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Immunity to Infection
Introductory article
Article Contents
Anders Elm Pedersen, University of Copenhagen, Copenhagen, Denmark
. Infection versus Disease
The immune system comprises innate and adaptive immune responses coordinated to
prevent infection. Innate immune responses are early responses based on preformed
cells and effector molecules with a limited repertoire of antigen receptors. In contrast,
adaptive immune responses take several days to mount, but take advantage of a very
large repertoire of antigen receptors and comprises memory. The immune system must
constantly face pathogen invasion strategies and at the same time avoid destruction of
non-infected host tissue. In the following review the role of the various components of
the immune system and their role in immunity to infections is described.
Infection versus Disease
We are coexisting with a tremendous number of microorganisms such as bacteria, fungi, parasites and viruses.
A number of these are strict pathogens that lead to lethal
infectious disease, e.g. orthopoxvirus (smallpox) and
Mycobacterium tuberculosis (tuberculosis), whereas others
are microorganisms of the normal microbial flora that
cause opportunistic infections only in an immunocompromised host (e.g. Candida infection in a patient with Human
immunodeficiency virus (HIV)), or when the microorganism
is transported to an unprotected site (e.g. bacteraemia
caused by abdominal surgery). See also: Infections in the
Immunocompromised Host; Microorganisms
Thus, whether or not an infectious agent causes disease is
a delicate balance between the genetic (e.g. X-linked
agammaglobulinaemia) or acquired (e.g. patients with acquired immune deficiency syndrome (AIDS) or stressed,
traumatized individuals) immune status of the host and the
virulence of the pathogen (the ability of the microorganism
to destroy immunological barriers and grow at the expense
of host tissue). See also: Immunodeficiency
Some pathogens cause disease by direct tissue destruction.
Staphylococcus aureus produces the enzyme hyaluronidase,
which promotes the spread of the bacteria by destroying
connective tissue. In contrast, an organism such as
Clostridium tetani does not cause significant local symptoms
at the site of inoculation. Instead the muscle cramps known
as tetanus are caused by a toxin secreted into the bloodstream. Many of the symptoms of infection are not related to
the specific microorganism involved. In fact, symptoms such
as fever, exanthema and tumour, rubor and dolor are caused
by the host inflammatory response elicited by the microorganism. Indeed, some diseases are the result of an overvigorous immune response to an otherwise fairly harmless
microorganism (e.g. acute hepatitis caused by hepatitis B
virus). See also: Toxin Action: Molecular Mechanisms
Nonspecific Resistance
Most of the microorganisms in our environment never
cross the epithelial barriers that cover the body surfaces.
. Nonspecific Resistance
. Innate Immune Response: Humoral
. Innate Immune Response: Cellular
. Acquired Immune Response: Humoral (B Cells)
. Acquired Immune Response: Cellular (T Cells)
. Activation of the Most Appropriate Immune Response
to a Given Infectious Agent
. Pathological Sequelae of the Immune Response
. Microbial Evasion from the Host Immune Response
. Regional versus Central Immune Response
doi: 10.1002/9780470015902.a0000478.pub2
Epithelial surfaces function as a physical barrier. Likewise,
mucosal epithelium expels most microorganisms simply by
mucus secretion and ciliary action. The flushing action of
saliva and urine also protects mucosal surfaces. See also:
Skin: Immunological Defence Mechanisms
Epithelial cells also secrete components that actively inhibit colonization with pathogenic microorganisms. For
instance, free fatty acids produced in sebaceous glands together with lactic acid from perspiration and low pH make
the skin a hostile environment to most bacteria. Also, many
of the secreted body fluids (e.g. tears, mucus, saliva) contain microbicidal factors. For example, lysozyme, which
cleaves the peptidoglycan layer of Gram-positive bacteria,
induces bacterial lysis and lactoferrin (an iron-binding enzyme) competes with microorganisms for iron and thereby
inhibit their growth. See also: Lysozyme
Innate Immune Response: Humoral
When a pathogen crosses the epithelial barrier despite the
barrier function of the epithelial surface, the first counterstrike of the immune system is the innate immune response.
This is composed of preexisting antimicrobial molecules
and cells, and is actually capable of defeating most infections at an early stage. Only when innate host defence is
overwhelmed, the induction of an adaptive immune response is required.
