Phagocytosis
Phagocytosis, and hence the immune system, evolved to take care of the nutritional basic need of the cell.
The phagosome which contains the engulfed 'food' particle fuses with the lysosome, containing digestive enzymes called lysozymes, proteases and lipases to form the phagolysosome.
Phagocytosis can take place in the absence of inflammation i.e. without the blood vessel involvement and recruitment of leucocytes from blood. In fact, resident macrophages, mast cells, dendritic cells, fat progenitor cells and, for that matter, all body cells have lysosmes, vesicles containing digestive enzymes, and carry out phagocytosis i.e they are technically phagocytes(cells that eat). These lysosomes store food(proteins, carbohydartes and fats) and contain lysozymes that digest carbohydrates and proteases and lipases, which are enzymes that digest the other food substances and make them energy- or structure-convertible. In fact, this is the way the cell gets rid of old, degenerate organelles, damaged proteins and renews self(rejuvenation) as well as kills and harvests food from foreign organisms(microbes).
So phagocytosis(endocytosis) evolved in the cell to take care of the host cell's nutritional needs, firstly, by protecting itself from losing its ATP and foodstuff to the microbe, whose attachment to the host cell nibs the cell membrane and causes these substances to leak out and, secondly, by harvesting food directly from the microbe, following its digestion in the phagolysosome. The reverse process(exocytosis) sends out digestive and toxic wastes, first to the secretory apparatus, the Golgi apparatus, and then out of the membrane to the exterior of the cell.
Hence, when the body senses intruders, like an infection, it bolsters this mechanism to kill and harvest its food from the microbes. To sense these microbes, initial damage is inflicted by the microbes to the host's cell, followed by the release of ATP, which is, in turn, harvested by the microbes for their own energy requirements and growth. So, there is a constant battle to feed from each other, between the host cell and the microbe, with each one using all sorts of strategies to survive in the warfare.
When phagocytosis involves a cell eating its own damaged proteins or organelles, it is known as autophagy; microphagy and macrophagy, respectively. It is known as allophagy if the corresponding phagosomes are formed from the content of another cell. For example, just after fertilization, the mitochondria of the spermatozoid is degraded in the embryo by an autophagosome, to prevent heteroplasmy, following ubiquitination. Phagocytosis of a microbe is, in fact, allophagy and macrophagy, at the same time.
When the relationship between the host and the intruder microbe is such that the host readily supplies microbes with unusable or unwanted food, like in the digestive tract, as well as from epithelial debris, say, from the shedding of the skin(in constant supply), no invasion or invasive attachment to the host cell is usually necessary and a common-ground beneficial or non-detrimental co-existence will be established between the two. Typically, type ii immunocompatibility compex sensed by the innate lymphocytes and formed between the the microbe protein and these lymphocytes, establishes a cordial no-threat co-existence between the immune system phagocytes and the microbe. Hence, we then call the harmless microbes, the normal flora.
There is little need for phagocytosis or immunological response to be mounted against normal flora, as the process will not obviously be energetically beneficial to either party. In fact, by colonizing their host, the normal flora prevent the often stressed and harmful pathogens from gaining access to the host's body and inflicting damage, in their attempt to harvest ATP and other nutrients, and survive, often, using toxins that they do produce. It should be observed here that nutritional stress(deficiency) in microbes out in the wild will give rise to their rapid growth when they colonize the host and find plentiful supplies and this subsequently leads to food depletion and more nutritional stress and another wave of production of microbial toxins, increased attachment to the host's cell(invasion) and, hence, increased virulence of a microbe.
When the damage to the host's cell is substantial, new leucocytes are recruited from the blood to help do the job of immune defence and surveillance, and phagocytosis is amplified as it is self-perpetuated Otherwise, residential phagocytes take care of the little that is to be done. No inflammation will be obvious, if threat is small. In fact, people with low fat stores, will have more available free fat progenitor, residential cells to carry out phagocytosis. This will reduce the need for blood-derived phagocytic support and inflammation. Sores in muscles will cause the recruitment of these progenitor cells in situ to first phagocytose the debris in the muscles and then promote esinophils to facilitate more muscle cells to form, as they emerge from the fat progenitor cell, in what has been termed positive stress response or eustress.
So keeping a good body weight supplements macrophage phagocytosis and decreases inflammation as it increases the number of free fat progenitor cells available for phagocytosis. In fact, this is one way the high doses of anabolic steroids decrease inflammation; another is by the prevention of cytokines formation. Good, balanced nutrition will repair the damage caused by the 'by-stander' effect and 'frustrated' phagocytosis. Too much inflammation is counterproductive to phagocytosis as these phagocytes are equally damaged by their own products. The neutrophils are more susceptible than macrophages to these 'by-stander' effect and 'frustrated phagocytosis'.
