My Hypothesis that Long Hauler's is a Type III Hyper Sensitivity Reaction & a Possible MOA for LL
I've been thinking about this for some time now.
I really believe that Long Hauler Covid is actually a Type 3 Hyper Sensitivity Reaction.
In Type 3, there are Free Antibodies floating in the blood plasma. They are called Serum Immune Complexes. They are antigen-antibody complexes. For long haulers, the antigen-antibody complex would be the more numerous <covid 19 Spike protein mated with the antibody our body made against the spike protein> OR less in number <covid 19 Spike protein mated with the vaccination antibody given to us in vaccine>.
Type 3 is a rather delayed reaction.
Type 1 is fastest, such as after a bee sting, which could be immediate anaphylaxis or an asthma, angioedema, (usually humoral pre-formed antibodies, IgE, eosinophil mediated, mast cell, histamine),
Type 2 is like Type 3 with antigen-antibody complex, but it is not free floating in the blood. Rather, the complex is attached to the cell, so it is cytotoxic. An example of this hypersensitivity reaction is when your body rejects organs in Graft vs. Host Disease, or Myasthenia Gravis / Pemphigus Vulgaris which are more delayed than immediate.
Type 4, is cell to cell mediated hypersensitivity. The T cells do the killing, not the antibody. Here T Cells and Cytokines, CD4 T lymphocytes secrete interferon gamma which stimulate macrophages to make a granuloma. It is the most delayed and the slowest because it takes a long time to make a granuloma which are found in Tuberculosis, histoplasmosis, coccidiomycosis or Sarcoidosis.
Long Covid is right up this time range. It comes on 2-3 weeks after a person had covid and can last for months to years it seems.
Since the antigen-antibody complex is in the blood, it is circulating through out the body. This complex can end up being deposited in the wall of the blood vessels causing Vasculitis, into the joints, causing immune-complex Arthritis which is what happens in Rheumatoid Arthritis & Lupus, they can get stuck in the kidneys, causing immune-complex mediated Nephritis, in the liver causing Hepatitis (children found with hepatitis following vaccination), in the heart, causing myoCarditis (following covid and following vaccine), etc, etc. All of these are common in Long Covid and even following vaccination.
Type 3 could be a generalized reaction all over the body or it could be a localized reaction. When these antigen-antibody complexes are deposited all over the body, into all the tissues and organs, the Complement Cascade system is activated via IgM antibody 1st and IgG 2nd response, (very good at Complement Activation) and subsequently, the patient gets a shit load of C-complements (proteins) into the blood as well. Complements are proteins made by the liver, leading to the complement cascade which results in the MAC which attacks all foreigners. This Complement System acts like a link or a bridge between the Innate and Adaptive Immunity. Complements are made by the liver to help fight the invader, the antigen-antibody complex. The end result of the Complement Cascade results in an entity called the Membrane Attack Complex, MAC which destroys the antigen-antibody complex. But, in a massive overload situation, they may destroy the tissues as well. Why? Because these complexes are deposited in the tissues of the body.
In a massive overload situation as in long covid (long term), or post vaccination syndrome, (short term), this could result in Hypocomplementemia because all the complements are being consumed being used over and over and over again, to destroy the myriad of antigen-antibody complexes imbedded in the tissues. A real life example of hypocomplementemia is lupus, an auto-immune disease where the body creates MAC, but there are no antigen-antibody complexes, so the body is attacking itself, destroying its own tissues. Many Rheumatological disease like RA have increased complement which leads to joint deformity, kidney disease glomerulonephritis, vascular, endocarditis, myocarditis, vasculitis.
Another idea here is that if the liver is weakened by the huge deposition of antibody-antigen complexes and it is spurred into manufacture of all these complements, but it can not do so because it is itself infected with the antibody-antigen complexes and is therefore unable to develop the building blocks of the MACs via the cascade. That would mean that the only way to get rid of these antibody-antigen complexes is either waiting for them to disintegrate in the tissues or by our Natural Killer Cells.
One test to determine if there is a Complement Deficiency in Long Covid would be the CH50 test. It's a screening test of the Markers which indicate the cascade. If it is low, then order the Early Complement Level. We would expect C4 to be low for it to indicate a Classical Pathway, (auto-immune) pointing to Long Covid or post viral.
There is a complement system regulating protein called Decay Accelerating Factor (DAF) which, on the cell's surface, inhibits both complement 3 convertase and complement 5 convertase; another action is to inhibit Natural Killer Cells, both of which may be how the cells are protected from getting destroyed by the complements. DAF interferes with the escalation of the complement cascade whos final result is the Membrane Attack Complex, (MAC); MAC fails to develop.
I'm guessing here, but I'm considering that Leronlimab may have an effect in upregulation of DAF so the tissues can heal while the antigen-antibody complexes get destroyed by Natural Killer Cells which we already know are suppressed by T regulator cells when Leronlimab is given. So Leronlimab may have a double effect on curbing the onslaught on these antigen-antibody complexes, but may prolong the time it takes to get rid of them.
