The innate immune response plays a crucial role in the proin-flammatory response to infection and relies upon the ability of host defenses to differentiate self from nonself so that only invading organisms are targeted. The leukocytes involved in this response recognize certain evolutionarily retained patterns present on the surface of pathogens and in response bind to the membrane and destroy the invading organism through the process of phagocytosis (Fig. 13.3).
Invading pathogens contain conserved structures in their cell membranes termed pathogen-associated molecular patterns (PAMPs), which are recognized by the cells of the innate immune system because they possess a limited number of 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 including the synthesis and release of cytokines, chemokines, and cell adhesion molecules. The PAMPs recognized by the host PRRs are made up of a combination of sugars, lipid molecules, 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 recognition. The human complement of PRRs is very extensive (approximately 1000) so the classes of pathogens recognized by them are very diverse. Therefore, pathogens of very different 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 binding of pathogens to the PRRs on leukocytes, which in turn initiates the signaling events that lead to complement activation, 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.
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 protein, which is responsible for the resistance of Drosophila to bacterial and fungal infections. Structurally, TLRs are integral glycoproteins that possess an extracellular or luminal ligand-binding site containing leucine-rich repeats and a cytoplasmic signaling toll/interleukin-1 (IL-1) domain. 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 activation 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 macrophages, DCs, neutrophils, T cells, B cells, and non–bone marrow cells including epithelial and fibrocytes. Eleven different TLRs have been identified in humans, and they each recognize distinct PAMPs derived from various microorganisms including bacteria, viruses, fungi, and protozoa.
Human TLRs can be divided into subfamilies that primarily recognize related PAMPs. TLR1, TLR2, TLR4, and TLR6 recognize lipids and lipopolysaccharides (LPS), whereas TLR3, TLR7, TLR8, and TLR9 recognize nucleic acids. TLRs can also be classified according to their cellular 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. These receptors are involved in responses to widely divergent types of molecules that are commonly expressed by microbial, but not mammalian, cell types. For example, TLR4 is essential for phagocytic recognition and response to the LPS present in gram-negative bacteria. TLR2 binds to peptidoglycan, which is an essential component of the cell wall of gram-positive bacteria. Finally, TLR5 can recognize the protein flagellin found in flagellated bacteria. In addition to their role in the immune response, TLRs have been shown to have a pathologic role in disorders such as atherosclerosis, allergies, and certain autoimmune diseases.