It is more likely that apoptosis, which arises from less severe cellular trauma, and may result from ubiquination and autophagy, as opposed to the more severe necrosis, will favor non-inflammatory response(phagocytosis) with resident phagocytes, few in number and less aggressive due to a low activated status, since this will not involve substantial tissue damage due to warrant mast cell(histamine, prostaglandins and chymase) or blood cell(prostaglandins) response, except perhaps in the brain where astrocytes are abundant and much more active. The complement products, C3a and C5a are mast cell chemoattractants, which mast cell secretes chymase that is a serine protease that opens up tissue and exposes serine to tag the cell as 'foreign' and permit phagocytosis to take place. Another phenomenon that provokes phagocytosis is the exposure of complex polysaccharides, that appear foreign, to the host, in damaged tissue. It is interesting to note that this serine residue or polysaccharide exposures are at the base of residential phagocytosis that follows apoptosis. Without such phagocytosis, autoimmune diseases can be generated.
It should be made known that if the phagocytes are strongly stimulated by, say, metabolic stimulants, including micronutrients(which ramp up metabolism) and capsaicin(pepper), these 'non-inflammation-based' resident phagocytes can wake up from slumber and react more aggressively to intracellular dormant microbes to kill them and to tissue debris or may even rage havoc on the host's own tissue and they, then, can generate inflammation, not by the direct stimulus of a microbe and/or cytokine but by generalized metabolic activation.
In infectious disease, carriers(who carry less metabolically active macrophages) will then experience heightened response to a hitherto quiescent infection, when such heightened generalized metabolic activation occurs from, say, niacin or other irritants like capsaicin,and through oxidative stress produce a oxidized ligand that stimlates the savenger/TAM receptors or when the microbe titre rises to a dangerously high level that will activate the Toll-like receptors and cause cytokines to be released and stimulate these hitherto innocuous macrophages and promote inflammation. More harm to the body may now lead to an unexpected, sudden medical event(from a cytokine storm). It appears that the carrier state results from chronic stress-induced tolerance(inactivity) in the immune system or a genetic defect that usually leads to substantial debris accumulation in tissues.
Good mitochondrion, the powerhouse of the cell, and its enzymes, the power horses, will promote good metabolism so that when food is eaten, it will be burned rather than get stored, because there is improved capacity to do so. Chronic or severe stress, be it psychological, diseased-induced, will lead to, first, increased metabolism, then damage to organelles, especially the mitochondria and the activation of the alternative pentose phosphate pathway. Stress can lead to alternative mRNA splicing, destructive autophagy or apoptosis, which may be damaging to the body and will adversely affect phagocytic clean up.
The functions of the liver, kidney, the brain and other organs are compromised. Microbes attain a persistent, low growth, dormant, more adhesive(adhesin), less mobile, since they are under nutritional stress, as malabsorption, from poor debris disposal, prevents food access into the body. This multicellular microbial behavior is crucial for the disease state since 80% of human bacterial chronic inflammatory and infectious diseases involve biofilm. The signs of toxins in the body range from foul stool, bad breath to headache.
In microbes, nutritional stress will cause degradation of antitoxins, from the initial exponential growth. This stress leads to cleavage of mRNA and reduced production of large proteins encoded by uncleaved mRNA in favor of the production of small proteins and peptides encoded by cleaved mRNA that are death proteins and stress proteins and will help microbial cells cope with stress, promote their stay and prevent good health in the host.
Inflammation and immunity occur mostly at night when phagocytosis is most active; repair and rest follow and the biological clock will be readjusted with sleep-rest by GABA
The essence of inflammation is the production of homeostasis i.e. the re-establishment of the constant internal environment in the face of threat to it. To do this, the body may have to cause more damage so as to invoke a commensurate response. Damage to the skin will stimulate chymase and serine proteases to be released from mast cells and this will cause more damage to be sensed at the level of the blood cells and produce changes that will facilitate the migration of leucocytes to fend off the threat.
The release of histamine(chemical pain/itch stimulant), possibly through neuropetide release, will result in the dilation(leakage of capillaries and veins). Bradykinin, a polypeptide from blood, with its precursor synthesized in the liver, produces its effects by causing the release of histamine from mast cells(around the blood vessels and nerves). Histamine, prostaglandins, heparin and chymase are released from mast cells and may cause shock, pain or swelling(erythema) if substantial damage is caused in the tissue to accommodate the exudate and the stimulation of bradykinin synthesis will lead to angioedema. Prostaglandins are produced principally by all white blood cells and sensitize the tissue to pain(lower pain threshold). C3a and C5a, which are complement products, will cause mast cell cell migration(chemoattractants) and histamine release(anaphylatoxins); the former being more of a chemoattractant and the latter more of an anaphylactoxin. Complement proteins are synthesized in the liver and put into blood.
