Immunology

Cover
Inside Front cover
Immunology
Copyright
Preface to the 9th edition
Contributors
1 Introduction to the Immune System
Cells and soluble mediators of the immune system
Cells of the Immune System
Phagocytes internalize antigens and pathogens and break them down
B cells and T cells are responsible for the specific recognition of antigens
Cytotoxic cells recognize and destroy other cells that have become infected
Auxiliary cells control inflammation
Soluble Mediators of Immunity
Complement proteins mediate phagocytosis, control inflammation and interact with antibodies in immune defence
Cytokines signal between lymphocytes, phagocytes and other cells of the body
Inflammation
Leukocytes enter inflamed tissue by crossing venular endothelium
Immune responses to pathogens
Effective immune responses vary depending on the pathogen
Innate immune responses are the same on each encounter with an antigen
Adaptive immune responses display specificity and memory
Antigen recognition
Antigens initiate and direct adaptive immune responses
Functions of Antibodies
Antibody specifically binds to antigen
Each antibody binds to a restricted part of the antigen called an epitope
Fc regions of antibodies act as adapters to link phagocytes to pathogens
Peptides from intracellular pathogens are displayed on the surface of infected cells
Antigen presentation
Antigen activates specific clones of lymphocytes
Antigen elimination
Antibodies can directly neutralize some pathogens
Phagocytes kill pathogens in endosomes
Cytotoxic cells kill infected target cells
Termination of immune responses limits damage to host tissues
Immune responses to extracellular and intracellular pathogens
Vaccination
Immunopathology
Inappropriate Reaction to Self Antigens - Autoimmunity
Ineffective Immune Response - Immunodeficiency
Overactive Immune Response - Hypersensitivity
Normal but inconvenient immune reactions
2 Cells, Tissues and Organs of the Immune System
Cells of the immune system
Cells of the innate immune system include mononuclear phagocytes, granulocytes, mast cells, and innate lymphoid cells
Antigen-presenting cells (APCs) link the innate and adaptive immune systems
Adaptive immune system cells are lymphocytes
Myeloid cells
Mononuclear phagocytes and polymorphonuclear granulocytes are the two major phagocyte lineages
Mononuclear phagocytes are widely distributed throughout the body
There are three different types of polymorphonuclear granulocyte
Neutrophils comprise over 95% of the circulating granulocytes
Granulocytes and mononuclear phagocytes develop from a common precursor
Monocytes express CD14 and significant levels of MHC class II molecules
Neutrophils express adhesion molecules and receptors involved in phagocytosis
Eosinophils, basophils and mast cells in inflammation
Eosinophils play a role in immunity to parasitic worms
Basophils and mast cells play a role in immunity against parasites
Platelets have a role in inflammation and clotting
Adipocytes produce inflammatory cytokines
Antigen-presenting cells
Dendritic cells are derived from several different lineages
Langerhans cells and interdigitating dendritic cells are rich in MHC class II molecules
FDCs lack class II MHC molecules and are found in B cell areas
Lymphocytes
Lymphocytes are phenotypically and functionally heterogeneous
Lymphocytes are morphologically heterogeneous
Lymphocytes express characteristic surface and cytoplasmic markers
Marker molecules allow lymphocytes to communicate with their environment
Identification of lymphocyte subsets
Marker molecules allow lymphocytes to be isolated from each other
T cells can be distinguished by their different antigen receptors
There are three major subpopulations of αβ T cells
Th subsets are distinguished by their cytokine profiles
γδ T Cells and NKT Cells
γδ T cells maintain epithelial integrity, kill stressed cells and contribute to antimicrobial immunity
iNKT cells recognize glycolipid antigens
B cells recognize antigen using the B cell receptor complex
Other B-cell markers include MHC class II antigens and complement and Fc receptors
CD5+ B-1 cells and marginal zone B Cells produce natural antibodies
Marginal zone B cells are thought to protect against polysaccharide antigens
B cells can differentiate into antibody-secreting plasma cells
Innate lymphoid cells (ILC)
ILCs are lymphocytes that do not express rearranged antigen receptors
Five groups of ILC are defined by lineage and functional traits
NK cells kill virally infected and cancerous cells
NK cells are identified by their expression of CD56 and CD16
Helper ILCs polarize the immune response by producing cytokines
ILC2 and ILC3 help to maintain epithelial integrity
Lymphocyte development
Lymphoid stem cells develop and mature within primary lymphoid organs
T cells develop in the thymus
Three types of thymic epithelial cell have important roles in T-cell production
Stem cell migration to the thymus initiates T-cell development
T cells change their phenotype during maturation
Stage I thymocytes are CD4-, CD8-
Stage II thymocytes become CD4+ and CD8+
Stage III thymocytes become either CD4+ or CD8+
The T cell receptor is generated during development in the thymus
Positive and negative selection of developing T cells takes place in the thymus
Adhesion of maturing thymocytes to epithelial and accessory cells is crucial for T-cell development
Negative selection may also occur outside the thymus in peripheral lymphoid tissues
Regulatory T cells are involved in peripheral tolerance
There is some evidence for extrathymic development of T cells
B cells
B cells develop mainly in the fetal liver and bone marrowImage 1
B cells are subject to selection processes
Immunoglobulins are the definitive B-cell lineage markers
B cells migrate to and function in the secondary lymphoid tissues
Lymphoid organs
Lymphoid organs and tissues protect different body sites
The spleen is made up of white pulp, red pulp and a marginal zone
The white pulp consists of lymphoid tissue
The red pulp consists of venous sinuses and cellular cords
The marginal zone contains B cells, macrophages and dendritic cells
Lymph nodes filter antigens from the interstitial tissue fluid and lymph
Lymph nodes consist of B and T cell areas and a medulla
Secondary follicles are made up of a germinal centre and a mantle zone
In the germinal centres B cells proliferate, are selected and differentiate into memory cells or plasma cell precursors
MALT includes all lymphoid tissues associated with mucosa
Follicle-associated epithelium is specialized to transport pathogens into the lymphoid tissue
Lamina propria and intra-epithelial lymphocytes are found in mucosa
Lymphocyte recirculation
Lymphocytes leave the blood via high endothelial venules
Lymphocyte trafficking exposes antigen to a large number of lymphocytes
Antigen stimulation at one mucosal area elicits an antibody response largely restricted to MALT
The microbiome modulates lymphocyte development
Further reading
3 Mechanisms of Innate Immunity
Innate immune responses
Inflammation - a response to tissue damage
Inflammation brings leukocytes to sites of infection or tissue damage
Cytokines control the movement of leukocytes into tissues
Leukocytes migrate across the endothelium of microvessels
Leukocyte traffic into tissues is determined by adhesion molecules and signalling molecules
