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Topic 1: Introduction to the Immune System

The immune system has evolved to protect us from pathogens. Intracellular pathogens infectindividual cells (e.g. viruses), whereas extracellular pathogens divide extracellularly within tissues or

the body cavities (e.g. many bacteria). Phagocytes and lymphocytes are key mediators of immunity. Phagocytes internalize pathogens and

degrade them. Lymphocytes (B and T cells) have receptors that recognize specific molecular

components of pathogens and have specialized functions. B cells make antibodies, cytotoxic T

lymphocytes (CTLs) kill virally infected cells, and helper T cells coordinate the immune response by

direct cellcell interactions and the release of cytokines.

Specificity and memory are two essential features of adaptive immune responses. As a result theimmune system mounts a more effective response on second and subsequent encounters with a

particular antigen. Nonadaptive (innate) immune responses do not alter on repeated exposure to an

infectious agent.

Antigens are molecules that are recognized by receptors on lymphocytes. B cells usually recognizeintact antigen molecules, whereas T cells recognize antigen fragments on the surface of other cells.

An immune response occurs in two phases antigen recognition and antigen eradication. In thefirst phase clonal selection involves recognition of antigen by particular clones of lymphocytes,

leading to clonal expansion of specific clones of T and B cells and differentiation to effector and

memory cells. In the effector phase, these lymphocytes coordinate an immune response, which

eliminates the source of the antigen.

Vaccination depends on the specificity and memory of adaptive immunity. Vaccination is based onthe key elements of adaptive immunity, namely specificity and memory. Memory cells allow the

immune system to mount a much stronger response on a second encounter with antigen.

Inflammation is a response to tissue damage. It allows antibodies, complement system molecules,and leukocytes to enter the tissue at the site of infection, resulting in phagocytosis and destruction

of the pathogens. Lymphocytes are also required to recognize and destroy infected cells in the

tissues.

The immune system may fail (immunopathology). This can lead to immunodeficiency,hypersensitivity, or autoimmune diseases.

Normal immune reactions can be inconvenient in modern medicine , for example blood transfusionreactions and graft rejection.

1. Adaptive and innate immunityAny immune response involves, firstly, recognition of the pathogen or other foreign material, and

secondly, mounting a reaction against to eliminate it. There are two different types of immuneresponse:

Innate or not-adaptive immune responses Adaptive immune responses

The important difference between these is that an adaptive immune response is highly specific for a

particular pathogen and improves with each successive encounter with the same pathogen: in effect the

adaptive immune system remembers the infectious agent and can prevent it from causing disease

later. So the two key features of the adaptive immune response are thus specifity and memory.

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2. AntigensAntigens or immnunogen are molecules that initiate adaptive immune responses (e.g. components of

pathogenic organisms), generating antibodies. Antigen molecules each have a set of antigenic

determinants, also called epitopes. Epitopes are molecular shapes recognized by antibodies and T-cell

receptors of the adaptative immune system. Each antibody receptor recognizes one epitope rather than

the whole antigen. Ever simple microorganisms have many different antigens which may be protein,

lipid or carbohydrate.

Antigens are the initiators and driving forces of all adaptive immune responses. The immune system

has evolved to recognize antigens, destroy them, and eliminate the source of their production. When

antigen is eliminated, immune responses switch off. Both T cell receptors and immunoglobulin

molecules (antibody) bind to their cognate antigens with a high degree of specificit (T cells use their

antigen-specific receptors (TCRs) to recognize the antigenic peptides bound to MHC molecules

expressed on the surface of the antigens).

T cells recognize antigens that originate within other cells, such us as viral peptides frominfected cells. They do this by binding specifically to antigenic peptides presented on the surface

of the infected cells by molecules encoded by the major histocampatibility complex (TCRs) to

recognize the unique combination of MHC molecule plus antigenic peptide. Unlike B cells, whichrecognizes is made up of residues from the MHC molecule and the antigen peptide.

