Acute inflammation. Most chemokines stimulate leukocyte attachment to endothelium by acting on leukocytes to increase the affinity of integrins, and also serve as chemoattractants, thereby guiding leukocytes to sites of infection or tissue damage. Because they mediate aspects of the inflammatory reaction, they are sometimes called inflammatory chemokines. Their production is induced by microbes and other stimuli.
Maintenance of tissue architecture. Some chemokines are produced constitutively by stromal cells in tissues and are sometimes called homeostatic chemokines. These organize various cell types in different anatomic regions of the tissues, such as T and B lymphocytes in discrete areas of the spleen and lymph nodes (Chapter 5).
Although the role of chemokines in inflammation is well established, it has proved difficult to develop chemokine antagonists that suppress inflammation, perhaps because of the functional redundancy of these proteins.
The list of cytokines implicated in inflammation is huge and constantly growing. In addition to the ones described earlier, two that have received considerable interest are IL-6, made by macrophages and other cells, which is involved in local and systemic reactions, and IL-17, produced mainly by T lymphocytes, which promotes neutrophil recruitment. IL-6 receptor antagonists are used in the treatment of rheumatoid arthritis, and IL-17 antagonists are very effective in psoriasis and other inflammatory diseases. Type I interferons, whose normal function is to inhibit viral replication, contribute to some of the systemic manifestations of inflammation. Cytokines also play key roles in chronic inflammation; these are described later in the chapter.
The complement system is a collection of soluble proteins and their membrane receptors that function mainly in host defense against microbes and in pathologic inflammatory reactions. There are more than 20 complement proteins, some of which are numbered C1 through C9. They function in both innate and adaptive immunity for defense against microbial pathogens. In the process of complement activation, several cleavage products of complement proteins are elaborated that cause increased vascular permeability, chemotaxis, and opsonization. The activation and functions of complement are outlined in
Fig. 3.11
Complement proteins are present in inactive forms in the plasma, and many of them are activated to become proteolytic enzymes that degrade other complement proteins, thus forming an enzymatic cascade capable of tremendous amplification. The critical step in complement activation is the proteolysis of the third (and most
EFFECTOR FUNCTIONS C5a, C3a: Inflammation
Recruitment and Destruction of microbes activation of leukocytes by leukocytes
Fig. 3.11 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).
abundant) component, C3. Cleavage of C3 can occur by one of three pathways:
The classical pathway, which is triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen
The alternative pathway, which can be triggered by microbial surface molecules (e.g., endotoxin, or LPS), complex polysaccharides, and other substances, in the absence of antibody
The lectin pathway, in which plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1