Selectins bind to carbohydrates to slow the circulating leukocytes
Chemokines and other chemotactic molecules trigger the tethered leukocytes
Chemokines, receptors have promiscuous binding properties
Other molecules are also chemotactic for neutrophils and macrophages
Integrins on the leukocytes bind to cell-adhesion molecules on the endothelium
Integrins and Cell-Adhesion Molecules – Families of Adhesion Molecules
Leukocyte migration varies with the tissue and the inflammatory stimulus
Different chemokines cause different types of leukocyte to accumulate
Preventing leukocyte adhesion can be used therapeutically
Leukocyte migration to lymphoid tissues
Chemokines are important in controlling cell traffic to lymphoid tissues
Mediators of inflammation
The kinin system generates powerful vasoactive mediators
The plasmin system is important in tissue remodelling and regeneration
Mast cells, basophils and platelets release a variety of inflammatory mediators
Pain is associated with mediators released from damaged or activated cells
Lymphocytes and monocytes release mediators that control the accumulation and activation of other cells
Pathogen-associated molecular patterns
PRRs allow phagocytes to recognize pathogens
Soluble Pattern Recognition Molecules
Pentraxins
Collectins and ficolins opsonize pathogens and inhibitinvasiveness
Phagocytes have receptors that recognize pathogens directly
Toll-like receptors activate phagocytes
Further reading
4 Complement
Complement and inflammation
Complement activation pathways
The classical pathway links to the adaptive immune system
The classical pathway is activated by antibody bound to antigen and requires Ca2+
C1 activation occurs only when several of the head groups of C1q are bound to antibody
C1s enzyme cleaves C4 and C2
C4b2a is the classical pathway C3 convertase
C4b2a3b is the classical pathway C5 convertase
The ability of C4b and C3b to bind surfaces is fundamental to complement function
The alternative and lectin pathways provide antibody-independent innate immunity
The lectin pathway is activated by microbial carbohydrates
Alternative pathway activation is accelerated by microbial surfaces and requires Mg2+
The C3bBb complex is the C3 convertase of the alternative pathway
The alternative pathway is linked to the classical and lectin pathways
Complement protection systems
C1 inhibitor controls the classical and lectin pathways
C3 and C5 convertase activity is controlled by decay and enzymatic degradation
Control of the convertases is mediated in two complementary ways
Decay Acceleration
Cofactor Activity
The membrane attack pathway
Activation of the pathway results in the formation of a transmembrane pore
Regulation of the membrane attack pathway reduces the risk of `bystander damage to adjacent cells
CD59 protects host cells from complement-mediated damage
Membrane receptors for complement products
Receptors for fragments of C3 are widely distributed on different leukocyte populations
CR1, CR2, CR3, and CR4 bind fragments of C3 attached to activating surfaces
Receptors for C3a and C5a mediate inflammation
Receptors for C1q are present on phagocytes, mast cells, and platelets
The plasma complement regulator FH binds cell surfaces
Complement functions
C5a is chemotactic for macrophages and polymorphs
C3a and C5a activate mast cells and basophils
C3b and iC3b are important opsonins
C3b disaggregates immune complexes and promotes their clearance
The MAC damages some bacteria and enveloped viruses
Immune complexes with bound C3b are very efficient in priming B cells
Complement deficiencies
Classical pathway deficiencies result in tissue inflammation
Deficiencies of MBL are associated with infection in infants
Alternative pathway and C3 deficiencies are associated with bacterial infections
Terminal pathway deficiencies predispose to Gram-negative bacterial infections
C1 inhibitor deficiency causes hereditary angioedema
C1inh deficiency is a dominant condition
Deficiencies in alternative pathway regulators cause a secondary loss of C3
FH or FI deficiency predisposes to bacterial infections
Properdin deficiency causes severe meningococcal meningitis
Autoantibodies against complement components, regulators and complexes also cause disease
Complement polymorphisms and disease
Complement therapeutics
Further reading
5 Mononuclear Phagocytes in Immune Defence
Macrophages: the `big Eaters'
Macrophages are heterogeneous
Macrophage Origin
M-CSF is required for macrophage differentiation
Macrophages can act as antigen-presenting cells
Macrophages act as sentinels within the tissues
Phagocytosis and endocytosis
Soluble compounds are internalized by endocytosis
Large particles are internalized by phagocytosis
Macrophages sample their environment through opsonic and non-opsonic receptors
Studying Macrophage Phenotypes
Opsonic receptors require antibody or complement to recognize the target
The best characterized non-opsonic receptors are the Toll-like receptors
TLRs activate macrophages through several different pathways
Lectin and scavenger receptors are non-opsonic receptors that recognize carbohydrates and modified proteins directly
Cytosolic receptors recognize intracellular pathogens
Mechanism of action of NLRs
Mechanisms of action of RLH receptors
Infection can activate autophagy in macrophages
Functions of phagocytic cells
Clearance of apoptotic cells by macrophages produces anti-inflammatory signals
Macrophages coordinate the inflammatory response
Recognition of necrotic cells and microbial compounds by macrophages initiates inflammation
Resident macrophages recruit neutrophils to inflammatory sites
Monocyte recruitment to sites of inflammation is promoted by activated neutrophils
Macrophages and neutrophils have complementary microbicidal actions
Phagocytes kill pathogens with reactive oxygen and nitrogen intermediates
Some pathogens avoid phagocytosis or escape damage
Functions of Secreted Molecules
Resolution of inflammation by macrophages is an active process
Different pathways of macrophage activation
Further reading
6 T-Cell Receptors and Major Histocompatibility Complex Molecules
MHC genes
The MHC is polygenic and polymorphic
The Class I Region
The Class II Region
The Class III Region
HLA may be defined serologically or by genotyping
MHC molecules
MHC molecules allow T cells to recognize antigens
MHC class I molecules consist of an MHC-encoded heavy chain bound to β2-microglobulin
β2-Microglobulin is essential for the expression of MHC class I molecules
α1 and α2 domains form the class I antigen-binding groove
The groove of an MHC class I molecule typically accommodates a peptide of eight to ten residues
Variations in amino acid sequence change the shape of the binding groove
Peptides are held in the binding groove by characteristic anchor residues
MHC class II molecules are structurally similar to MHC class I molecules
The MHC class II binding groove accommodates longer peptides than that of MHC class I
CD1 is a class I-like molecule that presents lipid antigens
T-cell receptors
The TCR is a highly variable disulfide-linked heterodimer
αβ TCRs recognize peptides presented by MHC molecules
γδ TCRs can recognize antigen without the need for presentation by MHC molecules
Some T cells express αβ TCRs with limited diversity, which recognize class-I-like molecules
Generation of T-cell receptor diversity
