Porth's Pathophysiology, 9e

Chapter 13 Innate and Adaptive Immunity    287

TNF- α and lymphotoxins are cytokines that are structur- ally related and that have similar cytotoxic activities. 23 The two cytokines differ in that TNF- α can be secreted by a variety of immune cells, but the lymphotoxins are predominantly secreted by activated lymphocytes and NK cells. These cytokines regu- late development of the lymphoid tissues and the inflammatory process through induction of adhesion molecules and other cytokines/chemokines. 23 The IFNs are another family of cyto- kines that are critically involved in initiating and enhancing the cellular immune response to viral infection of host cells. In addition, they play a key role in amplifying the presentation of antigens to specific T cells. Type I interferon (IFN- α and IFN- β ) is secreted by virus-infected cells, while type II, immune or gamma interferon (IFN- γ ), is mainly secreted by T cells, NK cells, and macrophages. 23,24 When activated IFNs interact with specific cellular receptors, causing the expression of antiviral and immune modulatory genes. IFNs activate macrophages, induce B cells to switch Ig type, alter T-helper response, inhibit cell growth, promote apoptosis, and induce an antiviral state in uninfected cells. Finally, ILs help to regulate the immune response by increasing the expression of adhesion molecules on endothelial cells, stimulating migration of leukocytes into infected tissues, and by stimulating the production of antibod- ies by the cells of the adaptive immune response. Acute-Phase Proteins Two acute-phase proteins that are involved in the defense against infections are the mannose-binding ligand (MBL) and C-reactive protein (CRP). MBL and CRP are produced in the liver in response to activation of proinflammatory cytokines. MBL binds specifically to mannose residues, and CRP binds to both phospholipids and sugars that are found on the surface of microbes. These substances act as “costimulatory” opso- nins and enhance the binding of phagocytic cells to subopti- mally opsonized invading microorganisms. 25 They also act as activators of the alternative complement pathway. The Complement System The complement system is a powerful effector mechanism of both innate and adaptive immunity that allows the body to local- ize infection and destroy invading microorganisms. The com- plement system is composed of group of proteins found in the circulation and in various extracellular fluids. The proteins of the complement system normally circulate as inactive precur- sors. When activated a series of proteolytic and protein–protein interactions is initiated that ultimately culminates in opsoniza- tion of invading pathogens, migration of leukocytes to the site of invasion, initiation of a localized inflammatory reaction, and ultimate lysis of the pathogen. 25 The proteins of the complement system are mainly proteolytic enzymes and make up approxi- mately 10% to 15% of the plasma proteins. For a complement reaction to occur, the complement components must be activated in the proper sequence. Inhibitor proteins and the instability of the activated complement proteins at each step of the process prevent uncontrolled activation of the complement system.

There are three parallel but independent pathways that result in activation of the complement system during the innate immune response: the classical, the lectin, and the alternative pathways. The reactions of the complement systems can be divided into three phases: 1. Initiation or activation 2. Amplification of inflammation 3. Membrane attack response The three pathways differ in the proteins used in the early stage of activation, but all ultimately converge on the key comple- ment protein C3, which is essential for the amplification stage. Activated C3 then activates all subsequent complement mol- ecules (C5 through C9) resulting in the ultimate lysis of cells. The classic pathway is initiated by an antigen–antibody complex (either IgG or IgM mediated), which causes a specific reactive site on the antibody to be “uncovered” so that it can bind directly to the C1 molecule in the complement system. Once C1 is activated, a “cascade” of sequential reactions is set in motion. Initially a small amount of enzyme is produced, but with activa- tion of successive complement proteins successively increas- ing, concentrations of proteolytic enzymes are produced. This process is known as amplification . In the lectin or alternative complement pathway, inactive circulating complement proteins are activated when they are exposed to microbial surface poly- saccharides, MBL, CRP, and other soluble mediators that are integral to innate immunity. Like the classic pathway, the lectin and alternative pathways create a series of enzymatic reactions that cleave successive complement proteins in the pathway. During the activation phase of the complement cascade, cleavage of C3 produces C3a and C3b. C3b is a key opsonin that coats bacteria and allows them to be phagocytized after binding to type I complement receptor on leukocytes. The presence of C3a triggers the migration of neutrophils into the tissues to enhance the inflammatory response. Production of C3a, C4a, and C5a also leads to activation of mast cells and basophils causing them to release histamine, heparin, and other substances. These mediators of the inflammatory response increase tissue blood flow and increase localized capillary per- meability allowing increased leakage of fluids and protein into the area. In addition, they stimulate changes in the endothelial cells in order to stimulate chemotaxis of neutrophils and mac- rophages to the site of inflammation. During the late phase of the complement cascade, cleavage of C5 triggers the assembly of a membrane attack complex from the C5 to C9 proteins. The resulting complex creates a tubelike structure, which pen- etrates the microbial cell membrane allowing the passage of ions, small molecules, and water into the cell, causing the cell to ultimately burst. The multiple and complementary func- tions of the complement system make it an integral compo- nent of innate immunity and inflammation. It also serves as an essential bridge between the innate and humoral responses. Pathophysiological manifestations associated with deficiencies of complement range from increased susceptibility to infection to inflammatory tissue and autoimmune disorders that are the result of impaired activated complement clearance.