MHC (major histocompatibility complex) a genetic region found in all mammals, encodingmore than 100 genes. Class I and class II molecules are primarily responsible for transporting

peptide antigens to the surface of a cell for recognition by T cells. Recognition of MHC class I

and II molecules also underlies graft rejection.d

Clonal selection involves proliferation of cells

that recognize a specific antigen

Each antibody-producing cell (B cell) is programmed to

make just one antibody, which is placed on its surface

as an antigen receptor (B cell in this example). In this

way these cells are stimulated to proliferate and

mature into antibody-producing cells, and the longer-

live memory cells, all having the same antigen-binding

specifity.

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Topic 2: Cells involved in the Immune Response

Many cells of different lineages are adapted to carry out specialized functions in the immuneresponse.

B and T lymphocytes express specific antigen receptors and other surface molecules (markers)important for their different functions.

Antigen-preenting cells are required by T cells to enable them to respond to antigens. Blymphocytes recognize native antigens not processed and presented by other cells.

There are functional subpopulations of T lymphocytes which have heper, suppressor andcytotoxic activities.

New surface molecules appear on lymphocytes following activation by specific antigens. Phagocytic cells with specific surface markers are found in the circulation (monocytes and

granulocytes) and reside in tissues (e.g. Kupffer cells in the liver).

1. Origin of cells involved in the immune response

All hemopoietic cells are derived from pluripotent stem cells which give rise to two main lineages:

One for lymhoids cells: the common lymphoid progenitor has the capacity to differentiate intoeither T cells or B cells depending on the microenvironment to which it homes. In mammals, T

cells develop in the thymus while B cells develop in the fetal liver and bone narrow. The precise

origin of some antigen-presenting cells (APCs) is uncertain, although they do develop ultimately

from the haemopoietic stem cells. NK cells also derive from the common lymphoid progenitor

cells. Lymphocytes recirculate through secondary lymphoid tissues.

And the other for myeloid cells: myeloid cells differentiate into committed cells whosecollective name is granulocytes, and are formed by cells eosinophils, neutrophils andbasophils.

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Moreover also find:

Platelets produced by megakaryocytes are released into the circulation. Blood platelets are notcells, but cell fragments derived from megakaryocytes in the bone marrow. They contain

granules, microtubules, and actin/myosin filaments, which are involved in clot contraction.

Platelets are also involved in immune responses, especially in inflammation. Monocytes, cells of the mononuclear phagocytic system are found in virtually all organs of the

body where the local microenvironment determines their morphology and functional

characteristics (e.g. in the lung as alveolar macrophages and in the liver as Kupffer cells). The

main role of the mononuclear phagocytes is to remove particulate matter of foreign origin

(e.g.microbes) or self origin (e.g. aged erythrocytes).

Myeloid progenitors in the bone marrow differentiate into pro-monocytes and theninto circulating monocytes, which migrate through the blood vessel walls into organs

to become macrophages.

Mast cells (mastocyte) is a resident cell ofseveral types of tissues and contains many

granules rich in histamine and heparin.

Although best known for their role in allergy

and anaphylaxis, mast cells play an

important protective role as well, being

intimately involved in wound healing and

defense against pathogens.

Interdigitating cells and dendritic cells act asantigen-presenting cells (APCs) in secondary

lymphoid tissues.

APCs (antigen-presenting cells):a variety of leucocytes that carry

antigen in a form that can

stimulate lymphocytes.

Bone marrow-derived APCs are found especially in

lymphoid tissues, in the skin, and in mucosa. APCs in

the form of Langerhans cells are found in the

epidermis and are characterized by special granules

(the tennis racquet-shaped Birbeck granules; not

shown here). Langerhans cells are rich in MHC class II

molecules, and carry processed antigens. They

migrate via the afferent lymphatics (where they

appear as veiled cells) into the paracortex of the

draining lymph nodes. Here they make contact with T

cells. These interdigitating dendritic cells (IDCs),

localized in the T cell areas of the lymph node,

present antigen to T helper cells. Antigen is exposed

to B cells on the follicular dendritic cells (FDCs) in the

germinal centers of B cell follicles. Some

macrophages located in the outer cortex and

marginal sinus may also act as APCs. In the thymus,

APCs occur as IDCs in the medulla. (HEV, highendothelial venule).

