruritis and, as a base, binds protons and promotes the cross-linking of keratin which leads to the formation of melanoidins. The skin becomes leathery and dark; and ages, in the long run.
UV light, trauma, alcohol, NSAIDS, polymixin antibiotic, morphine, cold and heat all cause the release of histamine and eosinophil infiltration. Histamine also promotes the release of neurotrophic factor from neuronal axons, and this leads to lichen planus, lichen sclerosis, and the growth of mast cells as well as other cells. The tissue is prone to cancer. Autoimmunity leads to hair loss, and localized hydrogen peroxide production leads to the bleaching of hair. Paleness in many advanced disease states could be the result of the production of hydrogen peroxide. In the beginning, the production of melanoidins may annul this effect but eventually the melanoids, themselves, will become bleached.
Tryptase from mast cell granules sensitizes neuronal axons. Stress stimulates mast cells to degranulate through the endocrine and neuronal pathways.
Dr. Oliver Verbe Birnso MD.
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