Porth's Pathophysiology, 9e

Chapter 13 Innate and Adaptive Immunity    285

(approximately 1000) so the classes of pathogens recognized by them are very diverse. Therefore, pathogens of very dif- ferent biochemical composition are recognized by relatively similar mechanisms by host PRRs, and no single class of pathogens is sensed by only one type of PRR. Therefore, the host genetic code allows for the unique receptors involved in both innate and adaptive immunity to recognize fine details of molecular structure. The ability of the innate immune response to limit microbes early in the infectious process results from the bind- ing of pathogens to the PRRs on leukocytes, which in turn initiates the ­signaling events that lead to complement activa- tion, phagocytosis, and autophagy. Once initiated, white blood cells, ­neutrophils, and monocytes migrate from the blood to the ­tissues, along with other body fluids causing peripheral edema. Blood monocytes mature into macrophages as they traverse the tissues and join the macrophages and DCs already present in the tissues. PRRs present on these cells become activated, which amplifies the inflammatory response through enhanced secretion of all chemical mediators including cytokines and complement. Toll-Like Receptors The most studied PRRs associated with the innate immune response are the Toll-like receptors ( TLRs ). TLRs derive their name from the study of the Drosophila melanogaster toll pro- tein, which is responsible for the resistance of Drosophila to bacterial and fungal infections. 3,4 Structurally, TLRs are inte- gral glycoproteins that possess an extracellular or luminal ligand-binding site containing leucine-rich repeats and a cyto- plasmic signaling toll/interleukin-1 (IL-1) domain. 17 Binding of PAMP to a TLR induces a conformational change in the receptor, which subsequently triggers intracellular signal transduction and activation of cellular processes, such as acti- vation of transcription factors such as nuclear factor κβ (NF- κβ ). NF- κβ regulates the production of a number of proteins that are important components of innate immunity. TLRs can be found in most of the bone marrow cells including the mac- rophages, DCs, neutrophils, T cells, B cells, and non–bone marrow cells including epithelial and fibrocytes. Eleven dif- ferent TLRs have been identified in humans, and they each recognize distinct PAMPs derived from various microorgan- isms including bacteria, viruses, fungi, and protozoa. 18 Human TLRs can be divided into subfamilies that pri- marily recognize related PAMPs. TLR1, TLR2, TLR4, and TLR6 recognize lipids and lipopolysaccharides (LPS), whereas TLR3, TLR7, TLR8, and TLR9 recognize nucleic acids. 18 TLRs can also be classified according to their cel- lular distribution such that TLR1, TLR2, TLR4, TLR5, TLR6, TLR10, and TLR11 are expressed extracellularly and THR3, TLR7, TLR8, and TLR9 are mainly expressed in intracellular compartments. 19,20 These receptors are involved in responses to widely divergent types of molecules that are commonly expressed by microbial, but not mam- malian, cell types. For example, TLR4 is essential for phagocytic recognition and response to the LPS present in

NK cell

Activating receptor

Inhibitory receptor

Ligands for activating receptor

MHC-I self-recognition peptide

No cell killing

A

Normal cell

Inhibitory receptor not engaged

Virus inhibits MHC-I expression

Virus-infected cell

Cell killing

germline-encoded pattern recognition receptors ( PRRs ). Upon PAMP recognition, PRRs come in contact with the cell surface and/or send intracellular signals to the host that trigger proinflammatory and antimicrobial responses includ- ing the synthesis and release of cytokines, chemokines, and cell adhesion molecules. 3 The PAMPs recognized by the host PRRs are made up of a combination of sugars, lipid mole- cules, proteins, or patterns of modified nucleic acids and are essential to the functioning and infectivity of the pathogen. Because the PAMPs are essential for the functioning of the microorganism, mutation cannot help it avoid immune rec- ognition. The human complement of PRRs is very extensive B FIGURE 13.2  •  Natural killer (NK) cell receptors. ( A ) NK cells express activating receptors that respond to ligands from virus-infected or injured cells and inhibiting receptors that bind to the class I major histocompat- ibility complex (MHC-I) self-recognition molecules expressed by normal cells. Normal cells are not killed because inhibitory signals from normal MHC-I molecules override activating signals. ( B ) In virus-infected or ­tumor cells, increased expression of ligands for activating receptors and reduced expression or alteration of MHC molecules interrupts the inhibi- tory signals, allowing activation of NK cells and lysis of target cells.