The alternative pathway of complement
Complement activation leading to opsonization and killing
of pathogens can occur in three distinct ways. For example,
the classical pathway is dependent on antibody bound to
the surface of the pathogen. It therefore takes approximately 5–7 days to activate the complement system in this
way – the time needed for the adaptive immune system to
mount an effective antibody response. In contrast, the alternative complement pathway is a component of the
ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net
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Immunity to Infection
innate immune system and is activated spontaneously. This
occurs because the protein C3 is constantly cleaved to yield
C3b in the plasma. C3b, in turn, attaches to host or pathogen cells. Host cells, however, are protected against the
final assembly of complement, because they express protective proteins such as decay-accelerating factor and
membrane cofactor of proteolysis. Most pathogens lack
such proteins, and factor P is allowed to bind and stabilize
the components of complement on the surface of the pathogen. Eventually, the terminal complement components
are activated and the pathogen is lysed. See also:
Complement; Complement: Alternative Pathway
Interferons
Human cells have evolved a special strategy to avoid
spread of viral infection. Double-stranded ribonucleic
acid (RNA), which is made during the infectious cycle of
most viruses, induces the synthesis of interferon (IFN)a
and IFNb. These interferons in turn inhibit protein synthesis in local host cells and thereby inhibit viral replication. This is promoted by binding of the interferons to
receptors on neighbouring cells followed by induction of
intracellular enzymes that degrade viral RNA and inhibit
protein synthesis, in part by inactivating the eukaryotic
protein synthesis initiation factor, eIF-2. Interferons also
stimulate an increase in proteasome activity and expression of major histocompatibility complex (MHC) class I
molecules, thereby increasing the processing and presentation of viral antigens which increase the chance of
recognition and killing from cytotoxic CD8 T cells (see
later). See also: Interferons; Major Histocompatibility
Complex (MHC)
Innate Immune Response: Cellular
Whereas preformed effector molecules act immediately on
the pathogen, most cellular responses require a few hours
to respond to a pathogen. Macrophages derived from circulating monocytes are important in coordinating this
early induced immune response. They are found in great
numbers in connective tissue, and in the lung, liver and
spleen. These macrophages express, on their surface, several receptors for so-called microbial-associated molecular
patterns. An important group of such receptors are the
Toll-like receptors (TLR) of which about 10 have been
described to date. For example, bacterial lipopolysaccharide (LPS), which is part of the capsule of Gram-negative
bacteria, is bound to TLR-4 dimer+CD14 on the macrophage. Phagocytosis of the pathogen is often enough to
defeat an infection. However, the interaction between antigen and the TLR on the macrophage leads secretion of
cytokines that are pivotal in the induction of additional
immune responses if necessary. See also: Lipopolysaccharides; Macrophages
The effects of these cytokines (interleukin (IL)-1, IL-6,
IL-8, IL-12 and tumour necrosis factor (TNF)a) are
2
local as well as systemic. Local effects include initiation
of an acute inflammatory response characterized by pain,
redness, heat and swelling. This is in part initiated by
TNFa, which increases vascular permeability to allow
the entry of additional immunoglobulin, complement
and cells at the site of infection and to increase fluid
drainage to lymph nodes. Most cytokines are also involved in the activation and attraction of additional cells
of the immune system, such as neutrophils, lymphocytes
and natural killer (NK) cells. See also: Cytokines;
Tumour Necrosis Factors
The systemic effects of cytokines include the induction of
the acute-phase response and fever. The acute-phase response is initiated when IL-1, IL-6 and TNFa reach hepatocytes. The liver increases the secretion of acute phase
proteins into the blood plasma and suppresses the secretion
of other plasma proteins. C-reactive protein and mannosebinding protein are among the proteins secreted by the liver
during the acute-phase response. These proteins share the
ability to bind specific conserved antigens on fungal and
bacterial cell walls and to activate components of the complement system. This, in turn, facilitates the removal of
pathogens by phagocytes, or causes lysis of the pathogen.
