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Immunological response to infection: inflammatory and adaptive immune responses
PHYSIOLOGY
Immunological response to infection: inflammatory and adaptive immune responses
Learning Objectives After reading this article you should be able to describe: C the roles played by tissue macrophages C the components of the inflammatory response and its effects upon other tissues and organs C the components of the immune response C Delayed hypersensitivity
Peter J Wood
Abstract The immediate response to infection involves the innate immune system, which consists of many cell types and factors. The cells of the innate immune system include the different types of white-blood-cells and tissue residing cells such as macrophages and mast cells. This immediate response to infection involves an inflammatory response which locally causes vasodilation and increased vascular permeability thereby promoting the recruitment of cells and soluble factors from the bloodstream. Systemic inflammatory responses involve the brain, liver and bone-marrow. If the infection is not resolved the second arm of the immune system, the specific immune system generates new effector cells and mediators to deal with the infection. CD4 T cells are activated by antigens presented by dendritic cells and differentiate into helper T cells. Helper T cells are involved in the three major types of adaptive response: they help B cells to become antibody producing plasma cells; they help CD8 T cells differentiate into cytotoxic T cells that can kill cells infected with virus; they can activate macrophages to kill intracellular pathogens in a delayed-type hypersensitivity response.
Tissue damage and damage to the endothelium, which often accompany infection, result in activation of the clotting, kinin, fibrinolytic and complement systems. Activation of these systems leads to the generation of factors with many biological functions (Figure 1) including vasodilatation, increased vascular permeability and activation of mast cells. Activated mast cells degranulate, releasing the contents of their granules into the surrounding tissue. The granules contain histamine, heparin and degradative enzymes. Histamine is a powerful mediator of vasodilatation and increased vascular permeability. The net result is increased blood flow to the area and the recruitment of blood proteins and cells to the site. Cytokines released in the area increase the expression of adhesion molecules on the
Systems activated during inflammatory responses
Keywords Immune response; infection; mast cells; tissue macrophages
When a microbe enters the body, it or its products encounter tissue macrophages. If the macrophage recognizes the pathogen it is activated to release a range of factors. Nitric oxide causes vasodilatation and has antimicrobial activity. Oxygen radicals have antimicrobial activity. Prostaglandins and leukotrienes are important inflammatory mediators that cause vasodilatation and increased vascular permeability, and are chemotactic for (attract) neutrophils and eosinophils. Platelet-activating factor causes platelet aggregation and is chemotactic for neutrophils and eosinophils. Cytokines are hormone-like molecules involved in immune responses. They are small proteins and act in an autocrine and paracrine manner but seldom in an endocrine fashion. Three of the most important cytokines secreted by macrophages in an inflammatory response are interleukin1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factora (TNF-a).
System
Component
Function of component or cleavage product
Clotting
Hageman factor
Activates clotting, fibrinolytic and kinin systems Forms clot Increase vascular permeability, neutrophil chemotaxis Vasodilatation, smooth muscle contraction, pain Breaks down clots, activates complement system, activates Hageman factor Binds to antibody (C1q). Serine proteases (C1r, C1s) Inflammatory mediator (C4a), binds C2 Serine protease (C2a) Activates mast cells (C3a) Opsonin (C3b) Activates mast cells, chemotactic for neutrophils, monocytes, eosinophils and basophils Formation of pores in microbial cell walls causing cell lysis
Fibrin Fibrinopeptides Kinin
Bradykinin
Fibrinolytic
Plasmin
Complement C1 C4 C2 C3 C5a
C5–C9 Peter J Wood BSc (Hons) PhD is Senior Lecturer in Immunology in the Faculty of Life Sciences, University of Manchester, UK. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:6
Figure 1
269
Ó 2012 Elsevier Ltd. All rights reserved.
PHYSIOLOGY
mannose-binding lectin can bind mannose-containing molecules on the surface of microbes and activate complement.
endothelium, and chemokines (chemotactic cytokines) attract neutrophils and monocytes to the site. The neutrophils and monocyte/macrophages attempt to phagocytose and kill the infectious microbes and monocyte/macrophages also remove dead cells and damaged tissue.