TCR diversity is generated by V(D)J recombination
V(D)J recombination occurs first in the α and then in the β chain
V(D)J recombination relies on recombination activating genes (RAG) 1 and 2
The T-cell receptor complex
The CD3 complex associates with antigen-binding αβ or γδ heterodimers to form the complete TCR
The cytoplasmic domains of zeta chains mediate TCR signalling
Major histocompatibility complex haplotype and disease susceptibility
Certain HLA haplotypes confer protection from infection
Certain HLA haplotypes are associated with autoimmune disease
Further reading
7 Antigen Presentation
Antigen-presenting cells
Dendritic cells are crucial for priming T cells
Macrophages, B cells and some innate lymphoid cells present antigen to primed T cells
Antigen processing
Major histocompatibility complex class i pathway
Proteasomes partially degrade cytoplasmic proteins for presentation by MHC class I molecules
Transporters move peptides into the ER
A multimeric complex loads peptides onto MHC class I molecules
Antigen processing affects which peptides are presented
In some animals, antigen-processing genes are genetically linked to the MHC
The non-classical class I molecule HLA-E presents leader peptides from other class I molecules
Cross-presentation allows exogenous antigen to be presented on class I molecules
Major histocompatibility complex class ii pathway
Professional APCs endocytose and partially degrade antigen
Peptide loading onto class II molecules occurs in the MIIC
Non-classical class II molecules mediate peptide loading onto classical class II
Class II-peptide complexes recycle from the plasma membrane
CD1 Pathway
CD1 molecules present lipids and glycolipids
CO-Stimulation
Danger signals enhance T-cell activation
Co-stimulation by CD80/86 binding to CD28 is essential for T-cell activation
Ligation of CTLA-4 and PD-1 inhibit T-cell activation
T-Cell signalling
CD4 binds to MHC class II and CD8 binds to MHC class I
The immunological synapse is a highly ordered signalling structure
T-cell signalling requires phosphorylation of ITAMs
Intracellular signalling pathways activate transcription factors
Interleukin-2 drives T-cell division
Other cytokines contribute to activation and division
Activated T cells signal back to APCs
Further reading
8 Cell-Mediated Cytotoxicity
Cytotoxic lymphocytes
CTLs and NK cells mediate cytotoxicity
Effector CTLs home to peripheral organs and sites of inflammation
CTLs recognize antigen presented on MHC class I molecules
CTLs and NK cells are complementary in the defence against virally infected and cancerous cells
Human peripheral blood contains two kinds of NK cells
NK-Cell receptors
NK cells recognize cells that fail to express MHC class I
KIRs recognize MHC class I
NK-Cell Development
The lectin-like receptor CD94 recognizes HLA-E
LILRB1 recognizes all MHC class I molecules including HLA-G
NK cells are self-tolerant
Cancerous and virally-infected cells are recognized by NKG2D
The natural cytotoxicity receptors (NCRs) recognize a variety of ligands
NK cells can also recognize antibody on target cells using Fc receptors
The balance of inhibitory and activating signals controls NK cell activation
NK cells display some features of adaptive immune cells
Cytotoxicity
Cytotoxicity is effected by direct cellular interactions, granule exocytosis and cytokines
Cytotoxicity may be signalled via TNF receptor family molecules on the target cell
CTL and NK cell granules contain perforin and granzymes
Some cell types are resistant to cell-mediated cytotoxicity
Non-lymphoid cytotoxic cells
Macrophages and neutrophils primarily kill target cells by phagocytosis
Eosinophils kill target cells by ADCC
Further reading
9 B-Cell Development and the Antibody Response
B-Cell development
B-Cell receptor diversity is generated by V(D)J recombination
Pro-B cells develop into immature and then mature B cells
Recombination involves recognition of signal sequences
IL-3, IL-4, IL-7 and BAFF are important for B-cell development
Transcriptional controls in B-cell development
Abnormalities in B-cell development
B-Cell activation
Follicular dendritic cells act as antigen depots for B cells
B-cell activation and T-cell activation follow similar patterns
T-Independent antigens do not require T-cell help to stimulate B cells
T-independent antigens induce faster responses but poor memory
T-dependent B cells require T-cell help for activation
T-follicular helper cells provide help to B cells in germinal centres
Direct interaction of B cells and T cells involves Co-stimulatory molecules
Type 2 cytokines guide B-cell proliferation and differentiation
BAFF is important for B-cell development in germinal centres
Anergy limits the activation of self-reactive B cells
B-Cell differentiation and the antibody response
Affinity maturation and class switching occurs in germinal centres
Self-reactive B cells generated by somatic mutation are deleted
Somatic hypermutation and class-switch recombination
Somatic hypermutation and class switching require activation-induced cytidine deaminase
Affinity maturation depends on somatic hypermutation and cell selection
B cells recombine their heavy chain genes to switch immunoglobulin isotype
Class switching occurs during maturation and proliferation
Mechanisms of somatic hypermutation
Class switching may be achieved by differential splicing of mRNA
Class switching is mostly achieved by gene recombination
Immunoglobulin class expression is influenced by cytokines
Immunoglobulin class expression is influenced by the site of synthesis
Mechanism of class-switch recombination
Membrane and secreted immunoglobulins are produced bydifferential splicing of RNA transcripts of heavychain genes
Events in B-cell development shape the antibody response
Further reading
Further Reading
10 Antibodies
Antibodies and B-cell receptors
Antibodies are a family of glycoproteins
All antibody isotypes are bifunctional
Antibody class and subclass is determined by the sequence of the genetically encoded heavy chain
Different antibody isotypes activate different effector systems
IgG is the predominant antibody isotype present in normal human serum
IgM accounts for about 10% of the serum antibody pool
IgA is present in serum and seromucous secretions
IgD accounts for 1 % of serum antibody pool and is expressed as an antigen-specific receptor (mIgD) on mature B cells
IgE has a low serum concentration
The basic four-chain structure consists of a series of folded domains
Antibodies are prototypes of the immunoglobulin superfamily
The three-dimensional structure of an antibody molecule varies with class and subclass
Assembled IgM molecules have a `Star conformation
Secretory IgA is a complex of IgA, J chain and secretory component
Serum IgD exhibits antigen specificity and an IgG-like four- chain structure
The heavy chain of IgE consists of four constant region domains
Antigen-antibody interactions
The conformations of the epitope and the paratope are complementary
Antibody structural and serological variations
Antibody isotypes are the products of genes present within the genome of all healthy members of a species
Allotypes result from genetic variation at a locus within the species
Idiotypes result from unique antibody recognition specificity (paratope)
Antibody affinity is a measure of the strength of interaction between a paratope and its epitope
