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My MAC sC5b-9 Research
Has anyone checked their sC5b-9 blood level? Before, during and after IVIg, Rituximab, Soliris, Ultomiris or Vyvgart therapy?
SC5b-9 is an abbreviation for soluble C5b-9, which is also known as the terminal complement complex (TCC) or the membrane attack complex (MAC). SC5b-9 is a marker of complement system activation, which is a part of the innate immune system that helps to eliminate pathogens and foreign substances. SC5b-9 is formed when the complement protein C5 is cleaved into C5a and C5b, and C5b binds to C6, C7, C8, and multiple copies of C9 to form a pore-like structure that can insert into cell membranes and cause cell lysis.
A blood test for SC5b-9 can measure the level of SC5b-9 in plasma and provide information on the degree of activation of the terminal complement pathway. This test can help to confirm the diagnosis of complement-related diseases, such as atypical hemolytic uremic syndrome (aHUS) or C3 glomerulopathy (C3G), which are caused by excessive or uncontrolled complement activation. This test can also help to monitor anti-complement therapy efficiency, such as eculizumab or ravulizumab, which are monoclonal antibodies that inhibit the cleavage of C5 and prevent the formation of SC5b-934.
The test is done in a laboratory and the results are reported in nanograms per milliliter (ng/mL). The normal range for SC5b-9 level may vary depending on the laboratory and the method used, but it is generally between 100 and 400 ng/mL3. Higher levels may indicate increased complement activation and lower levels may indicate complement deficiency or inhibition.
C5 is a component of the complement system, a part of the innate immune system that plays an important role in inflammation and host defense. C5 is cleaved by a convertase enzyme into C5a and C5b fragments. C5a is a potent inflammatory mediator that can recruit immune cells and activate mast cells. C5b initiates the formation of the membrane attack complex (MAC), which can cause cell lysis and necrosis.
C5 is involved in the pathogenesis of MG by mediating complement activation and MAC formation at the NMJ. The binding of AChR autoantibodies to AChR triggers the classical pathway of complement activation, which leads to the generation of C5 convertase and subsequent cleavage of C5. The MAC formed by C5b and other complement components damages the postsynaptic membrane and reduces the number and function of AChR. MAC also induces inflammation and alters synaptic structure and function.
Inhibiting C5 may be a therapeutic strategy for MG by preventing complement activation and MAC formation at the NMJ. Several drugs target C5 or its cleavage.
The membrane attack complex (MAC) is a complex of proteins that forms on the surface of pathogen cell membranes or targeted cells as a result of the activation of the host’s complement system. The MAC consists of the complement components C5b, C6, C7, C8 and several C9 molecules that assemble into a ring structure that forms a pore in the membrane1. The pore allows free diffusion of molecules in and out of the cell, leading to cell lysis and death. The MAC is an effector of the immune system that can directly kill pathogens or cause tissue damage and inflammation in some autoimmune and inflammatory diseases. The MAC can also induce intracellular signaling and cell activation in the absence of lysis, which may have proinflammatory effects.
There is no definitive answer to how often MAC should be measured in MG patients, as different methods may have different advantages and limitations, and the optimal frequency of MAC measurement may depend on the individual patient’s condition, treatment and response. However, some general guidelines are:
• MAC measurement may be useful at the time of diagnosis to confirm the presence of complement activation and MAC deposition in MG patients with AChR autoantibodies
• MAC measurement may be helpful during the course of treatment to monitor the efficacy of complement inhibitors or other immunosuppressive therapies in reducing complement activation and MAC formation in MG patients
• MAC measurement may be beneficial during disease exacerbations or relapses to assess the degree of complement-mediated inflammation and tissue damage in MG patients and guide the adjustment of treatment
MAC membrane attack complex test is a laboratory test that measures the amount of soluble C5b-9 (sC5b-9) complex in the plasma. The sC5b-9 complex is formed by the C5b fragment along with C6, C7, C8 and several C9 molecules, which together constitute the membrane attack complex (MAC) that can cause cell lysis and inflammation. The sC5b-9 complex is released into the circulation when MAC is formed on cell membranes or in fluid phase. The MAC membrane attack complex test can be used to assess the degree of complement activation and MAC formation in various diseases and conditions, such as masthenia gravis (MG). The MAC membrane attack complex test can help evaluate the role of complement activation and MAC deposition in MG patients with acetylcholine receptor (AChR) autoantibodies and monitor the response to treatment with eculizumab or zilucoplan, drugs that inhibit C5 cleavage or binding and prevent MAC formation.