Neutrophil granulocytes make up the first wave of cells
that cross the permeable vasculature at the site of inflammation. Lymphocyte function-associated antigen-1 (LFA-1)
binds intercellular adhesion molecule 1 (ICAM-1) on activated endothelial cells and induces diapedesis of the neutrophil across the endothelial cells. The neutrophil is then
attracted to the infectious site by chemokines and act as very
potent phagocytic effector cells. They are often recruited in
massive numbers and die a few days after they entered the
inflamed tissue.
Some viruses are capable of blocking the synthesis and
transport of MHC class I molecules (Figure 1) to the cell
surface. This makes infected cells susceptible to killing by
natural killer (NK) cells which kill cells that lack expression
of MHC class I molecules on the cell surface. The activity of
NK cells is greatly amplified during an infection when exposed to IFNa, IFNb and IL-12. Particular infections with
herpes viruses and Listeria monocytogenes are known to be
susceptible to NK cell activity. Also, NK cell activation
might be important for the subsequent direction of the
adaptive immune response, since they secrete large
amounts of IFNg, which induces a TH1 response. See also:
Immune Defence: Microbial Interference; Natural Killer
(NK) Cells
Acquired Immune Response: Humoral
(B Cells)
The fundamental difference between the innate and the
adaptive immune systems is the diversity and the capacity
for memory. Recognition mechanisms in the innate immune system are limited to conserved epitopes of pathogens and take generations to develop. This is due to the fact
ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net
Immunity to Infection
Innate immune response
Cells in
antiviral state
IFNα
Adaptive immune response
NK cell
Virus-infected cells
Killing of virus-infected cells
Virus
Macrophage phagocytosing
pathogens
Bacteria
Activation of macrophage
CD4 TH1 cell
Antigen uptake
CD8 T cell
Epithelial
barrier
Dendritic cell
IL-2
Neutrophils
Migration to regional
lymph node
IFNγ
TCR
MHC-I
IL-2
CD28
Cell-mediated
immune
response
IFNγ
B7
B7
CD28
TCR
MHC-II
Antigen-presenting cell
CD4 TH0 cell
IL-2
IL-4
Antibody secretion
TCR
MHC-II
Plasma cell
CD4 TH2 cell
CD40L
CD40
Humoral
immune
response
Naive B cell
Figure 1 Innate and adaptive immune responses. Macrophages, neutrophils and natural killer cells are attracted to the site of pathogen entry. Dendritic
cells take up antigen and migrate to regional lymph nodes. Here antigen presentation to T cells take place, and these differentiate into helper T cells (TH1 or TH2
CD4 T cells) and cytotoxic T cells (CD8 T cells). Activation of B cells and immunoglobulin production are also initiated.
that only receptor molecules encoded by germline deoxyribonucleic acid (DNA) can be employed in innate
immunity. In contrast, adaptive immunity has evolved
the potential for an enormous diversity, because germline DNA can be recombined whenever necessary to encode new antigen receptors, such as immunoglobulin and
the T cell antigen receptor (TCR). At the same time,
adaptive immunity includes the potential for memory.
See also: B Lymphocytes; Epitopes; Immunity: Humoral
and Cellular
Initiation of the adaptive immune response requires the
activation of T cells. This is performed by antigen-presenting cells (APCs) such as macrophages, B cells and in particular dendritic cells (DCs) that are known as professional
APCs. DCs take up antigen at the site of infection, process it,
present it on MHC molecules and transport it to the regional
lymph node where presentation to T cells occurs. Other
kinds of DCs are specialized to store whole antigens on the
surface and in this way present it to B cells in the lymph
nodes. See also: Antigen-presenting Cells; Dendritic Cells
(T-lymphocyte Stimulating); T Lymphocytes: Helpers
Activation of B cells
Circulating B cells express immunoglobulin (Ig) M molecules on the cell surface, the so-called B-cell antigen receptor (BCR). When antigen is bound to a specific B cell, the
sIgM: antigen complex is internalized by endocytosis
and the B cell is activated to secrete IgM. In turn, fragments of antigen are bound to MHC class II molecules
(Figure 2) and transported to the cytoplasmic membrane.
This enables recognition by T helper cells and is important
for the production of immunglobulins with higher affinity
and specificity than IgM. When the B cell receives a
T-cell signal in addition to ligation of the BCR, the B cell in
the germinal centre of a lymph node can undergo extensive
proliferation and somatic hypermutation. The result of
this is the production of high-affinity IgG and the
differentiation of B cells into plasma and memory cells.