Antibodies form multiple Non-covalent bonds with antigen
Antigen-antibody interactions are reversible
Avidity is likely to be more relevant than affinity
Cross-reactive antibodies recognize more than one antigen
Antibodies recognize the conformation of antigenic determinants
Antibody effector functions
IgM predominates in the primary immune response
IgG is the predominant isotype of secondary immune responses
Serum IgA is produced during a secondary immune response
IgD is a transmembrane antigen receptor on B cells
IgE may Have evolved to protect against helminth parasites infecting the gut
Fc receptors
The three types of Fc receptor for IgG are FcγRI, FcγRII and FcγRIII
FcγRI is involved in phagocytosis of immune complexes and mediator release
FcγRIII is expressed as FcγRIIIa and FcγRIIIb
Polymorphism in FcγRIIIa and FcγRIIIb may affect disease susceptibility
Interaction sites of IgG-Fc for multiple ligands have been identified
Glycosylation of both the IgG-Fc and FcγR is essential for receptor binding to IgG
The FcR for IgA is FcαRI
The two types of Fc receptor for IgE are FcεRI and FcεRII
Cross-linking of IgE bound to FcεRI results in histamine release
FcεRII is a type 2 transmembrane molecule
IgE receptors bind to IgE by different mechanisms
Antibody engineering
Human therapeutic antibodies have low immunogenicity
Engineering for tailored antibody-effector function
Alterations that affect effector functions
Alterations that affect half-life and biodistribution
Engineering of variable regions
Alternative forms
Conjugates
Production of antibodies as drugs
Further reading
Further reading
11 Immunological Tolerance
Generation of autoreactive antigen receptors during lymphocyte development
T-Cell tolerance
Central T-cell tolerance develops in the thymus
Generation of their clonal TCR is the first step in T-Cell development
Thymocytes are positively selected for their ability to interact with self MHC molecules
Positive selection occurs predominantly in the thymic cortex
Lack of survival signals leads to death by neglect
Thymocytes are negatively selected if they bind strongly to self peptides on MHC molecules
A library of self antigens is presented to developing T cells in the thymus
AIRE controls promiscuous expression of genes in the thymus
Thymic dendritic cells can also cause negative selection
Peripheral T-cell tolerance
Some self antigens are sequestered in immunologically privileged tissues
Lymphocyte activation enhances their migration into non-lymphoid tissues
The amount of released self antigen critically affects sensitization
Antigen-presenting cells reinforce self tolerance
Dendritic cells can present antigen in a tolerogenic manner
Self-reactive T cells and experimental autoimmunity
Immunological ignorance occurs if T cells do not encountertheir cognate antigen
Tolerogenic DCs mature under steady-state conditions
Regulatory T cells
DC surface receptors involved in promoting tolerance
Regulatory T cells suppress immune responses
The transcription factor FoxP3 controls Treg development
Defects in FoxP3 result in multi-system autoimmune diseases
Natural Treg cells differentiate in the thymus
Selection of nTregs is partly related to the affinity for antigen/MHC
IL-2 is required for the development of Tregs
iTreg cells differentiate in the periphery
The phenotype of Treg cells
Treg effector functions
Tregs secrete immunosuppressive cytokines
Tregs can deplete IL-2
Cytolysis
Modulation of DC maturation and function
In vitro assays of Treg effector functions
In vivo analyses of Treg effector functions
Can loss of Treg function explain autoimmune disease?
T-Cell anergy
The induction of anergy is an active process
T cells can be deleted in the periphery
Cytokine withdrawal can induce apoptosis
T cells can be killed by ligation of Fas
B-Cell tolerance
B cells undergo negative selection in the bone marrow
Receptor editing allows potentially self-reactive B cells to avoid negative selection
B-cell anergy can be induced by self antigens
Somatic hypermutation can generate autoreactive B cells
B-cell tolerance because of lack of T-cell help
Further reading
12 Regulation of the Immune Response
T-Cell and B-Cell Regulation by Antigen
Different antigens elicit different kinds of immune response
Large doses of antigen can induce tolerance
Antigen route of administration can determine whether an immune response occurs
Regulation by the antigen-presenting cell
T-Cell Regulation of the Immune Response
Differentiation into CD4+ Th subsets is an important step in selecting effector functions
Cytokine balance is a major regulator of T-cell differentiation
Th cell subsets determine the type of immune response
CD8+ T cells can also be divided into subsets on the basis of cytokine expression
CD4+ T cells display some plasticity between TH1, TH2 and TH17
Innate lymphoid cells polarize the immune response by producing cytokines
ILCs can affect the immune response via cell-cell interactions
Immune Regulation by Selective Cell Migration
T-Cell expression of different molecules can regulate tissue localization
Regulatory T Cells
Treg differentiation is induced by Foxp3
There is a Reciprocal Developmental Relationship Between Induced Tregs and Th17 Cells
Tr1 are Induced by IL-10 and Do Not Express FoxP3
Tregs Suppress the Immune Response Using Multiple Mechanisms
Tregs Prevent Immune-Mediated Pathology in Infection but Can also Dampen Protective T-Cell Responses
NKT cells produce immunoregulatory cytokines and chemokines
Regulation of the Immune Response by Immunoglobulins
IgM enhances the immune response to its antigen
IgG antibody can regulate specific IgG synthesis
Immune complexes may enhance or suppress immune responses
Regulatory B Cells Produce IL-10
Apoptosis in the Immune System
At the End of an Immune Response, Antigen-Specific Cells Die by Apoptosis
Metabolic Regulation of the Immune Response
T-Cell Activation Involves a Switch from Oxphos to Glycolysis
Neuroendocrine Regulation of Immune Responses
Corticosteroids are immunosuppressive
Sex hormones affect immune cell function
Further Reading
13 Immune Responses in Tissues
Tissue-Specific Immune Responses
Some tissues are immunologically privileged
Locally produced cytokines and chemokines influence tissue-specific immune responses
Endothelium controls which leukocytes enter a tissue
Immune Reactions in the CNS
The blood-brain barrier excludes most antibodies from the CNS
Neurons suppress immune reactivity in neighbouring glial cells
Immunosuppressive cytokines regulate immunity in the normal CNS
Immune reactions in CNS damage oligodendrocytes
Immune Reactions in the Eye
Immune Responses in the Gut and Lung
Gut enterocytes influence the local immune response
The gut immune system tolerates many antigens but reacts to pathogens
Intra-epithelial lymphocytes produce many immunomodulatory cytokines
Chronic Inflammation in the Gut
Immune Responses in the Lung
Immune Reactions in the Liver
Immune Reactions in the Skin
Conclusions
Further Reading
14 Immunity to Viruses
Innate Immune Defences Against Viruses
Microbicidal peptides have broad-spectrum antiviral effects
Interferons have critical antiviral and immunostimulatory roles
Type I interferons are produced when PRRs detect viral PAMPs
Interferons act on cells to produce an antiviral state
Interferons Enhance The Antiviral Activity of Macrophages And Nk Cells