The normal ranges of sC5b-9 levels in plasma may vary depending on the method and the laboratory that performs the test. However, some general reference values are:
• ≤250 ng/mL according to Mayo Clinic Laboratories
• <450 ng/mL according to a study by Chen et al
• 129.1 ng/mL (median) according to a study by Kavanagh et al
sC5b-9 levels in plasma may increase due to complement activation and MAC formation in various diseases and conditions, such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, systemic lupus erythematosus and transplant-associated thrombotic microangiopathy. sC5b-9 levels in plasma may also increase due to spontaneous generation of sC5b-9 at 37°C or due to hemolysis. Therefore, it is important to follow the proper specimen collection and handling procedures and interpret the results in the context of the clinical situation.
The best way to lower your sC5b-9 levels in plasma is to treat the underlying cause of complement activation and MAC formation, if any. Depending on the diagnosis and the severity of the condition, your doctor may prescribe you medications that can inhibit the complement system or reduce inflammation. Some examples of these medications are:
• Eculizumab: A monoclonal antibody that binds to C5 and prevents its cleavage by convertases, thereby blocking the formation of C5a and C5b-9. Eculizumab is approved for the treatment of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome and generalized myasthenia gravis.
• Ravulizumab: A monoclonal antibody that binds to C5 and prevents its cleavage by convertases, thereby blocking the formation of C5a and C5b-9. Ravulizumab is a longer-acting version of eculizumab and is approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.
• Zilucoplan: A small peptide that binds to C5 and prevents its binding to convertases, thereby blocking the formation of C5a and C5b-9. Zilucoplan is an investigational drug that is being tested for the treatment of generalized myasthenia gravis.
• Steroids: Anti-inflammatory drugs that can suppress the immune system and reduce the production of autoantibodies and complement components. Steroids are often used as first-line or adjunctive therapy for various autoimmune and inflammatory diseases, such as systemic lupus erythematosus and myasthenia gravis.
Imuran is the brand name of azathioprine, a drug that belongs to the class of immunosuppressants. Imuran is used to prevent your body from rejecting a transplanted kidney or to treat symptoms of rheumatoid arthritis1. Imuran may also be used to treat inflammatory bowel disease (Crohn’s disease or ulcerative colitis).
Prednisone is not a complement inhibitor. Prednisone is a glucocorticoid that has anti-inflammatory and immunosuppressive effects, but it does not directly block the complement system. Prednisone is commonly used as a first-line therapy for MG patients, but it may have many side effects and may not be effective in some cases. Complement inhibitors are a newer class of drugs that specifically target the complement pathway and prevent the formation of the membrane attack complex (MAC) that causes cell lysis.
Imuran is not a direct complement inhibitor, meaning that it does not bind to or block any specific component of the complement system. However, Imuran can indirectly affect the complement system by reducing the production of autoantibodies and complement components that can activate the complement system and cause inflammation and tissue damage. Therefore, Imuran may have some beneficial effects on diseases that involve complement-mediated pathology, such as systemic lupus erythematosus or myasthenia gravis.