See also: B Lymphocytes; B Lymphocytes: Receptors;
Clathrin-coated Vesicles and Receptor-mediated Endocytosis; Germinal Centres; Lymphocytes: Recirculation;
T-lymphocyte Activation
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Immunity to Infection
MHC class I molecule
MHC class II molecule
CD4 T cell
NK cell
Primed CD8 T cell
TCR
KIR
Inhibition of NK cell
TCR
CD4
CD8
Initiation of
cytotoxicity
Cell surface
Endoplasmatic
reticulum
TAP transporter
Empty
MHC-I molecule
MHC-I
with peptide
molecule
Antigenic
protein
Cell surface
Internalization
of extracellular
antigen
Fusion of vesicles
containing antigenic
peptide with vesicles
containing MHC-II
molecules
Endoplasmatic
reticulum
Empty MHC-II
molecule
Antigenic peptides
Proteasome
Intracellular antigen
Figure 2 Major histocompatibility complex molecules. MHC class I molecules present peptides derived from intracellular antigens to CD8 T cells. Also
the presence of MHC-I molecules on the cell surface prevents attack by natural killer cells. In contrast, MHC class II molecules present peptides from extracellular
antigens and present these to CD4 T cells.
Antibodies of different isotypes have
different effector functions
The different immunoglobulin isotypes exert different
effector functions in the humoral immune response. IgM
is the first antibody produced during an immune response
and comprises 5–10% of the total immunoglobulin pool.
This antibody is produced before the B cell undergoes somatic hypermutation and is therefore of low affinity. However, IgM forms pentameric molecules, and the many
antigen-binding sites confer high avidity instead. Because
of the large size of the pentamers, IgM is primarily found in
the blood. Here it provides first-line immunity against bacteria with cell wall polysaccharides because IgM promotes
effective bacteriolysis through activation of the classical
complement system. See also: Antibody Classes; Somatic
Hypermutation in Antibody Evolution
B cells undergo somatic hypermutation in germinal centres of lymph nodes and switch to IgG production. The
benefit of this process is the high affinity of the IgG molecule and the initiation of various effector functions by the
Fc domain of the antibody. IgG is a monomeric molecule
which readily diffuses out of the bloodstream into the tissues. It comprises approximately 85% of the immunoglobulin pool and is involved in processes such as neutralization
of bacterial toxins and viruses. In particular, IgG1 is involved in a process called opsonization. When antibody is
bound to a pathogen, such as a bacterium or parasite, the
4
Fc domain is recognized by various effector cells such as
macrophages and neutrophils which then generate toxic
products and initiate phagocytosis. If the pathogen is
coated with IgG1 or IgG3, it can also be destroyed by antibody-dependent cell-mediated cytotoxicity (ADCC). In
this process, NK cells bearing the Fc receptor FcgRIII
(CD16) bind the Fc domain, and this triggers a cytotoxic
attack that destroys the target. See also: Antibodydependent Cell-mediated Cytotoxicity (ADCC); Fc Receptors; Immunoglobulin Gene Rearrangements; Phagocytosis: Enhancement
IgA exists both as a serum immunoglobulin and as a
secretory immunoglobulin (sIgA). sIgA binds to a receptor
on epithelial cells and is transported across the epithelial
barrier into, for example, intestinal and respiratory secretions, saliva and tears. Here it prevents attachment of bacteria or toxins to the epithelial cells and is thus a major
component of mucosal immunity.
IgE comprises less than 1% of the total immunoglobulin
pool. It is important in infections with large parasites such as
helminths, where eosinophils recognize the Fc domain of
IgE bound to the parasite and release toxic proteins such as
major basic protein. See also: Immunity to Parasitic Worms
Memory in the humoral immune response
The benefit of the adaptive immune response is the induction of memory and thereby potential lifelong immunity.
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Immunity to Infection
When the individual is challenged with the pathogen a second time, specific antibody is already present and can prevent the pathogen from entering the epithelial surfaces.