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Topic 3: The Lymphoid System

Lymphoid organs and tissues are either primary (central) or secondary (peripheral). Thymus andbone marrow are the primary lymphoid organs.

Lymphocytes differentiate from stem cells in the primary organs but migrate to, and function in,secondary organs and tissues.

The systemic lymphoid system includes the spleen and lymph nodes. The mucosal systemincludes all the lymphoid tissues associated with mucosal surfaces.

Peyers patches are organized collections of lymphoid tissue present in the wall of the smallintestine which process antigens present in the gut.

The peripheral lymphoid tissues are equipped with phagocytic cells and other accessory cellsthat assist the function of T and B lymphocytes located there.

Lymphocytes are not sessile there is continuous lymphocyte traffic from the blood stream intolymphoid tissues and back again into the blood via the thoracic duct.

Primary lymphoid organs: Thymus and bone marrow are the primary (central) lymphoidorgans. They are the sites of maturation for T and B cells, respectively.

It is in the primary lymphoid organs that lymphocytes acquire their repertoire of specific

antigen receptors to cope with antigenic challenges received during thir lifespans. The cells are

selected for tolerance to autoantigens and are therefore capable of recognizing only non-self

antigens when the cells are in the periphery.

Cellular and humoral immune responses occur in the secondary (peripheral) lymphoid organs and

tissues.

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Secondary lymphoid organs: can be classified according to the body regions they defend. The spleen responds predominantly to blood-borne antigens. Lymph nodes mount immune responses to antigens circulating in the lymph, entering

through the skin (subcutaneous lymph nodes) or through mucosal surfaces (visceral

lymph nodes).

Tonsils, Peyers patches, and other mucosa-associated lymphoid tissues (MALT) (blueboxes) react to antigens that have entered via the surface mucosal barriers.

The bone marrow is both a primary and a secondary lymphoid organ because it gives rise to B and NK

cells, but is also the site of B cell terminal differentiation (long-lived plasma cells).

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Topic 4: Antibodies and their Receptors

Circulating antibodies recognize antigen in serum and tissue fluids. There are 5 classes of antibody: IgG,

IgA, IgM, IgD and IgE.

Immunoglobulins have a basic unit of two light chains and two heavy chains. The heavy chains differ

between classes: IgA and IgM occur as oligomers of the four chain unit. The chains are folded into

discrete regions called domains. There are two domains in the light chain and four or five in the heavy

chains, depending on their class.

Immunoglobulin fragments may be produced by proteolytic cleavage. These are useful experimentally

and therapeutically. Papain generates two antigen binding (Fab) fragments and one Fc fragment from

each IgG molecule whereas pepsin produces a large F(ab)2 fragment containing both antigen-binding

sites.

Hypervariable regions form the antigen-binding sites. There are three such regions in the Vdomains of each light and heavy chain. The folding of the domains causes them to be clustered

at the distal tips of the molecule, producing two antigen-binding sites for each four chain unit.

All antibodies are bifunctional, because they exhibit one or more effector functions in addition to

antigen binding. These biological activities are localized to sites that are distant from the antigen binding

sites (mostly in the Fc region).

Immunoglobulin receptor molecules are expressed by mononuclear cells, neutrophils, NK cells,

eosinophils and mast cells. They interact with the Fc regions of different classes of immunoglobulins and

promote activities such as phagocytosis, tumor cell killing and mas cell degranulation. Most of these Fc

receptors are members of the immunoglobulin superfamily and have two or three extracellular

immunoglobulin domains.

Antibody receptors

There are three classes of cell surface receptor for

IgG (FcR) are defined in humans:

FcRI (CD64); FcRII (CD32); and FcRIII (CD16).

Each receptor is characterized by a glycoprotein

chain that binds to antibody and has extracellular

domains homologous with immunoglobulin domains

that is; they belong to the immunoglobulin

superfamily, as do receptors for IgA (FcR) and IgE

(FcRI).

