Clinical Immunity

Immunogens or Antigens
* A foreign substance, when introduced into human body, stimulate formation of specific antibodies or sensitized lymphocytes
* Antigens have the ability to combine specifically with antibodies produced or
sensitized T-lymphocytes induced
Haptens:
- Low molecular weight substances
- These substances not immunogenic by itself
- If couple to a larger carrier molecule (albumin, globulins), they become immunogenic
- Examples :simple chemicals and drugs: penicillin, sulphonamid, aspirin, cosmetic, tranquillizers, neomycin skin ointment
Epitopes or Antigenic determinants:
* Sites on or within antigen with which antibodies react
* Antibodies are specific for epitopes
Types of Antigens:
Exogenous Antigens
1- Bacterial antigens:
a- Antigens related to bacterial cells
- Somatic antigen (O): part of cell wall gm –ve bacter.
- Capsular antigen: usually polysaccharide
- Flagellar Ag (H) : a protein made of flagellin
- Fimbrial Ag: surface antigens in fimbriated bacilli
b- Antigen secreted by bacteria:
- Exotoxins
- Enzymes
2- Viral antigens:
a- protein coat viral antigens
b- Soluble antigens (soluble nucleoproteins as in influenza)
Endogenous antigens : Human tissue antigens:
a- Blood group antigens: A, B and Rh antigens
b- Histocompatibility antigens: Glycoprotein molecules on all nucleotide cells:
- Major histocompatibility complex antigens (MHC)
- Human leucocyte antigen (HLA)
* MHC has an important function in presentation of antigens to T-cells
* Helper T-cells recognize foreign antigens on surface of APCs, only when these antigens are presented in the groove of MHC II molecule
* Cytotoxic T-cells will only recognize antigens, on the surfaces of virus infected cells or tumor cells only when these antigens are presented in the groove of Class I molecule (MHC restriction)
Superantigens (SAgs)
* They activate multiple clones of T-lymphocytes
* Bacterial toxins:Staph. aureus toxic shock syndrome toxin (TSST) and enterotoxins
Strpt. pyogenes pyrogenic toxin A
* They have the ability to bind both class II MHC molecules and TCR ? chain
* They act as a clamp between the two, providing a signal for T-cell activation
* They are active at very low concentration causing release of large amounts of cytokines
* The massive T-cell activation and release of large amounts of cytokines cause systemic toxicity
* This method of stimulation is not specific for the pathogen
* It does not lead to acquired immunity i.e no memory
Antigen Binding And Recognition Molecules :
Antigens are recognized by and bind to:
1) B-cell receptors (BCR) :
- These are membrane-bound immunoglobulins (IgM and IgD) on B-cells
- BCRs can be secreted in plasma as antibodies
2) T-cell receptors (TCR)
- ? and ? chains anchored to T-cells
- There is a groove which binds small peptides presented by MHC on surface of APCs
3) MHC molecules
They are essential for presentation of peptides so that they can be recognized and bind to TCRs
Factors influencing Immunogenicty
1-Foreigness : Foreign substances are immunogenic
2- Molecular size: High molecular weight increase immunogenicty
3- Chemical structure complexity: High complexity increase immunogenicty
4- Route of administration:Parenteral routes are more immunogenic to oral route
5- Method of administration:
a- Antigen dose:
Appropriate dose optimum antigenicty
Low dose low- zone tolerance
High dose high-zone tolerance
b- Adjuvant: Substance when injected with an antigen enhance immunogenicty
Humoral Immunity ( Antibody )
The humoral response is carried out by antibodies which are produced by Plasma cells.Plasma cells are derived from activated B-cells that are produced in the bone marrow
The innate immune system activates Acquired immunity :Cells of the innate immune system activate the specific immune response.A group of cells called Antigen presenting cells (APC) activate the acquired immune system.Macrophages, Dendritic cells and B-cells are examples of types of APCs. APCs turn on the acquired immune system by activating T-Helper cells (TH-cells). TH-cells in turn activate either the cell mediated or the humoral immune system The Microbial antigen is ingested by an APC and partially digested. Fragments from microbe bind with the MHC II to form a MHC II /Ag complex on the surface of the APC. A Helper T cell, specific for the presented antigen, binds to the MHC II/Ag complex. The helper T cell then activates an appropriate B cell by releasing IL-2 to it. The interaction between the TH-cell and the B-cell causes the B- cell to differentiate into Plasma cells and memory cells.
Memory cells Memory cells do not react right away but are held in reserve for later infections. The secondary response that is carried out by memory cells is different in 3 ways.
Memory cells produce antibodies that bind with greater affinity to their antigens than the antibodies produced in the initial response. The response time is much vaster than the primary response . A greater number of antibodies are produced.
Function of Antibodies:Antibodies function in 6 ways to protect the body
Aggltination: Enhances phagocytosis and reduces number of infectious units to be dealt with
Opsonization: Coating antigen with antibody enhances phagocytosis
Neutralization: blocks adhesion of bacteria and viruses to mucosa. Also blocks active site of toxin
Activation of complement
Increases inflammation through the byproducts of the complement system (C5a and C3a)
Antibody dependant cell mediated cytotoxicity: Antibodies attached to target cell cause destruction by non specific immune system cells.