Also, an already immunized host does not need to wait for
the adaptive immune response to be primed, and the reactivation of the adaptive immune system during a second
exposure to antigen is much faster than the primary immune response and the affinity of the antibody increases
with each challenge to a pathogen. See also: Immunological
Memory
However, for the T cell to be activated, the APC must express B7 molecules, which bind the costimulatory molecule
CD28 on the T cell. This process, called priming, is therefore most efficient when dendritic cells are involved. In
contrast, after priming, the armed effector T cells and
memory cells can respond to target cells expressing the relevant MHC molecules, without colligation of CD28.
See also: Major Histocompatibility Complex: Interaction
with Peptides; T-cell Receptors
Major histocompatibility complex molecules
Acquired Immune Response: Cellular
(T Cells)
T cells are pivotal in the activation and control of the
adaptive immune response. The production of T cells takes
place in the bone marrow, where after they undergo positive and negative selection in the thymus and then start
circulating in the lymph and bloodstream as naı̈ve CD4 and
CD8 T cells. As with naı̈ve B cells, these T cells must encounter antigen to proliferate and differentiate. Hence,
CD8 T cells become CD8 cytotoxic T cells. CD4 T cells are
Thelper (TH) cells and can differentiate into either TH1
cells, which are involved in the activation of macrophages,
or TH2 cells, which activate B cells to produce antibody
(Figure 1). As a part of the adaptive immune system, T cells
have the capability of memory function. See also:
T Lymphocytes: Cytotoxic; T Lymphocytes: Helpers
Antigen presentation to T cells
Macrophages and B cells are able to present antigen to
T cells. However, dendritic cells are by far the most effective
cells in this event, and are also called professional APCs
because they upon activation upregulate an abundance of
costimulatory molecules which is needed for effective
priming of T cells. DCs take up antigen by pinocytosis
and phagocytosis, process it and present it to T cells as
peptide antigens in combination with MHC molecules.
Antigen uptake and activation of DCs take place in the
periphery, where they are activated by inflammatory
cytokines and binding of microbial-associated molecular
patterns to TLR. The activation also leads to induction of
chemokine receptors necessary for the migration through
lymph vessels to the lymph node, where activation of
T cells take place (Figure 1). See also: Antigen Presentation
to Lymphocytes; Dendritic Cells (T-lymphocyte Stimulating); Lymph Nodes; T Lymphocyte Responses:
Development
All T cells express the TCR. The TCR recognizes MHC
molecules in combination with the relevant antigen on the
surface of either the APC or the target cell. CD8 on CD8 T
cells restricts this binding to MHC class I molecules,
whereas CD4 on CD4 T cells restricts the binding to MHC
class II molecules (Figure 2), which is only present on APCs.
MHC class I molecules are expressed on the cell surface of
all nucleated cells and consist of a heavy chain noncovalently bound to b2-microglobulin and a peptide. These
molecules are specialized in presenting antigens from intracellular pathogens, such as viruses, to CD8 T cells. Cellular proteins are constantly renewed. Old proteins are then
degraded by proteolytic enzymes called proteasomes.
Some of the resulting peptide fragments are transported
to the endoplasmic reticulum by transporters associated
with antigen processing (TAPs). Here peptide, b2-microglobulin and heavy chain assemble and the fully folded
MHC class I molecule is transported to the cell surface
(Figure 2). During a viral infection, viral peptides dominate
and will bind to the MHC class I molecule. See also:
Antigen Processing; Major Histocompatibility Complex:
Human
The MHC class II molecule consists of an a and a b
subunit and, like the MHC class I, binds an antigenic peptide. However, MHC class II molecules are expressed only
on APCs, and present exogenously derived peptides.