FcRs are expressed constitutively on a variety of

cell types and may be upregulated or induced by

environmental factors (e.g. cytokines).

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Biological activation results from cross-linking of the FcR and consequent aggregation of

immunoreceptor tyrosine-based activation (ITAM) or immunoreceptor tyrosine-based inhibitory (ITIM)

motifs in the cytoplasmic sequences.

Phosphorylation of the ITAM motif triggers activities such as:

phagocytosis; antibody-dependent cell-mediated cytotoxicity (ADCC); mediator release; and enhancement of antigen presentation.

Receptors for Fcin humans belong to the immunoglobulin superfamily, and have either two or three

extracellular immunoglobulin domains. Motifs (ITAM, ITIM) on the intracellular segments or on

associated polypeptides are targets for tyrosine kinases involved in initiating intracellular signaling

pathways.

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Topic 5: T-Cell Receptors and MHC Molecules

The T-cell antigen receptor (TCR) is a disulphide-linked heterodimetric (either or ) glycoprotein

that enables T cells to recognize a diverse array of antigens. It is associated at the cell surface with a

complex of polypeptides known collectively as CD3.

The major histocompatibility complex (MHC) encodes two sets of highly polimorfic cell surface

molecules, termed HCM class I and HMC class II. The TCR recognizes processed antigen as peptide

fragments bound to MHC class I or class II molecules. Both MHC and peptide residues associate with the

TCR.

A peptide binding cleft is formed by the folding of an MHC molecule. This accommodates peptides that

have been processed by the cell, to be presented to T cells. Peptides of 8 or 9 residues can bind to class I

molecules, whereas longer peptides can bind to class II molecules.

Binding pockets within the clefts are able to accommodate different peptides depending on the

haplotype. Since MHC molecules are highly polymorphic, and since a cell can express several different

MHC molecules, this explains how the cell can present many different antigenic peptides to a T cell.

T-Cell receptors

Antigen recognition by T lymphocytes is central to the

generation and regulation of an effective immune

response.

It was called TCR (or TCR) because it was a

heterodimeric molecules comprising an chain and a

chain linked by a disulphide bond.

The or heterodimers must associate with a series

of polypeptide chains collectively termed the CD3

complex for the antigen-binding domains of the TCR to

form a complete, functional receptor that is stably

expressed at the cell surface and is capable of

transmitting a signal upon binding to antigen. The four

members of the CD3 complex (, , , and ) are

sometimes termed the invariant chains of the TCR

because they do not show variability in their amino acid

sequences.

Organization of the TCR complex

The TCR and (or and ) chains each comprise an external V and C domain, a transmembrane

segment containing positively charged amino acids, and a short cytoplasmic tail. The two chains are

disulfide linked on the membrane side of their C domains. The CD3 , , and chains comprise an

external immunoglobulin-like C domain, a transmembrane segment containing a negatively charged

amino acid, and a longer cytoplasmic tail. A dimer of , , or is also associated with the complex.

Several lines of evidence support the notion that the TCRCD3 complex exists at the cell surface as a

dimer. The transmembrane charges are important for the assembly of the complex. A plausible

arrangement that neutralizes opposite charges is shown.

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Topic 6: The Generation of Diversity

The immune system is able to recognize and respond to many antigens by generating greatdiversity in the antibodies produced by the B cells, and in the antigen receptors expressed by T cells.

Immnoglobulins are composed of heavy and light chains, the light chains being either or. Thenumber of possible antigen-binding sites is the product of the number of heavy and light chains.

Inmmnoglobulin light chains are encoded by V and J gene segments; heavy chains are also encodedby V and J segment genes with additional diversity provided by the D gene segment.

Diversity is achieved by the recombination of a limited number of V, D and J gene segments toproduce a vast number of variable domains.

Immunoglobulin heavy and light chains undergo structural modifications after antigen stimulation,called somatic mutation. This does not occur with T-cell receptor.

The TCR is generated by flour different sets of genes: and genes are expressed in the majority ofperipheral T cells; and genes are expreseed in a subpopulation of thymic T cells and in a minor

population of peripheral T cells.