NK cells kill virally infected cells
Macrophages act at three levels to destroy virus and virus-infected cells
Adaptive Immune Responses To Viral Infection
Antibodies can neutralize the infectivity of viruses
NK cells are important in combatting herpes virusinfections
Complement is involved in the neutralization of some free viruses
Antibodies mobilize complement and/or effector cells to destroy virus-infected cells
T cells mediate viral immunity in several ways
CD8+ T cells target virus-infected cells
CD4+ T cells are a major effector cell population in the response to some virus infections
Host genetic variation affects antiviral immune defences
Virus Strategies To Evade Host Immune Responses
Viruses can impair the host immune response
Viruses have strategies to avoid recognition by host immune defences
Viruses avoid recognition by T cells by reducing MHC expression on infected cells
Mutation of viral target antigen allows escape from recognition by antibodies or T cells
Viruses have evolved strategies to avoid control by a broad range of immune effector mechanisms
Pathological Consequences Of Immune Responses Induced By Viral Infections
Excessive cytokine production and immune activation can be pathological
Poorly neutralizing antibodies can enhance viral infectivity
Antiviral antibodies can form immune complexes that cause tissue damage
Virus-specific T-cell responses can cause severe tissue damage
Viral infection may provoke autoimmunity
Further Reading
NK cells are important in combatting herpes virus infections
15 Immunity to Bacteria and Fungi
Innate recognition of bacterial components
There are four main types of bacterial cell wall
Pathogenicity varies between two extreme patterns
The first lines of defence do not depend on antigen recognition
Commensals can limit pathogen invasion
The second line of defence is mediated by recognition of bacterial components
LPS is the dominant activator of innate immunity in Gram-negative bacterial infection
Bacterial PAMPs activate cells via Toll-like receptors
Other bacterial components are also potent immune activators
Lymphocyte-independent effector systems
Complement is activated via the alternative pathway
Release of pro-inflammatory cytokines increases the adhesive properties of the vascular endothelium
Activation of innate lymphoid cells provides the next phase of phagocyte activation
Pathogen recognition generates signals that regulate the antigen-specific lymphocyte-mediated response
Antibody-dependent antibacterial defences
Pathogenic bacteria may avoid the effects of antibodies
Pathogenic bacteria can avoid the detrimental effects of complement
Bacterial killing by phagocytes
Bacterial components attract phagocytes by chemotaxis
The choice of receptors is critical
Uptake can be enhanced by macrophage-activating cytokines
Different membrane receptors vary in their efficiency at inducing a microbicidal response
Phagocytic cells have many killing methods
Some cationic proteins have antibiotic-like properties
Other anti-microbial mechanisms also play a role
Macrophage killing can be enhanced on activation
Optimal activation of macrophages is dependent on Th1 cells
Persistent monocyte recruitment and macrophage activation can result in granuloma formation
Successful pathogens have evolved mechanisms to avoid phagocyte-mediated killing
Intracellular pathogens may `hide in cells
Direct antibacterial actions of t cells
Infected cells can be killed by CTLs
Other T-cell populations can contribute to antibacterial immunity
Immunopathological reactions induced by bacteria
Excessive cytokine release can lead to endotoxin shock
The toxicity of superantigens results from massive cytokine release
The Schwartzman reaction is a form of cytokine-dependenttissue damage
The Koch phenomenon is necrosis in T-Cell-MediatedMycobacterial Lesions and Skin Test Sites
Some individuals suffer from excessive immune responses
Excessive immune responses can occur during treatment ofsevere bacterial infections
Heat-shock proteins are prominent targets of immuneresponses
Fungal infections
There are four categories of fungal infection
Innate immune responses to fungi include defensins and phagocytes
T-Cell mediated immunity is critical for resistance to fungi
Fungi possess many evasion strategies to promote their survival
New immunological approaches are being developed to prevent and treat fungal infections
Further reading
16 Immunity to Protozoa and Worms
Parasite Infections
Immune Defences Against Parasites
Host resistance to parasite infection may be genetic
Many parasitic infections are long-lived
Parasitic infections are often chronic and affectmany people
Host defence depends on a number of immunological mechanisms
Innate Immune Responses
Toll-like receptors recognize parasite molecules
Classical human PRRs also contribute to recognition of parasites
Complement receptors are archetypal PRRs
Adaptive Immune Responses to Parasites
T and B cells are pivotal in the development of immunity
Both CD4 and CD8 T Cells are needed for protection from some parasites
Cytokines, chemokines and their receptors have important roles
T-Cell Responses to Protozoa Depend on the Species
The immune response to worms depends upon Th2-secreted cytokines
Some worm infections deviate the immune response
The host may isolate the parasite with inflammatory cells
Parasites induce non-specific and specific antibody production
Immune Effector Cells
Macrophages can kill extracellular parasites
Activation of macrophages is a feature of early infection
Neutrophils can kill large and small parasites
Eosinophils are characteristically associated with worm infections
Eosinophils can kill helminths by oxygen-dependent and independent mechanisms
Eosinophils and mast cells can act together
Mast cells control gastrointestinal helminths
Platelets can kill many types of parasite
Parasite Escape Mechanisms
Parasites can resist destruction by complement
Intracellular parasites can avoid being killed by oxygen metabolites and lysosomal enzymes
Genetic influences may modify immune responses toparasites
Parasites can disguise themselves
African trypanosomes and malaria undergo antigenic variation
Other parasites acquire a surface layer of host antigens
Some extracellular parasites hide from or resist immune attack
Most parasites interfere with immune responses for their benefit
Parasites produce molecules that interfere with host immune function
Some parasites suppress inflammation or immune responses
Immunopathological Consequences of Parasite Infections
Vaccines Against Human Parasites
Further Reading
Further Reading
17 Vaccination
Vaccination
Vaccines apply immunological principles to human health
Vaccines can protect populations as well as individuals
Antigen preparations used in vaccines
Live vaccines can be natural or attenuated organisms
Natural live vaccines have rarely been used
Attenuated live vaccines have been highly successful
Herd immunity
Attenuated microorganisms are less able to cause disease in their natural host
Killed vaccines are intact but non-living organisms
Inactivated toxins and toxoids are the most successful bacterial vaccines
Subunit vaccines and carriers
Conjugate vaccines are effective at inducing antibodies to carbohydrate antigens
Conjugate meningitis vaccines
Antigens can be expressed from vectors
