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The Innate and Adaptive Immune Systems
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CHAPTER 44 THE INNATE AND ADAPTIVE IMMUNE SYSTEMS
44 THE INNATE AND ADAPTIVE IMMUNE SYSTEMS JÖRG J. GORONZY AND CORNELIA M. WEYAND
GENERAL PRINCIPLES OF THE IMMUNE SYSTEM
The immune system has evolved as a complex network of molecules, cells, and organs to defend against pathogenic microorganisms and noninfectious foreign substances. Beyond its role in host protection, it regulates tissue homeostasis and tissue repair. Cells of the immune system identify and remove injured, dead, and malignant cells. Immune system cells derive from hematopoietic stem cells in the bone marrow, circulate in the blood and lymph, form complex microstructures in specialized lymphoid organs, and infiltrate virtually every tissue. These cells express characteristic profiles of surface molecules, also referred to as cluster of differentiation (CD) molecules, with which they sense soluble or cell-bound ligands in their microenvironment. Molecular structure, ligands, and main functions of more than 300 molecules have been defined; a selected list is given in E-Table 44-1. The anatomic organization of immune system cells in lymphoid organs and their ability to circulate throughout the body and to migrate between blood and lymphoid tissues are crucial components of host defense. On activation, these cells transcribe and release cytokines, small soluble proteins that communicate between cells within the immune system or between immune system cells and cells in other tissues (Table 44-1).
Innate and Adaptive Immunity
Principally, host protection is accomplished by two types of immunity: innate and adaptive. The innate immune system is present in all vertebrates and is widely conserved among species. It provides the first line of defense and functions through immediate responses that use preformed proteins and preexisting cells. Innate immunity, broadly defined, includes physical barriers, such as epithelial layers, and chemical impediments, such as antimicrobial substances at these surfaces. Using a narrower definition, the innate immune system mediates nonspecific protection through a diverse set of cells, including monocytes, macrophages, dendritic cells, natural killer (NK) cells, eosinophils, basophils, neutrophils, and mast cells. A variety of chemical mediators, such as members of the complement system, acute phase reactants, and cytokines, contribute to inflammatory responses that develop to prevent tissue invasion by pathogens. The need for immediacy is irreconcilable with selectivity and adaptivity. Response patterns of the innate immune system are broad, and collateral tissue damage is often unavoidable. Despite the lack of specificity, innate immunity is highly effective; microbial invasion is frequently controlled, and pathogens are often eliminated. The pathogenicity of microorganisms is largely related to their ability to resist and overcome the first line of defense mounted by the innate immune system. If invading microorganisms succeed in escaping the host’s nonspecific defense mechanisms, a second line of defense, adaptive immunity, secures host survival. Adaptive immune responses depend on innate immunity for supplementation and augmentation and to provide crucial information about the nature of the attacker. The term adaptive relates to the ability of the system to adapt to the microbial challenge; it is also called acquired or specific immunity. The adaptive immune system has unique attributes, such as specificity, diversity, memory, specialization, tolerance, and homeostasis. Immune specificity relies on two major cell types: B lymphocytes and T lymphocytes. These cells possess receptors that specifically recognize antigenic determinants and that distinguish subtle differences. To contend with the gamut of possible antigens, the adaptive immune system requires an enormous spectrum of specific receptors. An extremely high degree of discriminatory specificity is achieved by clonal distribution of the recognition structures; each individual T cell and B cell expresses a unique receptor. The diversity of the adaptive immune system is not inherited; it is acquired somatically and is called the lymphocyte repertoire. The frequency of T or B cells in the naïve repertoire specific for a particular antigenic determinant is less than 1 in 105 and is therefore extremely low. On recognition of an antigen, the adaptive immune system reacts with clonal expansion of these infrequent
antigen-responsive cells to build up a line of defense. Proliferating antigenspecific cells acquire new properties, including effector functions and the ability to function as memory cells. Specificity and memory are prerequisites for heightened reactivity to recurrent or persistent infections and also provide the basis for vaccination. Another example of the adaptive power of the specific immune system lies in specialized responses to different classes of microbes (e.g., parasites vs. viral infections). Specialization is a consequence of differentiation during the evolution of the immune response; it results in selection of the most appropriate effector pathway for a particular microbial challenge. Molding the responding lymphocyte population to the antigenic profile of the invading pathogen inevitably involves the risk of generating cells that respond to self-antigens. To prevent injury to the host, the adaptive immune system discriminates between self and nonself. Nonreactivity to self is actively acquired and is maintained by several mechanisms, collectively called selftolerance. Distinguishing self and nonself is individualized for each host and requires the selection of an individual set of nonself-reactive receptors. Consequently, the outcome of self/nonself discrimination is not transferred from generation to generation and is devoid of evolutionary pressure. In contrast, innate immunity relies on genetically programmed recognition structures and receptors that have been evolutionarily selected to recognize pathogens but not self. Together with the capability of generating tremendous diversity and specificity, the adaptive immune system has a built-in ability to self-limit responses and to regain homeostasis. This mechanism is crucial in preventing excessive immune responses and in providing space for emerging lymphocytes that are required for a new specific immune response.
