Porth's Essentials of Pathophysiology, 4e

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Innate and Adaptive Immunity

C h a p t e r 1 5

structures are generally known as pathogen-associated molecular patterns (PAMPs), and the receptors that rec- ognize them as pattern recognition receptors (PRRs). The recognized structures of PAMPs are essential to the functioning and infectivity of the microbe. The microbe cannot, therefore, evade innate immune rec- ognition through mutation or a lack of production of the molecules because they would not survive. Humans inherit a limited number of germline genes for PRRs that effectively recognize major groups of microbes. One such receptor is the mannose-binding lectin (MBL), which is present as a free protein in the blood plasma. Pathogen recognition and discrimination of self from nonself by the MBL is due to the particular orientation and spacing of particular sugar residues, which are found only on microbes and not on host cells. The phagocytic cells of the innate immune system are also equipped with several cell surface receptors that recognize pathogen surfaces directly. Among these is the macrophage-mannose receptor. This receptor binds certain sugars found on the surface of many bacteria and viruses, including HIV. A second set of phagocytic receptors, called the scavenger receptors, were originally defined as molecules that bind and mediate endocytosis of oxidized or acetylated low-density lipoproteins (LDLs) that do not interact with the conventional LDL receptor (see Chapter 18). Macrophage scavenger receptors bind a variety of microbes in addition to LDL particles. Not all receptors that recognize pathogen-specific molecules are phagocytic receptors. The binding of pathogens to some receptors on leukocytes initiates a series of signaling events that lead to the tissue changes associated with acute inflammation. Stimulation of other pattern receptors leads macrophages and dendritic cells to display co-stimulatory molecules that enable them to act as antigen-presenting cells to lymphocytes and initi- ate an adaptive immune response. Toll-Like Receptors The best-defined activation pathway for the pathogen sensors of innate immunity is a family of transmembrane receptors called Toll-like receptors (TLRs). Interestingly,

the first protein to be identified in this family was the Drosophila Toll protein, which was found in the fruit fly Drosophila, where it functions in embryonic develop- ment as well as in protecting the fly from lethal fungal infections. Eleven different TLRs have thus far been identified, each specific for different components of microbes (Table 15-2). Although most TLRs are found on the surface of the leukocytes, a few are intracellular, where they recognize viruses and intracellular patho- gens such a Mycobacterium . Because there are only 11 recognized TLR genes, the Toll-like receptors have limited specificity compared with the antigen recep- tors of the adaptive immune system. Despite this lim- ited diversity, they can recognize elements of most microorganisms. Ligand binding to the TLR at the cell surface leads to an intracellular cascade of events which ultimately regulates the production of several proteins that are important components of innate immunity. Alterations in the structure of TLRs or mutations in the signaling system associated with TLRs have been suggested to play a pathologic role in disorders such as atherosclero- sis, allergies, and certain autoimmune diseases. Although cells of the innate immune system can commu- nicate critical information about microbial agents and self–nonself recognition through cell-to-cell contact, soluble mediators are essential for many other aspects of the response. Development of innate immunity and regulation of the behavior of effector cells both depend on the secretion of soluble mediators such as opsonins, cytokines, and proteins of the complement system. Opsonins Various soluble molecules can tag microorganisms for more efficient recognition by phagocytes. The coating of particles, such as microbes, is called opsonization, Soluble Mediators of Innate Immunity

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TABLE 15-2 Types of Toll-Like Receptors (TLRs) andTheir Recognized Ligands TRLs Ligands

Type of Microorganisms

TRL1 TRL2

Lipopeptides Peptidoglycan

Mycobacteria

Gram-positive bacteria

Lipoprotein

Mycobacteria

Zymosan

Yeast and other fungi

TRL3 TRL4 TRL5 TRL6 TRL7 TRL8 TRL9

Double-stranded RNA Lipopolysaccharide

Viruses

Gram-negative bacteria

Flagellin

Flagellated bacteria

Lipopolypeptide

Mycobacteria Yeast and fungi

Zymosan

Single-stranded RNA (ssRNA) Single-stranded RNA (ssRNA) CpG unmethylated dinucleotides

Viruses Viruses

Bacterial DNA

TRLs 10,11

Unknown