Diversification of TCR receptor also occurs by recombination between V, D and J gene segments,with minor variations in detail for each locus.

Recombination of V, D and J gene segments for both immunoglobulin and T-cell receptors iscontrolled, at least in part, by two recombination activating genes (RAG-1 and RAG-2).

In addition to simple conbinations of V,D and J regions , diversity in the TCR and immunoglobulinsdepends upon N-region diversification, joining-site variation and multiple D regions.

Immunoglobulin class switching involves recombination of VDJ genes with various C region genesand differential RNA splicing.

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Topic 7: Antigen Recognition

Antibodies are highly specific for three-dimensional conformation of eptopo.

Antibody affinity is a measure of the strength of the bond between an antibodys combiningsite and a single epitope. The functional affinity or avidity of the interaction also depends onthe number of binding sites on the antibody and their ability to react with multiple epitopes on

the antigen

T cells recognize cell-bound antigen in association with MHC class I or class II molecules. Peptide

fragments from processed antigen bind to grooves of MHC antigens.

MHC class I and class II molecules present peptides derived, respectively, from endogenousand exogenous antigens. This is reflected by the intracellular site which processed antigen

accesses and binds to the MHC molecules.

Peptides that bind to MHC class I molecules are produced in the cytoplasm, probably due tothe activity of an intracellular organelle called a proteosome. Peptides are transported across

the endoplasmtico reticulum by an ABC family transporter. The ternary complex of class I

heavy chain/2- microglobulin/peptide moves to the cell surface.

Peptides that bind to class II molecules are derives from endocytosed exogenous antigenwhich has been processed in an endosoma/lysosomal compartment. Class II molecules

complexed with invariant (Li) chain are transported through the Golgi complex to an acidic

endosomal compartment, where dissociation of Li and peptide loading occurs.

Peptide-MHC molecule complexes on the cell surface can be recognized by a specific T-cellreceptor. However, a variety of additional interactions involving accessory molecules are

required for T-cell activation.

1. Antibodies form multiple non-covalent bonds with antigenThe antigenantibody interaction results from the formation of multiple non-covalent bonds. These

attractive forces consist of:

hydrogen bonds; electrostatic bonds; van der Waals forces; and hydrophobic forces.

Each bond is relatively weak in comparison with covalent bonds, but together they can generate a high-

affinity interaction.

Thus interacting groups must be in quite intimate contact before these attractive forces come into play.

For a paratope to combine with its epitope the interacting sites must be complementary in shape,

charge distribution, and hydrophobicity, and in terms of donor and acceptor groups capable of forming

hydrogen bonds.

The affinity with which antibody binds antigen is the sum of the attractive and repulsive forcesbetween them. A high affinity antibody implies a good fit and conversely, a low affinity

antibody implies a poor fit

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2. Kinetics of antibody-antigen reactionsMeasurements of antibody affinity relate to equilibrium conditions. Affinity indicates the tendency of

the antibodies to form stable complexes with the antigen. However, for many biological activities of

antibodies, it is possible that kinetics of the reaction may also be significant.

Kinetics measures the forward rate (on rate) constant K1,2 (mol-1s-1) and the reverse rate (offrate). At equilibrium the ratio of the two constants gives the equilibrium constant or affinity of

the antibody.

3. T Cell-Antigen RecognitionThe T cell receptor or TCR is a molecule found on the surface ofT lymphocytes (or T cells) that is

responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules. The

binding between TCR and antigen is of relatively low affinity and is degenerate: that is, many TCR

recognize the same antigen and many antigens are recognized by the same TCR.

The TCR is composed of two different protein chains (that is, it is a heterodimer). In 95% of T cells, this

consists of an alpha () and beta () chain, whereas in 5% of T cells this consists of gamma anddelta (/) chains.

When the TCR engages with antigen and MHC, the T lymphocyte is activated through a series of

biochemical events mediated by associated enzymes, co-receptors, specialized accessory molecules, and

activated or released transcription factors.

