Ch 7 The complement system Important effector in

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) Ch. 7

Cascade: Many of the components are enzymes that become activated when cleaved into two peptides One peptide binds to the immune complex and becomes a functional part of it The other peptide diffuses away and can become an inflammatory mediator (binds to a receptor) Ch. 7

Four important functions: Lysis Opsonization Activation of inflammatory response Clearance of immune complexes Ch. 7

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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 Ch. 7

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p. 171 Ch. 7

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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 (Ig. M, some classes of Ig. G) Ch. 7

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p. 175 Ch. 7

Alternative pathway Four components: C 3, factor B, factor D, properdin Triggering substances may be pathogens or nonpathogens (see p. 173, Table 7 -1): bacterial cell wall components, fungi, viruses, parasites immune complexes, RBCs, polymers Ch. 7

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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 C 1 Ch. 7

p. 176 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 (p. 177) Ch. 7

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Biological effects of complement activation Complement fragments must bind to complement receptors expressed by various cells Ch. 7

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

Ch. 7 p. 182

Inflammation many of the released fragments help develop an inflammatory response C 3 a, C 4 a, C 5 a- 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 Ch. 7

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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 Ch. 7

p. 186 Ch. 7

Consequences of complement deficiency Early components of classical pathway (C 1, C 4, C 2)- immune complex disease can’t generate C 3 b, which is needed for solubilization Recurrent Staph and Strep infections (can’t lyse bacteria but seem to control infections) Early components of alternative pathwaynot as serious; tendency to infections by Neisseria Ch. 7

C 3 deficiencies (can’t activate C 5 and form MAC) Recurrent severe bacterial infections MAC deficiencies- recurrent Neisseria infections no immune complex disease Regulatory protein deficiencies edema RBC lysis 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. Ch. 7