Antigen is taken up into intracellular vesicles of the APCs
and degraded by the low pH in lysosomes. Somewhere
along the route of intravesicular transport, the vesicle containing antigen fragments fuses with a vesicle containing
newly synthesized MHC class II molecule. This allows the
MHC class II molecule to bind an antigenic peptide and be
transported to the cell surface, so making recognition by
CD4 T cells possible (Figure 2). See also: Major Histocompatibility Complex: Interaction with Peptides
CD4 T cells
When a naive CD4 T cell responds to a peptide: MHC class
II complex, it initiates an autocrine secretion of IL-2, begins to proliferate and can either become a TH1 or a TH2
cell, depending on the infectious agent and the cytokines
produced by the innate immune response. This step in
T-cell differentiation determines whether a humoral or a
cell-mediated immune response will predominate. TH1 cells
are specialized in the activation of macrophages. As a part
of the innate immune response, macrophages engulf pathogens and present antigenic peptides in combination with
MHC class II molecules. When recognizing the antigen
presenting macrophage, TH1 cells secrete cytokines such as
IFNg, granulocyte–macrophage colony-stimulating factor
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Immunity to Infection
(GM–CSF) and TNF, which activate the infected macrophage to increase the production of antibacterial agents
such as nitric oxide and oxygen radicals. In contrast, TH2
cells are specialized for B-cell activation. The B cell internalizes antigen through sIg, and the antigenic peptides are
presented in combination with MHC class II molecules. In
turn, TH2 cells binds the CD40 molecule at the surface of
the antigen bearing B cell and start to secrete cytokines such
as IL-4, IL-5 and IL-6, which stimulate B-cell proliferation
and differentiation (Figure 1) and thus a humoral immune
response. In addition to TH1 or a TH2 cells, it has recently
been demonstrated that a third subset of CD4+ T cells
exist, namely the TH17 cell which secretes high amounts of
IL-17. These cells are now known to be important in
chronic infections or chronic autoimmune diseases.
See also: Macrophages; T Lymphocytes: Helpers
Not all CD4 T cells are effector cells. Also, regulatory
cells exist that are known to dampen immune responses or
prevent activation of autoreactive T cells in the periphery.
Here, natural occurring CD4+CD25+ regulatory T cells
have attracted much attention and are the best studied
subset of regulatory T cells.
CD8 T cells
Cytotoxic CD8 T cells are pivotal in the destruction of
virally infected cells. When a primed CD8 T cell recognizes
a viral peptide in combination with a MHC class I molecule, it starts secreting perforin and granzymes. Perforin is
inserted into the membrane of the infected target cell and
promotes cell lysis, whereas the granzymes activate intracellular proapoptotic enzymes known as caspases in the
target cell. In addition, many CD8 T cells express Fas ligand on their surface. If the target cell expresses Fas, it will
initiate an additional cascade of proapoptotic molecules
and die by programmed cell death (apoptosis). See also:
Immunological Cytotoxic Factors; T Lymphocytes:
Cytotoxic
Activation of the Most Appropriate
Immune Response to a Given
Infectious Agent
Infectious agents can be divided into intracellular or extracellular bacteria, fungi, viruses and parasites and elicit
different kinds of immune response (Table 1). Again, the
differentiation of CD4 T cells into either TH1 or TH2 cells is
pivotal in the induction of either a primarily humoral or a
primarily cell-mediated immune response.
Intracellular bacteria such as mycobacteria evade the
immune system by hiding inside macrophages. In this case
a cell-mediated immune response is the best choice, since
the bacteria are protected from antibody. Activated TH1
cells enhance the ability of macrophages to kill the mycobacteria. Similar, intracellular parasites are best defeated
by a TH1 response. A special mechanism in the immune
response to intracellular bacteria is the formation of a
granuloma formed by giant and epithelioid cells. See also:
Immune Mechanisms Against Intracellular Pathogens
In contrast, extracellular bacteria are best defeated by
antibody in combination with complement activation,
ADCC and phagocytosis of the opsonized pathogen. Thus,
extracellular bacteria usually elicit a humoral immune response with the predominance of TH2 cells. See also:
Immune Mechanisms Against Extracellular Pathogens
The nature of the pathogen itself actually tends to determine the outcome of the adaptive immune response.
Macrophages and dendritic cells are stimulated in the early
phase of the infection by microbial-associated molecular
patterns to produce various cytokines. In turn, the combination of these cytokines influences the differentiation of
T cells and thus the induction of either a cell-mediated or a
humoral immune response. It has been shown that some
bacteria (e.g. Listeria) stimulate macrophages to secrete
IL-12, which in turn commits the CD4 T cell to differentiate
into TH1 cells. Also, the cytokines that commit this differentiation inhibit the differentiation of CD4 cells into TH2
Table 1 Immune responses to infectious agents
Neutrophils
Eosinophils
Macrophages
Natural killer cells
CD8 T cells
CD4 TH1 cells
IgM
IgG
IgA
IgE
Complement
Extracellular
bacteria
Intracellular
bacteria
Viruses
Fungi
Parasites
++
2
+
2
2
2
++
++
++
2
++
2
2
+
2
2
+
2
2
2
2
2
2
2
+
+
++
++
2
++
+
2
2
2
2
+
2
2
2
2
+
+
2
2
2
++
–
2
2
2
2
+
+
++
2
Note: TH, T helper; Ig, immunoglobulin. ++, very important component in the defence to the pathogen; +, important; –, less important.
