developmentc5b+c6+c7+c8+c9 activation of complements by antigen-associated antibody in the classical pathway, c1 binds with its c1q subunits to fc fragments (made of ch2 region) of igg or igm, which has formed a complex with antigens. c4b and c3b are also able to bind to antigen-associated igg or igm, to its fc portion. such immunoglobulin-mediated binding of the complement may be interpreted as that the complement uses the ability of the immunoglobulin to detect and bind to non-self antigens as its guiding stick. the complement itself can bind non-self pathogens after detecting their pathogen-associated molecular patterns (pamps), however, utilizing specificity of the antibody, complements can detect non-self targets much more specifically. some components have a variety of binding sites. in the classical pathway, c4 binds to ig-associated c1q and c1r2s2 enzyme cleaves c4 to c4b and 4a. c4b binds to c1q, antigen-associated ig (specifically to its fc portion), and even to the microbe surface. c3b binds to antigen-associated ig and to the microbe surface. ability of c3b to bind to antigen-associated ig would work effectively against antigen-antibody complexes to make them soluble. regulation the complement system has the potential to be extremely damaging to host tissues, meaning its activation must be tightly regulated. the complement system is regulated by complement control proteins, which are present at blood plasma and host cell membrane. some complement control proteins are present on the membranes of self-cells preventing them from being targeted by complement. one example is cd59, also known as protectin, which inhibits c9 polymerization during the formation of the membrane attack complex. the classical pathway is inhibited by c1-inhibitor, which binds to c1 to prevent its activation. another example, is a plasma protein called, factor h (fh), which has a key role in down-regulating the alternative pathway. factor h, along with another protein called factor i, inactivates c3b, the active form of c3. this process prevents the formation of c3 convertase and halts the progression of the complement cascade. c3-convertase also can be inhibited by decay accelerating factor (daf), which is bound to erythrocyte plasma membranes via a gpi anchor. role in disease complement deficiency main article: complement deficiency it is thought that the complement system might play a role in many diseases with an immune component, such as barraquer–simons syndrome, asthma, lupus erythematosus, glomerulonephritis, various forms of arthritis, autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome and ischemia-reperfusion injuries, and rejection of transplanted organs. the complement system is also becoming increasingly implicated in diseases of the central nervous system such as alzheimer's disease and other neurodegenerative conditions such as spinal cord injuries. deficiencies of the terminal pathway predispose to both autoimmune disease and infections (particularly neisseria meningitidis, due to the role that the membrane attack complex ("mac") plays in attacking gram-negative bacteria). infections with n. meningitidis and n. gonorrhoeae are the only conditions known to be associated with deficiencies in the mac components of complement. 40–50% of those with mac deficiencies experience recurrent infections with n. meningitidis. deficiencies in complement regulators mutations in the genes of complement regulators, especially factor h, have been associated with atypical hemolytic uremic syndrome, and c3 glomerulopathy. both of these disorders are currently thought to be due to complement overactivation either on the surface of host cells or in plasma, with the molecular location of genetic variation in complement proteins providing clues into the underlying disease processes. moreover, several single nucleotide polymorphisms and mutations in the complement factor h gene (the most common of which results in the protein change p.y402h) have been associated with the common eye disease age-related macular degeneration. polymorphisms of complement component 3, complement factor b, and complement factor i, as well as deletion of complement factor h-related 3 and complement factor h-related 1, also affect a person's risk of developing age-related macular degeneration. mutations in the c1 inhibitor gene can cause hereditary angioedema, a genetic condition resulting from reduced regulation of bradykinin by c1-inh. paroxysmal nocturnal hemoglobinuria is caused by complement breakdown of rbcs due to an inability to make gpi. thus the rbcs are not protected by gpi anchored proteins such as daf. diagnostic tools diagnostic tools to measure complement activity include the total complement activity test. the presence or absence of complement fixation upon a challenge can indicate whether particular antigens or antibodies are present in the blood. this is the principle of the complement fixation test. modulation of the body by complement with infection excessive complement activity contributes to severe covid-19 symptoms and disease. although complement is intended to protect the body systems, under stress there can be more damage than protection. research has suggested that the complement system is manipulated during hiv/aids, in a way that further damages the body. role in the brain research from over the last decade has shown that complement proteins of the classical complement pathway have an important role in synaptic pruning in the brain during early development.