Generation of the specific immune response The local inflammatory and acute-phase responses may be enough to resolve an infection. If not, the next response of the immune system is to generate a specific immune response, which can be divided into two stages (Figure 2): activation of CD4 T cells so that they divide and differentiate into helper T (Th) cells generation of effector cells and molecules that mediate the removal or neutralization of the pathogen (the generation of these cells is controlled by Th cells produced in the first stage of the response).
Acute-phase response If the inflammatory response is large enough, cytokines produced by macrophages appear in the bloodstream in sufficient concentrations to affect other tissues and organs. Brain e IL-1 acts on the hypothalamus to stimulate prostaglandin secretion which causes fever, somnolence and anorexia. Bone marrow e IL-6 and TNF-a stimulate stromal cells and macrophages in the bone marrow to release factors that stimulate increased production of leukocytes. Liver e IL-6 stimulates hepatocytes to produce increased amounts of acute-phase proteins, which are secreted into the blood and travel to sites of inflammation. Plasma levels of some of these proteins increase 100e1000-fold: serum amyloid A inhibits fever and platelet activation and provides a negative feedback loop. C-reactive protein binds to phosphoryl choline present on bacteria and some fungi and can act as an opsonin in a similar fashion to antibody (see below). Plasma levels of other factors increase only two- to fivefold: fibrinogen is involved in clotting and some of its breakdown products (the fibrinopeptides) are chemotactic for (attract) phagocytes (Figure 1) complement protein C3 has a number of biological activities, including activation of mast cells and promoting phagocytosis (Figure 1)
Generation of Th cells Specific immune responses occur in specialized lymphoid tissue. Responses against tissue pathogens generally occur in lymph nodes and responses against blood-borne organisms in the spleen. A crucial cell in the initiation of specific immune responses is the dendritic cell (DC). DCs are located throughout lymphoid and non-lymphoid tissue and bear extensive dendritic processes. Some tissue DCs have specialized features such as Langerhans cells in the skin, which possess Birbeck granules. Tissue DCs bear receptors for pathogen-associated molecular patterns (PAMPs) and have strong phagocytic activity. They are able to take up microbial products and are stimulated by them to migrate; tissue DCs enter the local lymphatic vessels and travel to the lymph node draining the site of infection. If there is vascular damage, DCs may enter the bloodstream and travel to the spleen.
The specific immune response Generation of CD4 Th Activation of CD4 T cells
Proliferation of CD4 T cells
Generation of effector cells CD4 Th
B cell stimulation Memory B cell
Plasma cell CD4 T cell
Macrophage activation (delayed hypersensitivity response)
Macrophag e
Activated macrophage Cytotoxic T cell (Tc) response
Dendritic cell
Tc Death signals Target cell CD8 T cell
Target cell killed
Figure 2
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Ó 2012 Elsevier Ltd. All rights reserved.
PHYSIOLOGY
The lymph nodes and spleen provide a filtration system whereby lymphocytes and antigen percolate through the tissue. Antigen can be picked up by macrophages or DCs in the lymphoid tissue and the lymphocytes filtering through can encounter antigenbearing DCs or macrophages. If a CD4 T-cell encounters a DC bearing antigen that its TcR can recognize, the CD4 T cell stays bound to the DC and is stimulated to divide and differentiate into a Th cell. Th cells coordinate the generation of other effector cells.