Adjuvants enhance antibody production
Adjuvants concentrate antigen at appropriate sites or induce cytokines
TLR-stimulating molecules as adjuvants
Vaccine administration
Most vaccines are delivered by injection
Mucosal immunization is a logical alternative approach
Vaccine efficacy and safety
Induction of appropriate immunity depends on the properties of the antigen
Vaccine safety is an overriding consideration
MMR controversy resulted in measles epidemics
Vaccines in general use have variable success rates
Some vaccines are reserved for special groups
New vaccines can be very expensive
Vaccines for parasitic and some other infections are only experimental
For Many Diseases There is no Vaccine Available
Passive immunization
Immunization against non-infectious conditions
Future vaccines
`Naked DNA can be transfected into host cells
Further reading
18 Primary Immunodeficiencies
B-Lymphocyte Deficiencies
Congenital agammaglobulinaemia results from defects of early B-cell development
Defects in terminal differentiation of B cells produces selective antibody deficiencies
Genetic defects in CVID
CVID is characterized by reduced levels of specific antibody isotypes
IgA deficiency is relatively common
Defects of Class-Switch Recombination
T-Lymphocyte Deficiencies
Severe combined immunodeficiency can be caused by many different genetic defects
Treatment of SCID
Th-cell deficiency results from HLA class II deficiency
DiGeorge's anomaly arises from a defect in thymus embryogenesis
Disorders of Immune Regulation
Defective function of regulatory T (Treg) cells causes severe autoimmunity
Impaired apoptosis of self-reactive lymphocytes causes autoimmune lymphoproliferative syndrome
Congenital defects of lymphocyte cytotoxicity result in persistent inflammation and severe tissue damage
Immunodeficiency Syndromes
Chromosomal breaks occur in TCR and immunoglobulin genes in hereditary ataxia telangiectasia
T-cell defects and abnormal immunoglobulin levels occur in Wiskott-Aldrich syndrome
Deficiency of STAT3 causes impaired development and function of Th17 cells in hyper-IgE syndrome
Genetic Defects of Phagocytes
Chronic granulomatous disease results from a defect in the oxygen-reduction pathway
LAD is caused by defects of leukocyte trafficking
Enzyme defects in CGD
Immunodeficiencies With Selective Susceptibility To Infections
Macrophage microbicidal activity is impaired by defects in IFNγ signalling
Defects of TLR-signalling cause susceptibility to pyogenic infections
Primary immune deficiencies with increased susceptibility to fungal infections
Genetic Deficiencies of Complement Proteins
Immune complex clearance, inflammation, phagocytosis and bacteriolysis can be affected by complement deficiencies
Hereditary angioneurotic oedema results from C1 inhibitor deficiency
Further Reading
19 AIDS, Secondary Immunodeficiency and Immunosuppression
Overview
Nutrient Deficiencies
Infection and malnutrition can exacerbate each other
Protein-energy malnutrition and lymphocyte dysfunction
Nutrition also affects innate mechanisms of immunity
Deficiencies in trace elements impact immunity
Vitamin deficiencies and immune function
Obesity is associated with altered immune responses
Immunodeficiency Secondary to Drug Therapies
Iatrogenic immune suppression post-organ transplantation
Glucocorticoids are powerful immune modulators
Functional effects of steroid treatment
Monoclonal antibody and fusion protein therapies
Other Causes of Secondary Immunodeficiencies
HIV causes AIDS
HIV life cycle
HIV targets CD4+ T cells and mononuclear phagocytes
Acute symptoms occur 2-4 weeks post-infection
Viral latency is associated with chronic infection
HIV infection induces strong immune responses
HIV can evade the immune response
Immune dysfunction results from the direct effects of HIV and impairment of CD4 T cells
AIDS is the final stage of HIV infection and disease
An effective vaccine remains an elusive goal
Further Reading
20 Autoimmunity and Autoimmune Disease
Autoimmunity and Autoimmune Disease
Autoimmune conditions present a spectrum between organ-specific and systemic disease
Hashimoto's thyroiditis is highly organ-specific
SLE is a systemic autoimmune disease
The location of the antigen determines where a disease lies in the spectrum
An individual may have more than one autoimmune disease
Genetic Factors in Autoimmunity
Usually, several genes underlie susceptibility to autoimmunity
Certain HLA haplotypes predispose to autoimmunity
Genes outside the HLA region also confer susceptibility to autoimmunity
Autoimmunity is associated with genes that control lymphocyte activation
Autoimmunity and Autoimmune Disease
Autoantibody production alone does not equal autoimmune disease
SLE is associated with multiple gene loci
Epigenetic factors in disease development
Progression to autoimmune disease occurs in stages
Autoimmunity results from antigen-driven self-reactive lymphocytes
Induction of Autoimmunity
Molecular mimicry by cross-reactive microbial antigens can stimulate autoreactive lymphocytes
Molecular mimicry operates in rheumatic fever
In some cases foreign antigen can directly stimulate autoreactive cells
Infection may trigger relapse in autoimmune disease
The `waste disposal hypothesis of SLE
Cytokine dysregulation, inappropriate MHC expression and failure of suppression may induce autoimmunity
Defective clearance of apoptotic cells may induceautoimmunity
Pre-existing defects in the target organ may increase susceptibility to autoimmunity
Autoimmune Processes and Pathology
Human autoantibodies can be directly pathogenic
Autoantibodies can give rise to a wide spectrum of clinical thyroid dysfunction
The pathogenic role of autoimmunity can be demonstratedin experimental models
TH cells are essential for induction of autoimmunity in EAE
Examples of spontaneous autoimmunity
A variety of other diseases are associated with autoantibodies
In pernicious anaemia an autoantibody interferes with the normal uptake of vitamin B12
Antibodies to the glomerular capillary basement membrane cause Goodpasture's disease
Blood and vascular disorders caused by autoantibodies include AHA and ITP
Immune complexes appear to be pathogenic in systemic autoimmunity
Autoantibodies to IgG provoke pathological damage in rheumatoid arthritis
Evidence for directly pathogenic T cells in human autoimmune disease is hard to obtain
The central role of Th1 cells in some autoimmune diseases has been challenged
The role of Th17 cells
The role of Tregs in autoimmune disease
The role of regulatory B cells in autoimmune disease
Autoantibodies for Diagnosis, Prognosis and Monitoring
Treatment of Autoimmune Diseases
Biologics: key players in the treatment of autoimmune disease
Less well-established approaches to treatment may become practicable
Further Reading
21 Transplantation and Rejection
Transplantation in clinical practice
Many solid organs are now routinely transplanted
Stem cell transplants are used to treat inherited immune deficiencies and leukaemia
Genetic barriers to transplantation
The supply of organs for transplantation is limited
Ethical issues are an important factor in living donation
Graft rejection
Host versus graft responses cause transplant rejection
There is a high frequency of T cells recognizing the graft
Histocompatibility antigens are the targets for rejection
What do allospecific T cells recognize?