Leronlimab, being a CCR5 blockade, binds to CCR5 with greatest affinity. Therefore, when it is introduced, it displaces any other cytokine attached to CCR5. This gains control of the Natural Killer Cells. It seems to have a regulating effect. A taming effect, reducing the rampant destruction of everything and anything that it doesn't like.
I suspect Leronlimab achieves this Taming Effect on our Immune Response by Activation of the Tregulatory Cells, the T suppressor cells. By activation of these T helper cells, the Immune Cascade is Tamed, it is quieted, it is quelled leading to less inflammation, less swelling, fewer side effects of the war, fewer symptoms. T regs prevent the attack upon our own cells and develop "Tolerance" of what is "Self" vs. "Non-Self or Foreign" thereby preventing Auto-Immune Disease which in effect a form of this Type III Hypersensitivity Reaction. Does Long Covid = Auto-Immune Disease???
AIDS, Acquired ImmunoDeficiency Syndrome is the attack on CD4+ T-Lymphocytes. That is an attack on T helper cells. T regulatory / T suppressor cells. When you kill these T helper lymphocytes, you kill the Adaptive Immune System. No help. B Lymphocytes are left clueless. Natural Killer cells are clueless. Leronlimab shuts down HIV 1 attack, (not HIV 2), and therefore eradicates AIDS when caused by HIV 1.
I think, although we most definitely can say that Leronlimab is a CCR5 blockade, we should probably say the its Mechanism of Action in the majority of its indications will be a T helper cell regulator. T helper cells help other T cells. It also helps Humoral Immunity by helping the B lymphocytes. T helper cells help T cytotoxic cells kill. They help T regulatory cells control/suppress/regulate the cell mediated attack. (T suppressor cells are now called T regulator cells and they help the immune system do its job, but they can suppress it too, so that the immune system does not kill self.) Leronlimab permits the passive response of the immune system, (memory, production of antibodies), while cutting down on the flank attack, (Tcytotoxic cells, Natural Killer Cells), therefore allows the generalized work of getting to the core of the problem without inducing secondary harm in the process. Therefore, the "real" Mechanism of Action that Leronlimab Helps the T helper cell. CCL5 RANTES is main deceiver of the T helper cell, but Leronlimab displaces CCL5 RANTES from its control of this incredibly important component of Cell-mediated Active Immunity and restores appropriate control of this cellular- immunoregulation necessary to promote recognition of self vs. non self.
I've been thinking about this for some time now.
I really believe that Long Hauler Covid is actually a Type 3 Hyper Sensitivity Reaction.
In Type 3, there are Free Antibodies floating in the blood plasma. They are called Serum Immune Complexes. They are antigen-antibody complexes. For long haulers, the antigen-antibody complex would be the more numerous <covid 19 Spike protein mated with the antibody our body made against the spike protein> OR less in number <covid 19 Spike protein mated with the vaccination antibody given to us in vaccine>.
Type 3 is a rather delayed reaction.
Type 1 is fastest, such as after a bee sting, which could be immediate anaphylaxis or an asthma, angioedema, (usually humoral pre-formed antibodies, IgE, eosinophil mediated, mast cell, histamine),
Type 2 is like Type 3 with antigen-antibody complex, but it is not free floating in the blood. Rather, the complex is attached to the cell, so it is cytotoxic. An example of this hypersensitivity reaction is when your body rejects organs in Graft vs. Host Disease, or Myasthenia Gravis / Pemphigus Vulgaris which are more delayed than immediate.
Type 4, is cell to cell mediated hypersensitivity. The T cells do the killing, not the antibody. Here T Cells and Cytokines, CD4 T lymphocytes secrete interferon gamma which stimulate macrophages to make a granuloma. It is the most delayed and the slowest because it takes a long time to make a granuloma which are found in Tuberculosis, histoplasmosis, coccidiomycosis or Sarcoidosis.
Long Covid is right up this time range. It comes on 2-3 weeks after a person had covid and can last for months to years it seems.
Since the antigen-antibody complex is in the blood, it is circulating through out the body. This complex can end up being deposited in the wall of the blood vessels causing Vasculitis, into the joints, causing immune-complex Arthritis which is what happens in Rheumatoid Arthritis & Lupus, they can get stuck in the kidneys, causing immune-complex mediated Nephritis, in the liver causing Hepatitis (children found with hepatitis following vaccination), in the heart, causing myoCarditis (following covid and following vaccine), etc, etc. All of these are common in Long Covid and even following vaccination.