6
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Immunity to Infection
cells, and vice versa. Interestingly, the balanced secretion of
cytokines also determines the predominance of effector cell
or regulatory T-cell activation. For example, a combination of TGFb and IL-6 secretion from APCs induces TH17
effector cells and at the same time turns off the function of
CD4+CD25+ regulatory T cells. See also: Cytokines;
Immune Mechanisms Against Intracellular Pathogens
The MHC affinity and TCR avidity of the antigen influences CD4 T-cell differentiation. In general, antigenic
peptides that are in abundance and cause a strong
TCR:MHC class II interaction stimulate a cell-mediated
immune response, whereas antigenic peptides that are less
likely to produce strong TCR:MHC class II interactions
stimulate a humoral immune response.
Viral infections produce a mixed TH1 and TH2 response,
but the TH1 response often dominates. CD8 T cells are
pivotal in controlling viral infections because they destroy
the viral reservoir contained in infected cells.
Pathological Sequelae of the Immune
Response
TNFa is a striking example of the balance between lifesaving actions and wasting, disastrous effects of the immune system. On the one hand, TNFa causes the activation
of endothelial cells, necessary to allow sufficient leucocytes
and lymphocytes to enter the site of infection and remove
the pathogen. On the other, if TNFa is secreted in excess
into the bloodstream, as seen in sepsis with Gram-negative
bacteria, systemic oedema follows and the patient may go
into shock. Eventually, disseminated intravascular coagulation, multiple organ failure and death ensue. Paradoxically, the fatal outcome is not so much due to bacteria in the
bloodstream as to the devastating effect of the systemic
TNFa production by the immune system. See also:
Septicaemic Shock; Tumour Necrosis Factors
Several other examples of such overreaction of the immune system exist and can be divided into the categories of
type I–IV hypersensitivities. See also: Hypersensitivity:
Immunological
Type I hypersensitivity is caused by IgE. The Fc domain
of this immunoglobulin is bound to mast cells. When IgE is
crosslinked by an antigen, reactions such as vasodilatation,
chemotaxis and smooth muscle contraction occur because
of the release of cytokines, histamine, proteases, prostaglandins, etc. This is an important event in the acute inflammatory response. However, when exaggerated,
asthmatic episodes and even anaphylactic shock may ensue because of vasodilatation. The most dramatic example
of this is the rupture of a hydatid cyst caused by larvae of
Echinococcus granulosus. Because of previous sensitization
with IgE, the sudden release of large amounts of antigen
causes an acute anaphylactic shock. See also: Hypersensitivity: Anaphylactic (Type I)
Type II hypersensitivity is caused by antibody that binds
specific cell surface molecules. Autoantibodies are actually
produced during a number of infections, but they rarely do
any harm. However, a classical example of disease is the
pancarditis sometimes observed after a streptococcal infection. In this case, group A b-haemolytic streptococci
express an antigen that is also expressed in the myocardium. See also: Autoimmune Disease: Pathogenesis;
Hypersensitivity: Antibody-mediated Cytotoxic (Type II)
Type III hypersensitivity is the result of deposition of
circulating immune complexes. When large amounts of
antigen exist in the blood, the antigen eventually forms
complexes with antibodies and is deposited in capillaries
and connective tissue. Here, the immune complexes activate the classical complement pathway and attract a
number of inflammatory cells. Again, streptococcal infection is an example of postinfective allergic reactions, here in
the form of the acute glomerulonephritis sometimes observed 2–3 weeks following infection. See also: Antigen–
Antibody Complexes; Hypersensitivity: Immune Complex
Mediated (Type III)
Type IV hypersensitivity is also known as cell-mediated
hypersensitivity and includes the formation of granuloma
and delayed-type hypersensitivity responses with the involvement of CD4 T cells, CD8 T cells and macrophages.