Leukocyte Migration and Homing
Mobility of the cellular constituents is fundamental to innate and adaptive immunity. To home to the site of tissue injury or to enter lymphoid organs, cells use a multistep process of adherence and activation. Initially, leukocytes roll on activated endothelial cells, activate chemokine receptors, increase adhesiveness, and eventually migrate through the endothelial layer across a chemokine gradient. The selectin family of proteins mediates the first steps of leukocyte migration. Selectins have a lectin domain and bind to carbohydrate ligands. L-selectin is present on virtually all leukocytes; P-selectin and E-selectin are expressed on activated endothelial cells, and P-selectin is also stored in platelets. Selectins capture floating leukocytes and initiate their attachment and rolling on activated endothelial cells. To transform attachment and rolling into firm adhesion, the concerted action of chemokines, chemokine receptors, and integrins is necessary. Integrins are heterodimers formed of many different α chains and β chains; different α/β combinations are expressed on different cell subsets. Only after activation can integrins interact with ligands on endothelial cells. Activation involves modification of the cytoplasmic domain of the β chain, which leads to a structural change of the extracellular domains. This process is termed inside-out signaling. The last step of homing is transendothelial migration. Here, the firmly attached leukocytes migrate through the endothelial cell monolayer and the basement membrane.
INNATE IMMUNE SYSTEM Principles of Innate Immune System Activation
Activation by Pattern Recognition Receptors
The strategy of the innate immune system is to focus on the recognition of a few highly conserved structures that are preserved in large groups of microorganisms shared by entire classes of pathogens and essential for their survival and pathogenicity. The system uses a few hundred receptor structures to identify microbial invaders. This set of receptors is insufficient to cover the entire spectrum of antigens expressed on infectious agents. Structures recognized by pattern recognition receptors (PRRs) are collectively referred to as pathogen-associated molecular patterns (PAMPs). Examples of PAMPs are bacterial lipopolysaccharides, peptidoglycans, mannans, bacterial DNA, doublestranded RNA, and glucans. PAMP-binding receptor families share structural characteristics, such as leucine-rich repeated domains, calcium-dependent lectin domains, and scavenger-receptor protein domains. They can be secreted to act as opsonins; the best-characterized receptor of this class is the mannose-binding lectin that binds to microbial carbohydrates and activates the lectin pathway of complement activation. Another functional class of PRRs is expressed on the
CHAPTER 44 THE INNATE AND ADAPTIVE IMMUNE SYSTEMS
44 THE INNATE AND ADAPTIVE IMMUNE SYSTEMS JÖRG J. GORONZY AND CORNELIA M. WEYAND
GENERAL PRINCIPLES OF THE IMMUNE SYSTEM
The immune system has evolved as a complex network of molecules, cells, and organs to defend against pathogenic microorganisms and noninfectious foreign substances. Beyond its role in host protection, it regulates tissue homeostasis and tissue repair. Cells of the immune system identify and remove injured, dead, and malignant cells. Immune system cells derive from hematopoietic stem cells in the bone marrow, circulate in the blood and lymph, form complex microstructures in specialized lymphoid organs, and infiltrate virtually every tissue. These cells express characteristic profiles of surface molecules, also referred to as cluster of differentiation (CD) molecules, with which they sense soluble or cell-bound ligands in their microenvironment. Molecular structure, ligands, and main functions of more than 300 molecules have been defined; a selected list is given in E-Table 44-1. The anatomic organization of immune system cells in lymphoid organs and their ability to circulate throughout the body and to migrate between blood and lymphoid tissues are crucial components of host defense. On activation, these cells transcribe and release cytokines, small soluble proteins that communicate between cells within the immune system or between immune system cells and cells in other tissues (Table 44-1).