Dr. Oliver Verbe Birnso, M.D.
The phagosome which contains the engulfed 'food' particle fuses with the lysosome, containing digestive enzymes called lysozymes, proteases and lipases to form the phagolysosome.
Phagocytosis can take place in the absence of inflammation i.e. without the blood vessel involvement and recruitment of leucocytes from blood. In fact, resident macrophages, mast cells, dendritic cells, fat progenitor cells and, for that matter, all body cells have lysosmes, vesicles containing digestive enzymes, and carry out phagocytosis i.e they are technically phagocytes(cells that eat). These lysosomes store food(proteins, carbohydartes and fats) and contain lysozymes that digest carbohydrates and proteases and lipases, which are enzymes that digest the other food substances and make them energy- or structure-convertible. In fact, this is the way the cell gets rid of old, degenerate organelles, damaged proteins and renews self(rejuvenation) as well as kills and harvests food from foreign organisms(microbes).
So phagocytosis(endocytosis) evolved in the cell to take care of the host cell's nutritional needs, firstly, by protecting itself from losing its ATP and foodstuff to the microbe, whose attachment to the host cell nibs the cell membrane and causes these substances to leak out and, secondly, by harvesting food directly from the microbe, following its digestion in the phagolysosome. The reverse process(exocytosis) sends out digestive and toxic wastes, first to the secretory apparatus, the Golgi apparatus, and then out of the membrane to the exterior of the cell.
Hence, when the body senses intruders, like an infection, it bolsters this mechanism to kill and harvest its food from the microbes. To sense these microbes, initial damage is inflicted by the microbes to the host's cell, followed by the release of ATP, which is, in turn, harvested by the microbes for their own energy requirements and growth. So, there is a constant battle to feed from each other, between the host cell and the microbe, with each one using all sorts of strategies to survive in the warfare.
When phagocytosis involves a cell eating its own damaged proteins or organelles, it is known as autophagy; microphagy and macrophagy, respectively. It is known as allophagy if the corresponding phagosomes are formed from the content of another cell. For example, just after fertilization, the mitochondria of the spermatozoid is degraded in the embryo by an autophagosome, to prevent heteroplasmy, following ubiquitination. Phagocytosis of a microbe is, in fact, allophagy and macrophagy, at the same time.
When the relationship between the host and the intruder microbe is such that the host readily supplies microbes with unusable or unwanted food, like in the digestive tract, as well as from epithelial debris, say, from the shedding of the skin(in constant supply), no invasion or invasive attachment to the host cell is usually necessary and a common-ground beneficial or non-detrimental co-existence will be established between the two. Typically, type ii immunocompatibility compex sensed by the innate lymphocytes and formed between the the microbe protein and these lymphocytes, establishes a cordial no-threat co-existence between the immune system phagocytes and the microbe. Hence, we then call the harmless microbes, the normal flora.
There is little need for phagocytosis or immunological response to be mounted against normal flora, as the process will not obviously be energetically beneficial to either party. In fact, by colonizing their host, the normal flora prevent the often stressed and harmful pathogens from gaining access to the host's body and inflicting damage, in their attempt to harvest ATP and other nutrients, and survive, often, using toxins that they do produce. It should be observed here that nutritional stress(deficiency) in microbes out in the wild will give rise to their rapid growth when they colonize the host and find plentiful supplies and this subsequently leads to food depletion and more nutritional stress and another wave of production of microbial toxins, increased attachment to the host's cell(invasion) and, hence, increased virulence of a microbe.
When the damage to the host's cell is substantial, new leucocytes are recruited from the blood to help do the job of immune defence and surveillance, and phagocytosis is amplified as it is self-perpetuated Otherwise, residential phagocytes take care of the little that is to be done. No inflammation will be obvious, if threat is small. In fact, people with low fat stores, will have more available free fat progenitor, residential cells to carry out phagocytosis. This will reduce the need for blood-derived phagocytic support and inflammation. Sores in muscles will cause the recruitment of these progenitor cells in situ to first phagocytose the debris in the muscles and then promote esinophils to facilitate more muscle cells to form, as they emerge from the fat progenitor cell, in what has been termed positive stress response or eustress.
So keeping a good body weight supplements macrophage phagocytosis and decreases inflammation as it increases the number of free fat progenitor cells available for phagocytosis. In fact, this is one way the high doses of anabolic steroids decrease inflammation; another is by the prevention of cytokines formation. Good, balanced nutrition will repair the damage caused by the 'by-stander' effect and 'frustrated' phagocytosis. Too much inflammation is counterproductive to phagocytosis as these phagocytes are equally damaged by their own products. The neutrophils are more susceptible than macrophages to these 'by-stander' effect and 'frustrated phagocytosis'.
