Page 64 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

50 C H A P T E R 2 Inflammation and Repair coat (opsonize) particles, such as microbes, for phagocyto-
sis and destruction, and contribute to the inflammatory
S U M M A RY response by increasing vascular permeability and leuko-
Major Cell-Derived Mediators of Inflammation cyte chemotaxis. Complement activation ultimately gener-
ates a porelike membrane attack complex (MAC) that
• Vasoactive amines—histamine, serotonin: Their main punches holes in the membranes of invading microbes.
effects are vasodilation and increased vascular Here we summarize the role of the complement system in
permeability. inflammation.

• Arachidonic acid metabolites—prostaglandins and leuko­ • Complement components, numbered C1 to C9, are
trienes: Several forms exist and are involved in vascular present in plasma in inactive forms, and many of them
reactions, leukocyte chemotaxis, and other reactions of are activated by proteolysis to acquire their own proteo-
inflammation; they are antagonized by lipoxins. lytic activity, thus setting up an enzymatic cascade.

• Cytokines: These proteins, produced by many cell types, • The critical step in the generation of biologically active
usually act at short range; they mediate multiple effects, complement products is the activation of the third com-
mainly in leukocyte recruitment and migration; principal ponent, C3 (Fig. 2–18). C3 cleavage occurs by three path-
ones in acute inflammation are TNF, IL-1, IL-6, and ways: (1) the classical pathway, triggered by fixation of
chemokines. the first complement component C1 to antigen-antibody
complexes; (2) the alternative pathway, triggered by bac­
• ROS: Roles include microbial killing and tissue injury. terial polysaccharides (e.g., endotoxin) and other micro-
• NO: Effects are vasodilation and microbial killing. bial cell wall components, and involving a distinct set of
• Lysosomal enzymes: Roles include microbial killing and plasma proteins including properdin and factors B and
D; and (3) the lectin pathway, in which a plasma lectin
tissue injury. binds to mannose residues on microbes and activates an
early component of the classical pathway (but in the
Plasma Protein–Derived Mediators absence of antibodies).

Circulating proteins of three interrelated systems—the • All three pathways lead to the formation of a C3 conver-
complement, kinin, and coagulation systems—are involved tase that cleaves C3 to C3a and C3b. C3b deposits on the
in several aspects of the inflammatory reaction. cell or microbial surface where complement was acti-
vated and then binds to the C3 convertase complex to
Complement form C5 convertase; this complex cleaves C5 to generate
The complement system consists of plasma proteins that play C5a and C5b and initiate the final stages of assembly of
an important role in host defense (immunity) and inflam- C6 to C9.
mation. Upon activation, different complement proteins

EFFECTOR FUNCTIONS
C5a, C3a: Inflammation

Alternative Microbe Recruitment and Destruction of microbes
pathway activation of leukocytes by leukocytes
C3b C3a
Classical C3b C3b: Phagocytosis
pathway

Antibody C3b is deposited Recognition of bound C3b Phagocytosis
on microbe by phagocyte C3b receptor of microbe

Lectin Mannose Formation of MAC: Lysis of
pathway binding lectin membrane attack microbe
complex (MAC)

Figure 2–18 The activation and functions of the complement system. Activation of complement by different pathways leads to cleavage of C3.
The functions of the complement system are mediated by breakdown products of C3 and other complement proteins, and by the membrane attack
complex (MAC).