Type 3 could be a generalized reaction all over the body or it could be a localized reaction. When these antigen-antibody complexes are deposited all over the body, into all the tissues and organs, the Complement Cascade system is activated via IgM antibody 1st and IgG 2nd response, (very good at Complement Activation) and subsequently, the patient gets a shit load of C-complements (proteins) into the blood as well. Complements are proteins made by the liver, leading to the complement cascade which results in the MAC which attacks all foreigners. This Complement System acts like a link or a bridge between the Innate and Adaptive Immunity. Complements are made by the liver to help fight the invader, the antigen-antibody complex. The end result of the Complement Cascade results in an entity called the Membrane Attack Complex, MAC which destroys the antigen-antibody complex. But, in a massive overload situation, they may destroy the tissues as well. Why? Because these complexes are deposited in the tissues of the body.
In a massive overload situation as in long covid (long term), or post vaccination syndrome, (short term), this could result in Hypocomplementemia because all the complements are being consumed being used over and over and over again, to destroy the myriad of antigen-antibody complexes imbedded in the tissues. A real life example of hypocomplementemia is lupus, an auto-immune disease where the body creates MAC, but there are no antigen-antibody complexes, so the body is attacking itself, destroying its own tissues. Many Rheumatological disease like RA have increased complement which leads to joint deformity, kidney disease glomerulonephritis, vascular, endocarditis, myocarditis, vasculitis.
Another idea here is that if the liver is weakened by the huge deposition of antibody-antigen complexes and it is spurred into manufacture of all these complements, but it can not do so because it is itself infected with the antibody-antigen complexes and is therefore unable to develop the building blocks of the MACs via the cascade. That would mean that the only way to get rid of these antibody-antigen complexes is either waiting for them to disintegrate in the tissues or by our Natural Killer Cells.
One test to determine if there is a Complement Deficiency in Long Covid would be the CH50 test. It's a screening test of the Markers which indicate the cascade. If it is low, then order the Early Complement Level. We would expect C4 to be low for it to indicate a Classical Pathway, (auto-immune) pointing to Long Covid or post viral.
There is a complement system regulating protein called Decay Accelerating Factor (DAF) which, on the cell's surface, inhibits both complement 3 convertase and complement 5 convertase; another action is to inhibit Natural Killer Cells, both of which may be how the cells are protected from getting destroyed by the complements. DAF interferes with the escalation of the complement cascade whos final result is the Membrane Attack Complex, (MAC); MAC fails to develop.
I'm guessing here, but I'm considering that Leronlimab may have an effect in upregulation of DAF so the tissues can heal while the antigen-antibody complexes get destroyed by Natural Killer Cells which we already know are suppressed by T regulator cells when Leronlimab is given. So Leronlimab may have a double effect on curbing the onslaught on these antigen-antibody complexes, but may prolong the time it takes to get rid of them.
Leronlimab, being a CCR5 blockade, binds to CCR5 with greatest affinity. Therefore, when it is introduced, it displaces any other cytokine attached to CCR5. This gains control of the Natural Killer Cells. It seems to have a regulating effect. A taming effect, reducing the rampant destruction of everything and anything that it doesn't like.
I suspect Leronlimab achieves this Taming Effect on our Immune Response by Activation of the Tregulatory Cells, the T suppressor cells. By activation of these T helper cells, the Immune Cascade is Tamed, it is quieted, it is quelled leading to less inflammation, less swelling, fewer side effects of the war, fewer symptoms. T regs prevent the attack upon our own cells and develop "Tolerance" of what is "Self" vs. "Non-Self or Foreign" thereby preventing Auto-Immune Disease which in effect a form of this Type III Hypersensitivity Reaction. Does Long Covid = Auto-Immune Disease???
AIDS, Acquired ImmunoDeficiency Syndrome is the attack on CD4+ T-Lymphocytes. That is an attack on T helper cells. T regulatory / T suppressor cells. When you kill these T helper lymphocytes, you kill the Adaptive Immune System. No help. B Lymphocytes are left clueless. Natural Killer cells are clueless. Leronlimab shuts down HIV 1 attack, (not HIV 2), and therefore eradicates AIDS when caused by HIV 1.
I think, although we most definitely can say that Leronlimab is a CCR5 blockade, we should probably say the its Mechanism of Action in the majority of its indications will be a T helper cell regulator. T helper cells help other T cells. It also helps Humoral Immunity by helping the B lymphocytes. T helper cells help T cytotoxic cells kill. They help T regulatory cells control/suppress/regulate the cell mediated attack. (T suppressor cells are now called T regulator cells and they help the immune system do its job, but they can suppress it too, so that the immune system does not kill self.) Leronlimab permits the passive response of the immune system, (memory, production of antibodies), while cutting down on the flank attack, (Tcytotoxic cells, Natural Killer Cells), therefore allows the generalized work of getting to the core of the problem without inducing secondary harm in the process. Therefore, the "real" Mechanism of Action that Leronlimab Helps the T helper cell. CCL5 RANTES is main deceiver of the T helper cell, but Leronlimab displaces CCL5 RANTES from its control of this incredibly important component of Cell-mediated Active Immunity and restores appropriate control of this cellular- immunoregulation necessary to promote recognition of self vs. non self.
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