It is more likely that apoptosis, which arises from less severe cellular trauma, and may result from ubiquination and autophagy, as opposed to the more severe necrosis, will favor non-inflammatory response(phagocytosis) with resident phagocytes, few in number and less aggressive due to a low activated status, since this will not involve substantial tissue damage due to warrant mast cell(histamine, prostaglandins and chymase) or blood cell(prostaglandins) response, except perhaps in the brain where astrocytes are abundant and much more active. The complement products, C3a and C5a are mast cell chemoattractants, which mast cell secretes chymase that is a serine protease that opens up tissue and exposes serine to tag the cell as 'foreign' and permit phagocytosis to take place. Another phenomenon that provokes phagocytosis is the exposure of complex polysaccharides, that appear foreign, to the host, in damaged tissue. It is interesting to note that this serine residue or polysaccharide exposures are at the base of residential phagocytosis that follows apoptosis. Without such phagocytosis, autoimmune diseases can be generated.
It should be made known that if the phagocytes are strongly stimulated by, say, metabolic stimulants, including micronutrients(which ramp up metabolism) and capsaicin(pepper), these 'non-inflammation-based' resident phagocytes can wake up from slumber and react more aggressively to intracellular dormant microbes to kill them and to tissue debris or may even rage havoc on the host's own tissue and they, then, can generate inflammation, not by the direct stimulus of a microbe and/or cytokine but by generalized metabolic activation.
In infectious disease, carriers(who carry less metabolically active macrophages) will then experience heightened response to a hitherto quiescent infection, when such heightened generalized metabolic activation occurs from, say, niacin or other irritants like capsaicin,and through oxidative stress produce a oxidized ligand that stimlates the savenger/TAM receptors or when the microbe titre rises to a dangerously high level that will activate the Toll-like receptors and cause cytokines to be released and stimulate these hitherto innocuous macrophages and promote inflammation. More harm to the body may now lead to an unexpected, sudden medical event(from a cytokine storm). It appears that the carrier state results from chronic stress-induced tolerance(inactivity) in the immune system or a genetic defect that usually leads to substantial debris accumulation in tissues.
Good mitochondrion, the powerhouse of the cell, and its enzymes, the power horses, will promote good metabolism so that when food is eaten, it will be burned rather than get stored, because there is improved capacity to do so. Chronic or severe stress, be it psychological, diseased-induced, will lead to, first, increased metabolism, then damage to organelles, especially the mitochondria and the activation of the alternative pentose phosphate pathway. Stress can lead to alternative mRNA splicing, destructive autophagy or apoptosis, which may be damaging to the body and will adversely affect phagocytic clean up.
The functions of the liver, kidney, the brain and other organs are compromised. Microbes attain a persistent, low growth, dormant, more adhesive(adhesin), less mobile, since they are under nutritional stress, as malabsorption, from poor debris disposal, prevents food access into the body. This multicellular microbial behavior is crucial for the disease state since 80% of human bacterial chronic inflammatory and infectious diseases involve biofilm. The signs of toxins in the body range from foul stool, bad breath to headache.
In microbes, nutritional stress will cause degradation of antitoxins, from the initial exponential growth. This stress leads to cleavage of mRNA and reduced production of large proteins encoded by uncleaved mRNA in favor of the production of small proteins and peptides encoded by cleaved mRNA that are death proteins and stress proteins and will help microbial cells cope with stress, promote their stay and prevent good health in the host.
Inflammation and immunity occur mostly at night when phagocytosis is most active; repair and rest follow and the biological clock will be readjusted with sleep-rest by GABA
The essence of inflammation is the production of homeostasis i.e. the re-establishment of the constant internal environment in the face of threat to it. To do this, the body may have to cause more damage so as to invoke a commensurate response. Damage to the skin will stimulate chymase and serine proteases to be released from mast cells and this will cause more damage to be sensed at the level of the blood cells and produce changes that will facilitate the migration of leucocytes to fend off the threat.
The release of histamine(chemical pain/itch stimulant), possibly through neuropetide release, will result in the dilation(leakage of capillaries and veins). Bradykinin, a polypeptide from blood, with its precursor synthesized in the liver, produces its effects by causing the release of histamine from mast cells(around the blood vessels and nerves). Histamine, prostaglandins, heparin and chymase are released from mast cells and may cause shock, pain or swelling(erythema) if substantial damage is caused in the tissue to accommodate the exudate and the stimulation of bradykinin synthesis will lead to angioedema. Prostaglandins are produced principally by all white blood cells and sensitize the tissue to pain(lower pain threshold). C3a and C5a, which are complement products, will cause mast cell cell migration(chemoattractants) and histamine release(anaphylatoxins); the former being more of a chemoattractant and the latter more of an anaphylactoxin. Complement proteins are synthesized in the liver and put into blood.
Dr. Oliver Verbe Birnso, M.D.
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