Innate and Adaptive Immunity
Principally, host protection is accomplished by two types of immunity: innate and adaptive. The innate immune system is present in all vertebrates and is widely conserved among species. It provides the first line of defense and functions through immediate responses that use preformed proteins and preexisting cells. Innate immunity, broadly defined, includes physical barriers, such as epithelial layers, and chemical impediments, such as antimicrobial substances at these surfaces. Using a narrower definition, the innate immune system mediates nonspecific protection through a diverse set of cells, including monocytes, macrophages, dendritic cells, natural killer (NK) cells, eosinophils, basophils, neutrophils, and mast cells. A variety of chemical mediators, such as members of the complement system, acute phase reactants, and cytokines, contribute to inflammatory responses that develop to prevent tissue invasion by pathogens. The need for immediacy is irreconcilable with selectivity and adaptivity. Response patterns of the innate immune system are broad, and collateral tissue damage is often unavoidable. Despite the lack of specificity, innate immunity is highly effective; microbial invasion is frequently controlled, and pathogens are often eliminated. The pathogenicity of microorganisms is largely related to their ability to resist and overcome the first line of defense mounted by the innate immune system. If invading microorganisms succeed in escaping the host’s nonspecific defense mechanisms, a second line of defense, adaptive immunity, secures host survival. Adaptive immune responses depend on innate immunity for supplementation and augmentation and to provide crucial information about the nature of the attacker. The term adaptive relates to the ability of the system to adapt to the microbial challenge; it is also called acquired or specific immunity. The adaptive immune system has unique attributes, such as specificity, diversity, memory, specialization, tolerance, and homeostasis. Immune specificity relies on two major cell types: B lymphocytes and T lymphocytes. These cells possess receptors that specifically recognize antigenic determinants and that distinguish subtle differences. To contend with the gamut of possible antigens, the adaptive immune system requires an enormous spectrum of specific receptors. An extremely high degree of discriminatory specificity is achieved by clonal distribution of the recognition structures; each individual T cell and B cell expresses a unique receptor. The diversity of the adaptive immune system is not inherited; it is acquired somatically and is called the lymphocyte repertoire. The frequency of T or B cells in the naïve repertoire specific for a particular antigenic determinant is less than 1 in 105 and is therefore extremely low. On recognition of an antigen, the adaptive immune system reacts with clonal expansion of these infrequent
antigen-responsive cells to build up a line of defense. Proliferating antigenspecific cells acquire new properties, including effector functions and the ability to function as memory cells. Specificity and memory are prerequisites for heightened reactivity to recurrent or persistent infections and also provide the basis for vaccination. Another example of the adaptive power of the specific immune system lies in specialized responses to different classes of microbes (e.g., parasites vs. viral infections). Specialization is a consequence of differentiation during the evolution of the immune response; it results in selection of the most appropriate effector pathway for a particular microbial challenge. Molding the responding lymphocyte population to the antigenic profile of the invading pathogen inevitably involves the risk of generating cells that respond to self-antigens. To prevent injury to the host, the adaptive immune system discriminates between self and nonself. Nonreactivity to self is actively acquired and is maintained by several mechanisms, collectively called selftolerance. Distinguishing self and nonself is individualized for each host and requires the selection of an individual set of nonself-reactive receptors. Consequently, the outcome of self/nonself discrimination is not transferred from generation to generation and is devoid of evolutionary pressure. In contrast, innate immunity relies on genetically programmed recognition structures and receptors that have been evolutionarily selected to recognize pathogens but not self. Together with the capability of generating tremendous diversity and specificity, the adaptive immune system has a built-in ability to self-limit responses and to regain homeostasis. This mechanism is crucial in preventing excessive immune responses and in providing space for emerging lymphocytes that are required for a new specific immune response.
Leukocyte Migration and Homing
Mobility of the cellular constituents is fundamental to innate and adaptive immunity. To home to the site of tissue injury or to enter lymphoid organs, cells use a multistep process of adherence and activation. Initially, leukocytes roll on activated endothelial cells, activate chemokine receptors, increase adhesiveness, and eventually migrate through the endothelial layer across a chemokine gradient. The selectin family of proteins mediates the first steps of leukocyte migration. Selectins have a lectin domain and bind to carbohydrate ligands. L-selectin is present on virtually all leukocytes; P-selectin and E-selectin are expressed on activated endothelial cells, and P-selectin is also stored in platelets. Selectins capture floating leukocytes and initiate their attachment and rolling on activated endothelial cells. To transform attachment and rolling into firm adhesion, the concerted action of chemokines, chemokine receptors, and integrins is necessary. Integrins are heterodimers formed of many different α chains and β chains; different α/β combinations are expressed on different cell subsets. Only after activation can integrins interact with ligands on endothelial cells. Activation involves modification of the cytoplasmic domain of the β chain, which leads to a structural change of the extracellular domains. This process is termed inside-out signaling. The last step of homing is transendothelial migration. Here, the firmly attached leukocytes migrate through the endothelial cell monolayer and the basement membrane.
INNATE IMMUNE SYSTEM Principles of Innate Immune System Activation
Activation by Pattern Recognition Receptors
The strategy of the innate immune system is to focus on the recognition of a few highly conserved structures that are preserved in large groups of microorganisms shared by entire classes of pathogens and essential for their survival and pathogenicity. The system uses a few hundred receptor structures to identify microbial invaders. This set of receptors is insufficient to cover the entire spectrum of antigens expressed on infectious agents. Structures recognized by pattern recognition receptors (PRRs) are collectively referred to as pathogen-associated molecular patterns (PAMPs). Examples of PAMPs are bacterial lipopolysaccharides, peptidoglycans, mannans, bacterial DNA, doublestranded RNA, and glucans. PAMP-binding receptor families share structural characteristics, such as leucine-rich repeated domains, calcium-dependent lectin domains, and scavenger-receptor protein domains. They can be secreted to act as opsonins; the best-characterized receptor of this class is the mannose-binding lectin that binds to microbial carbohydrates and activates the lectin pathway of complement activation. Another functional class of PRRs is expressed on the