IG stands for immunoglobulin, which is a type of protein that is produced by the immune system to fight infections and foreign substances. IG can be given intravenously (IVIG) or subcutaneously (SCIG) to patients with certain immune disorders or deficiencies. IG can help myasthenia gravis (MG) by:
• Neutralizing autoantibodies: IG can bind to and block the activity of autoantibodies that target acetylcholine receptors (AChR) or muscle-specific kinase (MuSK) on the postsynaptic membrane of the neuromuscular junction (NMJ), which are the main causes of MG
• Modulating immune cells: IG can affect the function and balance of various immune cells, such as B cells, T cells, dendritic cells, macrophages and natural killer cells, that are involved in the production and regulation of autoantibodies and inflammation in MG
• Regulating complement system: IG can inhibit the activation and deposition of the complement system, a part of the innate immune system that plays an important role in inflammation and tissue damage at the NMJ in MG
Cell lysis in myasthenia gravis is the process of breaking down the cell membrane and releasing the contents of the cell. Cell lysis can occur in myasthenia gravis due to the formation of the membrane attack complex (MAC) at the neuromuscular junction (NMJ). The MAC is a complex of proteins that is formed by the cleavage of C5 and subsequent assembly of C5b, C6, C7, C8 and several C9 molecules. The MAC forms a pore in the cell membrane that allows free diffusion of molecules in and out of the cell, leading to cell lysis and death. Cell lysis can cause damage and inflammation at the NMJ and reduce the number and function of acetylcholine receptors (AChR), which are essential for muscle contraction. Cell lysis can also release intracellular antigens that can trigger further immune responses and autoantibody production. Cell lysis can be prevented or reduced by inhibiting C5 or its cleavage, which blocks the formation of MAC. Several drugs that target C5 or its cleavage are under investigation for the treatment of myasthenia gravis, such as eculizumab, zilucoplan and RNAi therapeutics.
Cell lysis in myasthenia gravis can be detected by different methods, such as:
• Immunohistochemistry: A technique that uses antibodies to detect MAC on muscle biopsies from myasthenia gravis patients. This method can show the location and extent of MAC deposition and cell lysis at the NMJ and correlate it with AChR loss and muscle weakness.
• ELISA: A technique that uses antibodies to measure the levels of sC5b-9 complex in serum or other body fluids from myasthenia gravis patients. The sC5b-9 complex is formed by the C5b fragment along with C6, C7, C8 and several C9 molecules, which together constitute the MAC that can cause cell lysis and inflammation. This method can reflect the degree of complement activation and cell lysis in myasthenia gravis patients and correlate it with disease severity and response to treatment.
• Single-cell RNA sequencing: A technique that uses high-throughput sequencing to measure the expression of genes in individual cells from myasthenia gravis patients. This method can reveal the transcriptional heterogeneity and immune signatures of different cell types involved in myasthenia gravis, such as B cells, T cells, macrophages and muscle cells3. This method can also identify genes that are associated with cell lysis and inflammation in myasthenia gravis, such as C5AR1, C5AR2, C6, C7, C8A, C8B, C9 and TNF3.
Another way to prevent or treat cell lysis is by reducing the production of antibodies that bind to the neuromuscular junction proteins and activate the complement system. This can be achieved by using therapies that target B cells, which are the source of antibodies. One of the therapies that has been shown to be effective in some MG patients is rituximab, a chimeric monoclonal antibody that depletes peripheral B cells by binding to CD2023. Rituximab is especially beneficial for patients with anti-MuSK antibodies, who do not respond well to conventional immunosuppressive therapies2. Other B cell-targeted therapies that are being explored include ocrelizumab, ofatumumab, obinutuzumab, ublituximab, and inebilizumab2.
Another way to prevent or treat cell lysis is by interfering with the recycling of antibodies by the neonatal Fc receptor (FcRn), which prolongs their half-life and increases their serum levels. By blocking FcRn, the antibodies can be cleared faster from the circulation and reduce their pathogenic effects. One of the therapies that uses this mechanism is efgartigimod, a FcRn antagonist that has shown promising results in a phase II trial for MG patients. Other FcRn antagonists that are under development include rozanolixizumab and nipocalimab.
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