region of the H-chain, but it is important to appreciate that the V region, and hence antigen specificity, of the B cell does not change during class switch. Somatic mutation within the Ig genes is a mechanism that results in the production of antibody with much higher affinity (stronger binding) for the antigen. Highaffinity antibody is more efficient at carrying out the biological activities of antibody listed below. The final step in the B-cell response to antigen is differentiation into plasma cells or memory B cells (Figure 2). Plasma cells secrete large amounts of antibody. Memory B cells, because they have already undergone class switch and somatic mutation, provide increased numbers of high affinity B cells. They are long lived and ensure that if the same pathogen is encountered again there is a faster, bigger and better antibody response. Antibody is able to provide protection in a number of ways (Figure 3). Opsonization e phagocytes have receptors for the Fc part of the antibody molecule. Antibody bound to a microbe can be bound to the phagocyte, promoting uptake and phagocytosis. Neutralization e by binding to toxins, viruses or bacteria, antibody can prevent them binding to cellular receptors, thereby preventing entry into cells. Activation of complement e the complement system is a cascade of proteins that have a number of biological functions (Figure 1). Antibody binding to antigen undergoes a conformational change that enables the Fc part of the antibody to bind the first component of complement, C1, leading to activation of later components. Complement can also be activated in an antibody-independent fashion by the acute-phase protein, mannose-binding lectin, and by certain microbial products (e.g. zymosan in yeast cell walls). Antibody-dependent cell-mediated cytotoxicity (ADCC) e macrophages and natural killer (NK) cells (a type of lymphocyte) have receptors for the Fc part of the antibody. Antibody bound to an organism can be bound by the macrophage or by the
Effector responses Effector responses are the mechanisms that deal with the infectious organism, whether to kill it, neutralize it or cause its expulsion from the body. The cells and molecules that mediate effector responses are called effector cells and effector molecules. There are three types of specific effector response: antibody, cytotoxic CD8 T cells and delayed hypersensitivity. Antibody response: B cells that encounter antigen for which their surface Ig is specific are guided by chemokines to the region of the lymph nodes or spleen where CD4 T celleDC interactions take place. This brings into proximity the B cells and Th cells. B cells express class II major histocompatibility complex (MHC)/ antigen on their surface and if the Th cell is specific for the class II MHC/antigen it will be stimulated to produce cytokines, which will cause proliferation and differentiation of the B cell. Interaction of CD40 on the B-cell surface with CD154 on the Th-cell surface is also required for all but IgM production. The proliferating B cells and some of the Th cells form a structure called a germinal centre in the lymph node or spleen. In germinal centres, B cells divide rapidly and undergo class switch and somatic mutation in their Ig genes. Class switch means that instead of expressing IgM and IgD on their cell surface, B cells express IgG, IgA or IgE. This is due to a change in the constant
Antibody effector mechanisms Opsonization
Neutralization
Complement activation
Antibody-dependent cell-mediated cytotoxicity (ADCC)
Killer cell
Phagocyte Bacterium
Virus
Fc receptor
C5–9 Lysis of cell C3 Opsonin increases efficiency of phagocytosis
Target cell
Toxin
Death Figure 3
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:6
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Ó 2012 Elsevier Ltd. All rights reserved.
PHYSIOLOGY
NK cell, which triggers the cell to kill the organism in an extracellular manner. Macrophages and NK cells can kill infected host cells and tumour cells by ADCC. There is evidence that eosinophils can kill helminth worms in vitro in the same way. Generation of CD8 cytotoxic T cells: Th cells also help in the generation of CD8 cytotoxic T cells (Tc), which are capable of killing other cells expressing antigen on class I MHC (Figure 2). In the lymph node or spleen, DCs expressing antigen on their class II MHC to CD4 T cells can also express antigen derived from the same pathogen on their class I MHC. If a CD8 T cell, percolating through the lymph node or spleen, has a TcR specific for the antigen plus class I MHC it will bind to it and receive a signal for activation. The cytokine, IL-2, secreted by the CD4 T cell stimulates the CD8 T cell to divide and differentiate into a Tc. The Tcs migrate through the body, and if they encounter any cell type expressing the same antigen on its class I MHC they kill the cell.
generated in the lymph node draining the site of infection reenter the bloodstream and travel to the site of infection where they leave the bloodstream and enter the tissue. Infected macrophages, present at the site of infection, can present antigen on class II MHC on their cell surface and this stimulates the Th cells to release cytokines. Among these cytokines, TNF-a increases the expression of adhesion molecules on the local endothelium, thereby aiding the recruitment of monocytes from the blood. The monocytes and tissue macrophages are activated by other cytokines, particularly interferon-g and TNF-a, to differentiate into activated macrophages, which are better able to kill the pathogens (Figure 2). However, extensive activation of macrophages can also lead to tissue damage and hence the original description of the response as a hypersensitivity reaction. Much of the damage caused in chronic infections (e.g. tuberculosis, leprosy) is due to DTH reactions. A
Delayed hypersensitivity (DTH) responses: initially considered a pathological response, DTH is now recognized as an important protective response against some intracellular pathogens, especially those that can live in macrophages. Usually DTH responses are generated in response to tissue-dwelling pathogens. Th cells
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:6
FURTHER READING Murphy KM, Travers P, Walport M. Janeway’s immunobiology. 7th edn. Oxford: Garland Science, 2007. Roitt I, Brostoff J, Male D. Immunology. 5th edn. London: Mosby, 2006.