Structure of an Antibody : Antibody composed of two heavy chains and two light chains. These chains bind together to make a Y shaped molecule..The two sections located at the ends of Y’s arms are called variable (V) regions. The variable region is structurally identical for all antibodies synthesized by a particular plasma cell. The Antibodies from each plasma cell however are different or unique from all other antibodies produced by other plasma cell
The stem of the antibody molecule as well as the lower portion of the arms called constant (c) regions.
There are 5 major types of C regions which correspond to the 5 different classes of antibodies.
All plasma cells in the body are producing one of these classes of antibodies.
A particular plasma cell may switch the particular class of Antibody that it is producing in order to fight an infection in a different way.
The structure of Antibodies may be described by the way they are cut and digested by proteases.
The stem portion is referred to as the FC region
The Y portion with the top third of the stem is referred to as the Fab region.
The FC region often acts as the receptor for phagocytes during opsonization or Antibody dependant cell mediated cytotoxicity.
The FC region contains the antigen binding region
IgM IgM expressed as membrane bound anitbodies on B-cells
Pentamer
5 units held together by disulfide bonds
J (Joining) chain functions in the polymerization of monomers
First immunoglobulin class produced in a primary response to an antigen
Has 10 anitgen binding sites
More effective at stimulating complement
Large-size - does not diffuse well
The FC receptors on phagocytes bind IgM (opsinization)
IgD
Found on surface of mature B-cells.
Biological function unknown (thought to function in activation of B-cells)
IgG
Most abundant isotype in serum (80%)
Cross placenta and play important role in protecting fetus
Provides passive immunity to unborn fetus.
Placental cells bind the Fc portion of IgG and transfer Ab across the placental membrane.
Activate complement system
Opsonin—phagocytosis
IgE
Mediate the immediate hypersensitivity reactions (hayfever, asthma, hives, anaphylactic shock)
Mast cells and basophils bind fc portion of IgE
Cross-linkage of receptor bound IgE molecules by antigen, induces degranulaltion of the Mast and basophil cells
Parasitic response
Eosinophils express receptors for IgE
IgA
Most abundant Ab in the body
Found Predominantly in external secretions i.e. Breast Milk, Saliva, tears, mucus.
Serum form is a monomer
Secretory form is a dimer or tetramer linked together via a “secretory component” and a J chain.
J (Joining) chain functions in the polymerization of monomers.
Plasma cells that release IgA Abs are concentrated along the Mucus Membrane surface.
Provides passive immunity to infants through mothers breast milk
Cell Mediated Immunity
Host defenses against extracellular infection are
mediated by: - Antibody - Complement - Macrophages
* Intercellular infections are mediates by CMI
* CMI are responsible for:
- Resistance to intracellular pathogens
- Resistance to fungal and protozoal infections
- Resistance to tumors
* CMI may play a role in some harmful conditions:
- Hypersensitivity reactions type IV (contact dermatitis)
- Graft rejection
- Autoimmune diseases
* Cell mediated cytotoxicity mediated by:
- T-cytotoxic cells cells
- Natural killer cells
- Activated macrophages
Cellular immune response is mediated by:
- Subpopulation of T-lymphocytes
- Macrophages and their products
Cytokines stimulate other effectors cells of CMI and humoral immune response and mediate the following:
- Attract monocytes, macrophages and lymphocytes to the site
- Activate macrophages to kill intracellular microbes
- Promote activity of CD8 CTLs which directly kill virus infected cells, tumour cells, and graft rejection
- They activate NK cells increasing their cytotoxic functions
- Stimulate B-cells to differentiate into plasma cells that secret antibo
Phases Of CMI
1) Antigen processing and presentation . Protein antigens processed and converted to peptides then bind to MHC molecules on Antigen Presenting Cell (APCs ) to be presented to T-cells
a- Extracellular proteins are internalized into vesicular compartment of APCs (Dentritic, macrophages,B-cells)
- They are degraded to generate peptides
- These peptides bind into class II MHC molecules
- Peptide-MHC II complex is transported to surface
of APCs to be presented to CD4 TH cells (T Helper cell)
Outcome: Secretion of cytokines by TH cells
b- Endogenously synthesized proteins are degraded to peptides (all nucleated cells e.g virus infected cells
- They bind to class I MHC in endoplasmic reticulum
- Peptide-MHC I complex is expressed on surface of nucleotide cells to be represented to CD8 cytotoxic cells
Outcome: Killing of presenting cells by CTLs
2) Activation of T-cells
Mature CD4 and CD8 cells are activated by two signals:
- First signal is recognition of antigenic peptide-MHC complex on surface of APC by TCR-CD3 complex
- CD4 and CD8 molecules are co-receptors that stabilize the
interaction of TH cells and TC-cells respectively with APCs
- CD3,CD4, and CD8 act as signal transduction molecules
- Second co-stimulatory signal is: interaction of CD28 on T-cells with CD7 on APCs
TH-cells express IL-2 receptors and secrete cytokines including IL-2
* IL-2 auto activate TH-cells
* APC release IL-I which acts on both APC and TH cell to promote their activation
* All mentioned interactions lead to activation of mature TH-cells
* Mature TH-cells proliferate and differentiate into effectors antigen specific TH-cells releasing cytokines
* Some of them become memory cells which provide secondary immune response
* Cytokine released from activated TH-cells activate macrophages, NK and B-cells

Activated CD8 TC-cells proliferate and differentiate into a clone of effectors cells CTLs
* Effectors CTLs kill target cells i.e. nucleated cells (expressing MHC-I) infected with viruses, tumor cells or graft cells