complement system

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COMPLEMENT SYSTEM:

COMPLEMENT SYSTEM DR.GOGOI UNIVERSITY OF FIJI

Complement system:

Complement system The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime. However, it can be recruited and brought into action by the adaptive immune system. The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors (pro-proteins

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When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. The end-result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex. Over 25 proteins and protein fragments make up the complement system, including serum proteins, serosal proteins, and cell membrane receptors. They account for about 5% of the globulin fraction of blood serum.

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Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the lectin pathway

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The following are the basic functions of the complement Opsonization - enhancing phagocytosis of antigens Chemotaxis - attracting macrophages and neutrophils Cell Lysis - rupturing membranes of foreign cells Clumping of antigen-bearing agents

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Ch. 7 Ch. 7. The complement system Important effector in both innate and acquired immunity Over 30 circulating and membrane-bound proteins (synthesized in liver and other cells- immune and epithelial) Acts as a cascade (one event must occur before another takes place)

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Ch. 7 p. 169

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Ch. 7

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Ch. 7

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Ch. 7

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Ch. 7

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Ch. 7 Three pathways: classical, alternative, & lectin Final steps identical in all 3 pathways Classical - Initiated by formation of an Ag-Ab complex Alternative - Antibody-independent Part of innate immunity Initiated by foreign cell surfaces Lectin - Initiated by host proteins binding microbial surfaces

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Ch. 7 p. 170

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Ch. 7 Classical pathway Classical was discovered first (but actually evolved later) Initiated by: -formation of a soluble Ag-Ab complex -binding of antibody to a target such as a bacterial cell Only certain antibodies can initiate this (IgM, some classes of IgG)

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Ch. 7 p. 172

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Ch. 7

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Ch. 7

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Ch. 7

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Ch. 7

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Ch. 7 Alternative pathway Four components: C3, factor B, factor D, properdin Triggering substances may be pathogens or nonpathogens bacterial cell wall components, fungi, viruses, parasites immune complexes, RBCs, polymers

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Ch. 7 p. 173

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Ch. 7 p. 174

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Ch. 7 Lectin pathway Lectin is a protein that binds to carbohydrate MBL (mannose-binding lectin) binds to mannose on many bacterial cells MBL is produced by liver in acute-phase inflammatory reactions Once MBL binds to target cell, 2 serine proteases (MASP-1, MASP-2) bind Acts like C1

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Ch. 7 p. 176

Regulation of the complement system :

Regulation of the complement system 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 a higher concentration in the blood plasma than the complement proteins themselves. Some complement control proteins are present on the membranes of self-cells preventing them from being targeted by complement

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Ch. 7 Regulation of complement system Because it is nonspecific, several regulatory mechanisms are involved (otherwise there would be a lot of “collateral damage”) Many components are very labile Many regulatory proteins block activity through binding to target

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Ch. 7 p. 180

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Ch. 7 Amplifies humoral response Destroys invading bacteria and viruses (lysis by MAC) Inflammatory response Opsonization of antigen (enhances phagocytosis) Virus neutralization Clearance of immune complexes

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Ch. 7 Some bacteria can resist lysis Gram-positive bacteria Some microbes produce inactivating enzymes Nucleated cells are harder to lyse Not particularly effective against tumor cells (they can endocytose MAC and repair damage)

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Ch. 7 Inflammation many of the released fragments help develop an inflammatory response C3a, C4a, C5a- anaphylotoxins bind to receptors on mast cells and basophils; degranulation (smooth muscle contraction; capillary dilation; fluid influx) also play a role in blood cell chemotaxis

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Ch. 7 p. 184

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Ch. 7 Viral neutralization Some viruses activate alternative or lectin pathway Antibody-mediated (classical) pathway is more common Causes aggregation of viruses; can’t infect host cells; more vulnerable to phagocytes Enveloped viruses can be lysed

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Ch. 7 p. 186

Role in disease:

Role in disease complement system 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, 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 plays in attacking Gram-negative bacteria). Mutations in the complement regulators factor Hand membrane cofactor protein have been associated with atypical haemolytic uraemic syndrome.

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Ch. 7 Consequences of complement deficiency Early components of classical pathway (C1, C4, C2)- immune complex disease can’t generate C3b, which is needed for solubilization Recurrent Staph and Strep infections (can’t lyse bacteria but seem to control infections) Early components of alternative pathway- not as serious; tendency to infections by Neisseria

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Ch. 7 C3 deficiencies (can’t activate C5 and form MAC) Recurrent severe bacterial infections MAC deficiencies- recurrent Neisseria infections no immune complex disease Regulatory protein deficiencies edema RBC lysis

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Ch. 7 Summary The complement system comprises a group of serum proteins which, when activated, plays an important role in antigen clearance. The classical, alternative and lectin pathways have been described. Elaborate regulatory mechanisms are required to prevent damage to normal cells.

Complement Fixation:

40 Complement Fixation Figure 18.9.1

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