Immune responses involving these cells often cause tissue
damage, which leads to fibrosis and calcification. See also:
Hypersensitivity: T Lymphocyte-mediated (Type IV)
Microbial Evasion from the Host
Immune Response
The human immune system today is the result of millions of
years of coevolution with pathogens. Similarly, in order to
survive, pathogens must constantly evolve new strategies to
escape from the immune response. Many bacteria and viruses have a tremendous capacity for mutation. For instance, the influenza virus constantly introduces new point
mutations in the genes encoding the surface proteins, haemagglutinin and neuraminidase. This process is termed
antigenic drift and underlies the influenza epidemics seen
every 2–3 years, when the mutated virus is no longer recognized by the immune response elicited by the previous
virus strain. See also: Antigenic Variation in Microbial
Evasion of Immune Responses, Immune Response: Evasion and Subversion by Pathogens; Influenza Viruses
The parasites known as African trypanosomes have
evolved such antigen variation to virtuosity. The parasite is
covered by a variant surface glycoprotein. Although only
one variant is expressed on the surface, the genome actually
encodes about 1000 variants of the protein. When antibodies are raised against the first variant, a few parasites
have already begun expressing a new variant. The parasite
is therefore rarely cleared by the immune system. See also:
Trypanosomiases; Trypanosoma
Many viruses have evolved a number of advanced strategies for interference with antigen presentation which have
only recently been discovered. For instance, the E3 protein
ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net
7
Immunity to Infection
of adenovirus type 2 can form complexes with MHC molecules, thereby preventing correct glycosylation and transport to the cell surface. Also, proteins of viruses such as
Herpes simplex virus (HSV) and Cytomegalovirus (CMV)
have been shown to inhibit the function of TAP transporters (Figure 2), thus interfering with the binding of antigenic
peptides to MHC class I molecules. See also: Adenoviruses;
Immune Defence: Microbial Interference
The ultimate counterstrike against the immune system is
observed with HIV. By depleting CD4 cells, the virus not
only inhibits the immune response against the virus itself,
but also against a number of opportunistic pathogens, such
as Candida, mycobacteria, Pneumocystis carinii and CMV.
This is actually what causes the death of the patient with
AIDS. See also: AIDS: Clinical Manifestations
effective way to increase the capacity of the innate immune
response. Several of these cytokines also bind to receptors
in the central nervous system. Thus, IL-1 both acts
as a pyrogen, regulating the hypothalamus to increase
body temperature, and also stimulates increased adrenocorticotrophic hormone (ACTH) secretion. Although
poorly understood, the effect of fever might be to destabilize some pathogens. For instance, many viruses (including HSV) stop replicating at temperatures above 378C. The
increase in ACTH secretion leads to increasing plasma cortisol levels, which influences the conversion of protein to
glucose, which is crucial in fasting individuals including
those suffering from serious infections. In addition, cortisol
has a number of anti-inflammatory functions, probably
involved in limiting tissue damage during the inflammatory
response. See also: Acute-phase Proteins
Regional versus Central Immune
Response
Further Reading
Most effector systems of the immune response take place in
direct proximity to the pathogen. Granulocytes, macrophages and lymphocytes are attracted to the site of infection
by chemotaxis, and the priming of T cells and antibody
production take place in the regional lymph nodes.
See also: Lymph Nodes; Lymphoid System
Very early in the immune response, several cytokines,
including IL-1, IL-6 and TNF, are produced that trigger
central reactions to the infection. As mentioned earlier,
production of acute-phase proteins by the liver is an
Cresswell P (1995) Assembly transport and function of MHC class
II molecules. Annual Review of Immunology 12: 259–293.
Janeway CA and Travers P (2005) Immunobiology, 6th edn. New
York: Garland.
Murray PR, Rosenthal KS, Kobayashi GS and Pfaller MA (1998)
Medical Microbiology, 3rd edn. St Louis, MO: Mosby Yearbook.
Paul WE (2003) Fundamental Immunology, 5th edn. New York:
Lippincott-Raven.
Ploegh HL (1998) Viral strategies of immune evasion. Science 280:
248–253.
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ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net