Minor antigens can be targets of rejection even when donor and recipient MHC are identical
Graft versus host reactions result when donor lymphocytes attack the graft recipient
Immune effector mechanisms in graft rejection
Hyperacute rejection is immediate and mediated by antibody
Acute rejection occurs days to weeks after transplantation
ABO incompatible transplantation is nowbecoming possible
Chronic rejection is seen months or years after transplantation
Preventing Rejection
The better the HLA matching of donor and recipient, the less the strength of rejection
HLA matching is not always crucial
Immunosuppressive drugs prevent graft rejection
6-MP, azathioprine and MPA are anti-proliferative drugs
Ciclosporin, tacrolimus and sirolimus are inhibitors of T-cell activation
Corticosteroids are anti-inflammatory drugs used for transplant immunosuppression
Biologic agents are increasingly being used to prevent graft rejection
Desensitization reduces the titre of antibodies that recognize the graft
Agents that deplete lymphocytes or block IL-2 signalling are used in induction
Agents that block the interaction between CD28 and its ligands are used in maintenance
Biologic agents can also be used to treat rejection and underlying disease
Induction of donor-specific tolerance
There is evidence for the induction of tolerance in humans
Novel methods for inducing tolerance are being developed
Alloreactive cells can be made anergic
Immune privilege can be a property of the tissue or site of transplant
Limitations on transplantation
Alternative approaches to overcoming the shortage of donor organs are being investigated
Xenotransplantation may increase the supply of organs
Further reading
22 Immunity to Cancers
Non-specific stimulation of the immune system can have an anti-cancer effect
Tumour Immunity in the Primary Host
Cancers elicit protective immunity in the primary and syngeneic host
Specific immunity to induced and spontaneous tumours may develop
Spontaneous tumours are also antigenically distinct
Characterization of Tumour Antigens
Tumour-specific antigens recognized by T cells show a wide spectrum of specificity
Cancer/testes antigens are expressed on cancer cells and in testes
Differentiation antigens are expressed on normal tissues and tumours
T-cell epitopes of viral antigens have been identified
Tumour-specific antigens defined by antibodies are rarely tumour specific
Antibodies used in the diagnosis and treatment of cancer may not be tumour specific
Mutated oncogenes could be a source of tumour-specific antigens
Tumour-specific antigens can be defined using genomics and bioinformatics
Anti-Tumour Immune Responses
Successful tumour immunity is rare in patients who have cancer
Despite an immune response, tumours continue to grow
Concomitant immunity shows two aspects of tumour immunity
Immunization is effective prophylactically but rarely as therapy
The naive state and tumour-bearing state are essentially different
Downregulation of MHC I expression may result in resistance to recognition and lysis
T-cell activity is inhibited through CTLA-4 and PD-1
Abrogation of CD25+ Tregs leads to protective tumour immunity
Myeloid-derived suppressor cells inhibit the immune response to tumours
Extracellular adenosine suppresses T-cell anti-tumour functions
Immunotherapy for Human Cancer
Animal models are limited in the translation of therapy
Antibodies have been used successfully
Vaccination can be used to treat cancer
Idiotypes of B-cell lymphomas have been used as vaccines
Immunization with defined MHC I restricted epitopes does not lead to clinical benefit
Immunotherapy with DCs presenting a prostate antigen shows clinical benefit
Checkpoint blockade of CTLA-4, PD-1 or PD-L1/2 shows significant clinical benefit
Adoptive immunotherapy using T cells: the clinical benefits
T cells with chimeric antigen receptors are highly effective in therapy of several haematological malignancies
Further Reading
23 Immediate Hypersensitivity (Type I)
Classification of hypersensitivity reactions
Historical perspective on immediate hypersensitivity
Characteristics of type I reactions
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Most allergens are proteins
IgE is distinct from the other dimeric immunoglobulins
The half-life of IgE is short compared with that of other immunoglobulins
IgG4 is transferred across the placenta, but IgE is not
T cells control the response to inhalant allergens
IgE production is dependent on Th2 cells
Cytokines regulate the production of IgE
Both IgE and IgG4 are dependent on IL-4
Characteristics of allergens
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Allergens have similar physical properties
The inhalant allergens cause hay fever, chronic rhinitis and asthma
Small quantities of inhalant allergen cause immediate hypersensitivity
Only a small number of food proteins are common causes of allergic responses
Desensitization can be used to control type I hypersensitivity
Mediators released by mast cells and basophils
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Mast cells in different tissues have distinct granule proteases
Cross-linking of FcεRI receptors results in degranulation
In allergic individuals mast cells can be recruited to the skin and nose
Genetic associations with asthma
Skin tests for diagnosis and to guide treatment
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Positive skin tests are common
Late skin reactions probably include several different events
Pathways that contribute to the chronicity of allergic diseases
Atopic Dermatitis and the Atopy Patch Test
Epidermal spongiosis and a dermal infiltrate are features of a positive patch test
Allergens contribute to asthma
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BAL analysis after allergen challenge demonstrates mast cell and eosinophil products
Bronchial hyper-reactivity is a major feature of asthma
Evidence of inflammation of the lungs of patients with asthma is indirect
Treatments for type I hypersensitivity
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Immunotherapy is an effective treatment for hay fever and anaphylactic sensitivity to venom
Modified forms of allergen-specific immunotherapy
Allergen peptides can stimulate T cells
Modified recombinant allergens have decreased binding to IgE
Adjuvants can shift the immune response away from a simple Th2 response
DNA vaccines are being designed to change the immune response