272
Ó 2012 Elsevier Ltd. All rights reserved.
Immunological response to infection: inflammatory and adaptive immune responses
Learning Objectives After reading this article you should be able to describe: C the roles played by tissue macrophages C the components of the inflammatory response and its effects upon other tissues and organs C the components of the immune response C Delayed hypersensitivity
Peter J Wood
Abstract The immediate response to infection involves the innate immune system, which consists of many cell types and factors. The cells of the innate immune system include the different types of white-blood-cells and tissue residing cells such as macrophages and mast cells. This immediate response to infection involves an inflammatory response which locally causes vasodilation and increased vascular permeability thereby promoting the recruitment of cells and soluble factors from the bloodstream. Systemic inflammatory responses involve the brain, liver and bone-marrow. If the infection is not resolved the second arm of the immune system, the specific immune system generates new effector cells and mediators to deal with the infection. CD4 T cells are activated by antigens presented by dendritic cells and differentiate into helper T cells. Helper T cells are involved in the three major types of adaptive response: they help B cells to become antibody producing plasma cells; they help CD8 T cells differentiate into cytotoxic T cells that can kill cells infected with virus; they can activate macrophages to kill intracellular pathogens in a delayed-type hypersensitivity response.
Tissue damage and damage to the endothelium, which often accompany infection, result in activation of the clotting, kinin, fibrinolytic and complement systems. Activation of these systems leads to the generation of factors with many biological functions (Figure 1) including vasodilatation, increased vascular permeability and activation of mast cells. Activated mast cells degranulate, releasing the contents of their granules into the surrounding tissue. The granules contain histamine, heparin and degradative enzymes. Histamine is a powerful mediator of vasodilatation and increased vascular permeability. The net result is increased blood flow to the area and the recruitment of blood proteins and cells to the site. Cytokines released in the area increase the expression of adhesion molecules on the
Systems activated during inflammatory responses
Keywords Immune response; infection; mast cells; tissue macrophages
When a microbe enters the body, it or its products encounter tissue macrophages. If the macrophage recognizes the pathogen it is activated to release a range of factors. Nitric oxide causes vasodilatation and has antimicrobial activity. Oxygen radicals have antimicrobial activity. Prostaglandins and leukotrienes are important inflammatory mediators that cause vasodilatation and increased vascular permeability, and are chemotactic for (attract) neutrophils and eosinophils. Platelet-activating factor causes platelet aggregation and is chemotactic for neutrophils and eosinophils. Cytokines are hormone-like molecules involved in immune responses. They are small proteins and act in an autocrine and paracrine manner but seldom in an endocrine fashion. Three of the most important cytokines secreted by macrophages in an inflammatory response are interleukin1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factora (TNF-a).
System
Component
Function of component or cleavage product
Clotting
Hageman factor
Activates clotting, fibrinolytic and kinin systems Forms clot Increase vascular permeability, neutrophil chemotaxis Vasodilatation, smooth muscle contraction, pain Breaks down clots, activates complement system, activates Hageman factor Binds to antibody (C1q). Serine proteases (C1r, C1s) Inflammatory mediator (C4a), binds C2 Serine protease (C2a) Activates mast cells (C3a) Opsonin (C3b) Activates mast cells, chemotactic for neutrophils, monocytes, eosinophils and basophils Formation of pores in microbial cell walls causing cell lysis
Fibrin Fibrinopeptides Kinin
Bradykinin
Fibrinolytic
Plasmin
Complement C1 C4 C2 C3 C5a
C5–C9 Peter J Wood BSc (Hons) PhD is Senior Lecturer in Immunology in the Faculty of Life Sciences, University of Manchester, UK. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:6
Figure 1
269
Ó 2012 Elsevier Ltd. All rights reserved.
PHYSIOLOGY
mannose-binding lectin can bind mannose-containing molecules on the surface of microbes and activate complement.
endothelium, and chemokines (chemotactic cytokines) attract neutrophils and monocytes to the site. The neutrophils and monocyte/macrophages attempt to phagocytose and kill the infectious microbes and monocyte/macrophages also remove dead cells and damaged tissue.
Generation of the specific immune response The local inflammatory and acute-phase responses may be enough to resolve an infection. If not, the next response of the immune system is to generate a specific immune response, which can be divided into two stages (Figure 2): activation of CD4 T cells so that they divide and differentiate into helper T (Th) cells generation of effector cells and molecules that mediate the removal or neutralization of the pathogen (the generation of these cells is controlled by Th cells produced in the first stage of the response).