4. Antigen processingAntigen processing is a biological process that prepares antigens for presentation to special cells of

the immune system called T lymphocytes. This process involves two distinct pathways for processing of

antigens from an organism's own (self) proteins or intracellular pathogens (e.g. viruses), or

from phagocytosed pathogens (e.g. bacteria); subsequent presentation of these antigens on class

I or class II MHC molecules is dependent on which pathway is used. Both MHC class I and II are required

to bind antigen before they are stably expressed on a cell surface.

While the conventional distinction between the two pathways is useful, there are instances where

extracellular-derived peptides are presented in the context of MHC class I and cytosolic peptides are

presented in the context of MHC class II (this often happens in dendritic cells).

5. Antigen presentationAntigen presentation is a process in the body's immune system by which macrophages, dendritic

cells and other cell types capture antigens and then enable their recognition by T-cells.

The basis of adaptive immunity lies in the capacity of immune cells to distinguish between the body's

own cells and infectious pathogens.

The hosts cells express self antigens that identify them as such. These antigens are different from

those in bacteria ("non-self" antigens) or in virally infected host cells (missing-self). The ability of

the adaptive immune system to survey for infection requires specialized pathways of enabling

recognition of pathogen-derived antigens by T cells.

http://en.wikipedia.org/wiki/T_lymphocyteshttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Major_histocompatibility_complexhttp://en.wikipedia.org/wiki/Degeneracy_(biology)http://en.wikipedia.org/wiki/Heteromerhttp://en.wikipedia.org/wiki/Gamma/delta_T_cellshttp://en.wikipedia.org/wiki/Gamma/delta_T_cellshttp://en.wikipedia.org/wiki/Biological_processhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Antigen_presentationhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/T_cellhttp://en.wikipedia.org/wiki/Intracellularhttp://en.wikipedia.org/wiki/Pathogenhttp://en.wikipedia.org/wiki/Virushttp://en.wikipedia.org/wiki/Phagocytosishttp://en.wikipedia.org/wiki/Bacteriahttp://en.wikipedia.org/wiki/Major_histocompatibility_complex#MHC_class_Ihttp://en.wikipedia.org/wiki/Major_histocompatibility_complex#MHC_class_Ihttp://en.wikipedia.org/wiki/Major_histocompatibility_complex#MHC_class_IIhttp://en.wikipedia.org/wiki/Major_histocompatibility_complexhttp://en.wikipedia.org/wiki/Dendritic_cellshttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Macrophageshttp://en.wikipedia.org/wiki/Dendritic_cellshttp://en.wikipedia.org/wiki/Dendritic_cellshttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/T-cellshttp://en.wikipedia.org/wiki/Adaptive_immune_systemhttp://en.wikipedia.org/wiki/Adaptive_immune_systemhttp://en.wikipedia.org/wiki/T-cellshttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Dendritic_cellshttp://en.wikipedia.org/wiki/Dendritic_cellshttp://en.wikipedia.org/wiki/Macrophageshttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Dendritic_cellshttp://en.wikipedia.org/wiki/Major_histocompatibility_complexhttp://en.wikipedia.org/wiki/Major_histocompatibility_complex#MHC_class_IIhttp://en.wikipedia.org/wiki/Major_histocompatibility_complex#MHC_class_Ihttp://en.wikipedia.org/wiki/Major_histocompatibility_complex#MHC_class_Ihttp://en.wikipedia.org/wiki/Bacteriahttp://en.wikipedia.org/wiki/Phagocytosishttp://en.wikipedia.org/wiki/Virushttp://en.wikipedia.org/wiki/Pathogenhttp://en.wikipedia.org/wiki/Intracellularhttp://en.wikipedia.org/wiki/T_cellhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Antigen_presentationhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Biological_processhttp://en.wikipedia.org/wiki/Gamma/delta_T_cellshttp://en.wikipedia.org/wiki/Gamma/delta_T_cellshttp://en.wikipedia.org/wiki/Heteromerhttp://en.wikipedia.org/wiki/Heteromerhttp://en.wikipedia.org/wiki/Degeneracy_(biology)http://en.wikipedia.org/wiki/Major_histocompatibility_complexhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/T_lymphocytes

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Foreign protein or antigen (1) is taken up by an antigen-presenting cell (2). The antigen is processed and

displayed on a MHC II molecule (3), which interacts with a T helper cell (4). In the lower pathway; whole

foreign proteins are bound by membrane antibodies (5) and presented to B lymphocytes (6), which

process (7) and present antigen on MHC II (8) to a previously activated T helper cell (10), spurring the

production of antigen-specific antibodies (9).