Other forms of immune-based non-specific therapy
Humanized monoclonal anti-IgE
Monoclonal antibodies against IL-4Rα
Humanized monoclonal anti-IL-5 and anti-IL-5 receptor antibodies
Some new treatment approaches may not be practical
Further reading
Further reading
24 Hypersensitivity (Type II)
Mechanisms of tissue damage
Effector cells engage their targets using Fc and C3 receptors
Cells damage targets by releasing their normal immune effector molecules
TYPE II Reactions against blood cells and platelets
Transfusion reactions occur when a recipient has antibodies against donor erythrocytes
The ABO blood group system is of primary importance
The Rhesus system is a major cause of haemolytic disease of the newborn
Cross-matching ensures that a recipient does not have antibodies against donor erythrocytes
Transfusion reactions involve extensive destruction of donor blood cells
Hyperacute graft rejection is related to the transfusion reaction
HDNB is due to maternal IgG reacting against the child's erythrocytes in utero
Transfusion reactions can be caused by minor blood groups
Autoimmune haemolytic anaemias arise spontaneously or may be induced by drugs
Warm-reactive autoantibodies cause accelerated clearance of erythrocytes
Cold-reactive autoantibodies cause erythrocyte lysis by complement fixation
Drug-induced reactions to blood components occur in three different ways
Autoantibodies to platelets may cause thrombocytopenia
Type II Hypersensitivity Reactions in Tissues
Antibodies against basement membranes produce nephritis in Goodpasture's syndrome
Pemphigus is caused by autoantibodies to an intercellular adhesion molecule
Reactions against neutrophils can occur in several
autoimmune diseases
Autoantibodies to peripheral nerves are present in Guillain-Barré syndrome
In myasthenia gravis autoantibodies to acetylcholine receptors cause muscle weakness
Autoantibodies and Autoimmune Disease
Further reading
Further reading
25 Hypersensitivity (Type III)
Immune complex diseases
Persistent infection with a weak antibody response can lead to immune complex disease
Immune complexes can be formed with inhaled antigens
Immune complex disease occurs in autoimmune rheumatic disorders
Cryoglobulins precipitate at low temperature
Immune complexes and inflammation
Complement is an important mediator of immune complex disease
Autoantibodies to complement components can modulate complement activity
Immune complexes clearance by the mononuclear phagocyte system
Experimental Models of Immunecomplex Diseases
Serum sickness can be induced with large injections offoreign antigen
Autoimmunity causes immune complex disease in the NZB/NZW mouse
The role of Fc receptors in the treatment of immune complexdisease
Injection of antigen into the skin of pre-sensitized animalsproduces the Arthus reaction
Complement solubilization of immune complexes
Complement deficiency impairs clearance of complexes
The size of immune complexes affects their deposition
Immunoglobulin classes affect the rate of immune complex clearance
Phagocyte defects allow complexes to persist
Carbohydrate on antibodies affects complex clearance
Immune complex deposition in tissues
The most important trigger for immune complex deposition is probably an increase in vascular permeability
Immune complex deposition is most likely where there is high blood pressure and turbulence
Affinity of antigens for specific tissues can direct complexes to particular sites
The site of immune complex deposition depends partly on the size of the complex
The class of immunoglobulin in an immune complex can influence deposition
Diagnosis of immune complex disease
Further reading
26 Hypersensitivity (Type IV)
Delayed-type Hypersensitivity Reactions
There are four subgroups of type IV hypersensitivity reaction
Type IVa Reactions Require Macrophages as Effector Cells
Tuberculin-type hypersensitivity is a form of type IVa reaction
The tuberculin skin test reaction involves monocytes and lymphocytes
Tuberculin-like DTH reactions are used practically in two ways
Granulomatous hypersensitivity is a special type of delayed hypersensitivity
Epithelioid cells and giant cells are typical of granulomatous hypersensitivity
A granuloma contains epithelioid cells, macrophages and lymphocytes
T cells bearing αβ TCRs are essential
IFNγ is required for granuloma formation in humans
TNFα and lymphotoxin-α are essential for granuloma formation during mycobacterial infections
Granulomatous reactions occur in many chronic diseases
The immune response in leprosy varies greatly between individuals
The borderline leprosy reaction is a dramatic example of delayed hypersensitivity
Granulomatous reactions are necessary to control tuberculosis
Type IVb Reactions Involve Eosinophils as Effector Cells
Th2-mediated inflammation of the airways is seen in asthma
Granulomas surround the parasite ova in schistosomiasis
Type IVc Reactions Involve CD8+ T Cells as Effector Cells
Contact hypersensitivity requires sensitization by haptens
A contact hypersensitivity reaction has two stages - sensitization and elicitation
Keratinocytes produce cytokines important to the contact hypersensitivity response
Sensitization stimulates a population of memory T cells
Elicitation involves recruitment of CD4+ and CD8+ lymphocytes and monocytes
Suppression of the inflammatory reaction is mediated by multiple mechanisms
Type IVd Reactions Involve Neutrophils as Effector Cells
AGEP Is characterized by T-cell involvement
Further Reading
Critical thinking: Explanations
Specificity and Memory in Vaccination
Development of the Immune System
The Role of Adhesion Molecules in T-Cell Migration
Complement Deficiency
The Role of Macrophages in Toxic Shock Syndrome
The role of macrophages in Th1 and Th2 responses
MHC Restriction
Antigen Processing and Presentation
Mechanisms of Cytotoxicity
Development of the Antibody Response
The Specificity of Antibodies
Immunological Tolerance
Regulation of the Immune Response
Immune Reactions in the Gut
Virus-Immune System Interactions
Immunoendocrine Interactions in the Response to Infection
Immunity to Protozoa and Helminths
Vaccination
Hyper-IgM immunodeficiency
Secondary Immunodeficiency
Autoimmunity and Autoimmune Disease
Transplantation
Immunity to Cancers
Severe Anaphylactic Shock
Blood Groups and Haemolytic Disease of the Newborn
Type III Serum Sickness After Factor IX Administration
A Hypersensitivity Type IV Reaction
Inside Back Cover