Acute-phase response If the inflammatory response is large enough, cytokines produced by macrophages appear in the bloodstream in sufficient concentrations to affect other tissues and organs. Brain e IL-1 acts on the hypothalamus to stimulate prostaglandin secretion which causes fever, somnolence and anorexia. Bone marrow e IL-6 and TNF-a stimulate stromal cells and macrophages in the bone marrow to release factors that stimulate increased production of leukocytes. Liver e IL-6 stimulates hepatocytes to produce increased amounts of acute-phase proteins, which are secreted into the blood and travel to sites of inflammation. Plasma levels of some of these proteins increase 100e1000-fold: serum amyloid A inhibits fever and platelet activation and provides a negative feedback loop. C-reactive protein binds to phosphoryl choline present on bacteria and some fungi and can act as an opsonin in a similar fashion to antibody (see below). Plasma levels of other factors increase only two- to fivefold: fibrinogen is involved in clotting and some of its breakdown products (the fibrinopeptides) are chemotactic for (attract) phagocytes (Figure 1) complement protein C3 has a number of biological activities, including activation of mast cells and promoting phagocytosis (Figure 1)
Generation of Th cells Specific immune responses occur in specialized lymphoid tissue. Responses against tissue pathogens generally occur in lymph nodes and responses against blood-borne organisms in the spleen. A crucial cell in the initiation of specific immune responses is the dendritic cell (DC). DCs are located throughout lymphoid and non-lymphoid tissue and bear extensive dendritic processes. Some tissue DCs have specialized features such as Langerhans cells in the skin, which possess Birbeck granules. Tissue DCs bear receptors for pathogen-associated molecular patterns (PAMPs) and have strong phagocytic activity. They are able to take up microbial products and are stimulated by them to migrate; tissue DCs enter the local lymphatic vessels and travel to the lymph node draining the site of infection. If there is vascular damage, DCs may enter the bloodstream and travel to the spleen.
The specific immune response Generation of CD4 Th Activation of CD4 T cells
Proliferation of CD4 T cells
Generation of effector cells CD4 Th
B cell stimulation Memory B cell
Plasma cell CD4 T cell
Macrophage activation (delayed hypersensitivity response)
Macrophag e
Activated macrophage Cytotoxic T cell (Tc) response
Dendritic cell
Tc Death signals Target cell CD8 T cell
Target cell killed
Figure 2
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Ó 2012 Elsevier Ltd. All rights reserved.
PHYSIOLOGY
The lymph nodes and spleen provide a filtration system whereby lymphocytes and antigen percolate through the tissue. Antigen can be picked up by macrophages or DCs in the lymphoid tissue and the lymphocytes filtering through can encounter antigenbearing DCs or macrophages. If a CD4 T-cell encounters a DC bearing antigen that its TcR can recognize, the CD4 T cell stays bound to the DC and is stimulated to divide and differentiate into a Th cell. Th cells coordinate the generation of other effector cells.
