and macrophages
1‐Antitrypsin, α(α) 1‐antichymotrypsin
Figure 3.11 illustrates the importance of adhesion molecules in this process. The expression of L‐selectin by leukocytes and P‐ and E‐selectin by activated endothelial cells is mostly responsible for the tethering and rolling of leukocytes on the luminal endothelial blood surface. Selectins interact with glycosylated ligands expressed by the interacting cells. Leukocyte activation and firm adhesion to the endothelium are then rapidly induced by the engagement of leukocyte chemotactic receptors by chemotactic factors immobilized on glycosaminoglycans or heparin sulfates present in the milieu. Chemotactic factors include PAMPs such as formylated peptides, complement proteins (e.g., C5a and C3a), lipids, and chemokines such as IL‐8.
Fever
Although fever is one of the most common manifestations of infection and inflammation, there is still limited information about the significance of fever in the course of infection in mammals. In addition to the effects of acute phase proteins on the hypothalamus during inflammatory responses, fever is caused by many bacterial products, most notably the endotoxins (lipopolysaccharide [LPS]) of Gram‐negative bacteria. Exposure of innate immune cells (monocytes and macrophages) to LPS causes the release of cytokines called endogenous pyrogens. Examples of cytokines with endogenous pyrogenic properties include IL‐1 and certain interferons (see Chapter 11). Cells in other tissues can also produce these cytokines. For example, the keratinocytes present in skin contain IL‐1. Interestingly, when the skin is overexposed to the ultraviolet rays of the sun (sunburn), keratinocytes are physically damaged, causing them to release their contents, including IL‐1. Within a few hours, IL‐1 induces the hypothalamus to raise body temperature (fever)—a phenomenon many have experienced after a summer day at the beach, with accompanying chills and malaise. Fortunately, the ultraviolet rays can be blocked by a variety of topical products to prevent skin damage. Many tissues also synthesize substances that are harmful to microorganisms. Examples include degradative enzymes, toxic free radicals, and, as noted above, acute phase proteins
Figure 3.11. Adhesion molecules involved in leukocyte tethering, rolling, and adhesion to endothelium leading to transendothelial migration from blood to tissue
SUMMARY
1 There are two forms of immunity: innate and adaptive.
2 Innate immunity is broad and immune responses are rapid (minutes to hours).
3 Unlike adaptive immunity, innate immunity does not exhibit memory to antigenic exposure.
4 Many elements participate in innate immunity, including various physical barriers (e.g., skin), chemical barriers (e.g., low pH in stomach), cellular components (e.g., phagocytes, neutrophils, NKT cells), germline‐encoded pattern recognition receptors (e.g., TLRs, NLRs), and complement.
5 Alterations in expression of chemokine receptors and adhesion molecules facilitate the recruitment of immune cells to sites of injury.
6 Macrophages and neutrophils of the innate immune system facilitate destruction of invading organisms by upregulating phagolysosome activity and cytokine secretion.
7 When innate immune defense mechanisms fail to completely eliminate invading pathogens, defense mechanisms mediated by adaptive immune cells (B and T lymphocytes) are called into play and this process is facilitated by innate immune cells which play major roles in antigen presentation and cytokine activation of these cells.
8 Complement refers to a set of >50 serum proteins that cooperate with both innate and adaptive immune systems to eliminate pathogens. Its major roles include opsonization of microbes, recruitment of phagocytes to sites of infection, and, in some cases, direct killing of microbes as a result of the terminal stages of complement activation that can form the lysis‐promoting membrane attack complex.
9 The three major pathways of complement activation are: (a) the classic pathway initiated when C1q binds to antigen–antibody complexes; (b) the lectin pathway in which complement’s mannose‐binding lectin binds to conserved carbohydrates on pathogens; and (c) the alternate pathway involves direct binding of C3 to certain microbial surfaces such as LPS. C3 also undergoes constitutive spontaneous hydrolysis in solution at a low level and binds to host cell surfaces. The presence of inhibitory regulatory molecules in mammalian cells prevents damage to such cells. Because microbes lack these regulatory proteins, the binding of C3 to their surface initiates the cascade of complement activation that results in lysis of the microbe.
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14 Stekel