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Topic 8: Cell Cooperation in the Antibody Response

Immune activation to stimulate antibody production involves cell interaction between T cells andAPC, and later between these primed T cells and B cells.

T-cell activation involves antigen-specific interaction, cell adhesion molecules, and cytokines.The most potent co-stimulatory molecule is B7 (CD80 or CD86). In the absence of appropriate

co-stimulation, antigen recognition by nave T cells may result in clonal anergy.

Lymphocyte proliferation is indirect, occurring via the induction of receptors for lymphocyte growthfactors following cell activation. Lymphocyte growth factors (e.g. IL-2) are chiefly produced by T cells.

Two types of antigens induce antibody responses T-dependent and T-independent. T-dependentantigens induce secondary immune responses characterized by IgG production and affinity

maturation.

Cytokines are intercellular signaling proteins intimately involved in most biological processes cellgrowth, activation, inflammation, immunity, repair, fibrosis, chemotaxis. Cytokines include proteins

also known as interferons, interleukins, colony-stimulating factors and other growth factors.

Cytokines act at low molarity because they act on very high affinity receptors.

Cytokines

Cytokines are small cell-signaling protein molecules that are secreted by numerous cells and are a

category of signaling molecules used extensively in intercellular communication. Cytokines can be

classified as proteins, peptides, or glycoproteins; the term "cytokine" encompasses a large and diverse

family of regulators produced throughout the body by cells of diverse embryological origin.

The term "cytokine" has been used to refer to the immunomodulating agents, such as interleukins and

interferons.

Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages (many near

the interface with the external environment) are potent producers of IL-1, IL-6, and TNF-.

Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signalling then

alter cell functions. This may include the upregulation and/or downregulation of several genes and their

transcription factors, resulting in the production of other cytokines, an increase in the number of surface

receptors for other molecules, or the suppression of their own effect by feedback inhibition.

A classification useful in clinical and experimental practice divides immunological cytokines into those

that enhance cellular immune responses, type 1 (IFN-, TGF-, etc.), and type 2 (IL-4, IL-10, IL-13, etc.),

which favor antibody responses.

A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of

those in the other. Dysregulation of this tendency is under intensive study for its possible role in the

pathogenesis of autoimmune disorders.

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Topic 9: Cell Cooperation in the Antibody Response

Non-adaptative immune defences allow leucocytes to detect and respond to the presence ofpathogens, without involving the more recently evolved antigen-specific receptors of B cells

and T cells. Microbial structures are recognized early in a reaction, while specific immune responses are

developing. Release of cytokines is a major determinant of the type of response that is

subsequently activated.

The specific immune response is directed by helper T cells (Th), which respond to and releasedifferent cytokine profiles, and so drive distinct patterns of effector function.

Cell-mediated immune responses comprise numerous distinct effector functions. Activation ofan inappropriate effector function can lead to failure to eliminate the pathogen and to chronic

immunopathology.

There are two major types of cell-mediated effector mechanism. The first aims to destroyinfected cells (with or without the help antibody). The second involves pathways that activate

phagocytes to kill organisms and tissue cells to resist infection.

Cytokine mediators play a central role in positive and negative regulation of immune reactions,and in integrating them with other physiological compartments such as the endocrine and

haematopoietic systems.

Granuloma formation or chronic tissue-destructive inflammation occur when cell-mediatedreactions are nor resolved, due either to failure to eliminate an infection or an inability to clear

an antigen which has become persistent. Immnunopathology can result from microvascular

damage secondary to excessive cytokine release, or from direct destruction of essential cells.