region of the H-chain, but it is important to appreciate that the V region, and hence antigen specificity, of the B cell does not change during class switch. Somatic mutation within the Ig genes is a mechanism that results in the production of antibody with much higher affinity (stronger binding) for the antigen. Highaffinity antibody is more efficient at carrying out the biological activities of antibody listed below. The final step in the B-cell response to antigen is differentiation into plasma cells or memory B cells (Figure 2). Plasma cells secrete large amounts of antibody. Memory B cells, because they have already undergone class switch and somatic mutation, provide increased numbers of high affinity B cells. They are long lived and ensure that if the same pathogen is encountered again there is a faster, bigger and better antibody response. Antibody is able to provide protection in a number of ways (Figure 3). Opsonization e phagocytes have receptors for the Fc part of the antibody molecule. Antibody bound to a microbe can be bound to the phagocyte, promoting uptake and phagocytosis. Neutralization e by binding to toxins, viruses or bacteria, antibody can prevent them binding to cellular receptors, thereby preventing entry into cells. Activation of complement e the complement system is a cascade of proteins that have a number of biological functions (Figure 1). Antibody binding to antigen undergoes a conformational change that enables the Fc part of the antibody to bind the first component of complement, C1, leading to activation of later components. Complement can also be activated in an antibody-independent fashion by the acute-phase protein, mannose-binding lectin, and by certain microbial products (e.g. zymosan in yeast cell walls). Antibody-dependent cell-mediated cytotoxicity (ADCC) e macrophages and natural killer (NK) cells (a type of lymphocyte) have receptors for the Fc part of the antibody. Antibody bound to an organism can be bound by the macrophage or by the
Effector responses Effector responses are the mechanisms that deal with the infectious organism, whether to kill it, neutralize it or cause its expulsion from the body. The cells and molecules that mediate effector responses are called effector cells and effector molecules. There are three types of specific effector response: antibody, cytotoxic CD8 T cells and delayed hypersensitivity. Antibody response: B cells that encounter antigen for which their surface Ig is specific are guided by chemokines to the region of the lymph nodes or spleen where CD4 T celleDC interactions take place. This brings into proximity the B cells and Th cells. B cells express class II major histocompatibility complex (MHC)/ antigen on their surface and if the Th cell is specific for the class II MHC/antigen it will be stimulated to produce cytokines, which will cause proliferation and differentiation of the B cell. Interaction of CD40 on the B-cell surface with CD154 on the Th-cell surface is also required for all but IgM production. The proliferating B cells and some of the Th cells form a structure called a germinal centre in the lymph node or spleen. In germinal centres, B cells divide rapidly and undergo class switch and somatic mutation in their Ig genes. Class switch means that instead of expressing IgM and IgD on their cell surface, B cells express IgG, IgA or IgE. This is due to a change in the constant
Antibody effector mechanisms Opsonization
Neutralization
Complement activation
Antibody-dependent cell-mediated cytotoxicity (ADCC)
Killer cell
Phagocyte Bacterium
Virus
Fc receptor
C5–9 Lysis of cell C3 Opsonin increases efficiency of phagocytosis
Target cell
Toxin
Death Figure 3
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:6
271
Ó 2012 Elsevier Ltd. All rights reserved.
PHYSIOLOGY
NK cell, which triggers the cell to kill the organism in an extracellular manner. Macrophages and NK cells can kill infected host cells and tumour cells by ADCC. There is evidence that eosinophils can kill helminth worms in vitro in the same way. Generation of CD8 cytotoxic T cells: Th cells also help in the generation of CD8 cytotoxic T cells (Tc), which are capable of killing other cells expressing antigen on class I MHC (Figure 2). In the lymph node or spleen, DCs expressing antigen on their class II MHC to CD4 T cells can also express antigen derived from the same pathogen on their class I MHC. If a CD8 T cell, percolating through the lymph node or spleen, has a TcR specific for the antigen plus class I MHC it will bind to it and receive a signal for activation. The cytokine, IL-2, secreted by the CD4 T cell stimulates the CD8 T cell to divide and differentiate into a Tc. The Tcs migrate through the body, and if they encounter any cell type expressing the same antigen on its class I MHC they kill the cell.
generated in the lymph node draining the site of infection reenter the bloodstream and travel to the site of infection where they leave the bloodstream and enter the tissue. Infected macrophages, present at the site of infection, can present antigen on class II MHC on their cell surface and this stimulates the Th cells to release cytokines. Among these cytokines, TNF-a increases the expression of adhesion molecules on the local endothelium, thereby aiding the recruitment of monocytes from the blood. The monocytes and tissue macrophages are activated by other cytokines, particularly interferon-g and TNF-a, to differentiate into activated macrophages, which are better able to kill the pathogens (Figure 2). However, extensive activation of macrophages can also lead to tissue damage and hence the original description of the response as a hypersensitivity reaction. Much of the damage caused in chronic infections (e.g. tuberculosis, leprosy) is due to DTH reactions. A
Delayed hypersensitivity (DTH) responses: initially considered a pathological response, DTH is now recognized as an important protective response against some intracellular pathogens, especially those that can live in macrophages. Usually DTH responses are generated in response to tissue-dwelling pathogens. Th cells
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:6
FURTHER READING Murphy KM, Travers P, Walport M. Janeway’s immunobiology. 7th edn. Oxford: Garland Science, 2007. Roitt I, Brostoff J, Male D. Immunology. 5th edn. London: Mosby, 2006.
272
Ó 2012 Elsevier Ltd. All rights reserved.