Immunity mean protection from disease and more specifically, infectious disease. The cells and molecules responsible for immunity constitute the immune system There are two types of Immunity: Innate Immunity Adaptive Immunity

Immune response: It is the response made by the host to defend itself against a pathogen. It is described as appropriate (protective). Immune response must be regulated at the following level: 1.Response must be only to foreign antigen and no response to self antigen ……tolerance 2.Which type of immune response must be activated 3.Response termination…… Homeostasis

Tolerance is a physiologic state in which the immune system does not react destructively against components of an organism that harbors it or against antigens that are introduced into it. Central Tolerance Peripheral Tolerance

Central Tolerance through Clonal Deletion Clones of cells that have receptors for self-antigens are deleted during development but….. If all reactive lymphocytes which are recognizing self Ag are eliminated the repertoire is too limited! Not all peptides of the body are accessible in the thymus Some new peptides are expressed later in life. One TCR can see many peptides Peripheral Tolerance – Clonal Anergy- – Suppression of responses may occur by production of regulatory T cells – Ignorance to some self antigens may also exist

(Absence of Co-stimulation) Co-stimulation)

Development of T- Lymphocytes: -develop in BM and mature in the Thymus. -Acquiring TCR and then screened by the two selective processes: * Positive selection (MHC-restriction) * Negative selection (removing self- intolerant)

Differentiation of thymocytes cortex CD double pos small resting thymocyte CD double neg large & active thymocyte precursorthymocyte medulla CD4 + CD8 + Single pos small, resting thymocyte 5% negative selection export to the periphery mature naive T cells positive selection apoptosis 95%

Peripheral Tolerance 1. Clonal Anergy-failure of APC to deliver a second signal during antigen presentation (example: B7-CD28 interaction) 2.Suppression of responses may occur by production of regulatory T cells that inhibit immune response to self- antigen (example: TGF- , IL10 and Th1 vs. Th2 cytokines) 3.Ignorance to some self antigens may also exist

T cell activation The Two Signal Hypothesis for T-cell Activation MatureDendriticcellAPC T H T H cell cell CD28B7 MHC II TCR Signal 2 Signal 1 Activated Activated T H cell

CD28RestingB-cellAPC T H0 cell Tolerance (anergy or apoptosis) from lack of signal 2 Signal 1 Tolerant T cell T cell

Fas FasL cytokines Apoptosis Inhibition of proliferation & effector action Activated T cells Normal Response CD28 B7 Proliferation & differentiation Antigen Recognition without co-stimulation Anergy CTLA4B7 Functionally Unresponsive CTL4-B7 interaction Fas-FasL interaction Cytokine-mediated suppression Activation induced cell death Cytokine regulation

Regulatory T cells (sometimes known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens The latest research suggests that regulatory T cells are defined by expression of the forkhead family transcription factor FOXP3 (forkhead box p3). They are (CD4 + ) helper T cell population and express high levels of the interleukin-2 receptor alpha chain (CD25).

Bystander suppression – suppressive activity of Treg cells requires their prior activation through their T cell receptor – once activated, Treg cells suppress in an antigen- nonspecific way – Treg cells with one antigen specificity can suppress effector T cells (Teff cells) with many other distinct antigen specificities

Treg cell influence other T cells Treg cell alter APCs T cell derived suppression molecules

T cells Disarmed Loss of CTL effect Loss of IFN-  secretion Loss of graft rejection ability Lin C-Y; 2002; Nature Immunol Prevent CD8+T cells from differentiation into effector T cells but not proliferation in vivo

Naive CD4+T cell could differentiate into IL-10 or TGF-  secreting induced Treg cells in the presence of Treg cells in invivo and in vitro study

Treg cell could conjugate with dendritic cells documented by in vivo two-photon microscopy Treg cells could alter the dendritic cells functions in the following ways – DC silencing – Treg cell expansion: with the help of to TGF-  the differentiation of Teff to Treg cells)

Functionally Unresponsive T cell Production of IL-10 or TGF-  Regulatory T cell

Homeostatic control – Prevent potential outgrowth of auto-reactive T cells Damage control – Limit the tissue injury during inflammation caused by infection/autoimmune/transplantation Infectious Tolerance – Stabilized tolerance during the final stage of inflammation

Centeral tolerance: Apoptosis Receptor editing…… Peripheral Tolerance Anergy Apoptosis

Important regulatory decisions determine the branch of the immune system to be activated, the intensity of the response, and its duration.. Cytokines Involved in initiating immune response Involved in turning off immune response Some serve as direct effector molecules (e.g., TNFa)

cytokines of Th1 and Th2 Cells Th1 cell Th2 cell Macrophage B cell IFNγ Activates IL-4 IL-5 IL-10 Activates Inhibits production Inhibits proliferation Mast cell Eosinophil Antibodies (including IgE)

DiseaseTh1Th2 Experimental CureProgression Leishmaniasis Experimental autoimmuneProgressionPrevention encephalomyelitis TuberculosisCure/PreventionProgression AtopyPrevention?Progression Type 1 Diabetes (NOD)ProgressionPrevention

Immune response to foreign antigens are self limited and wane as antigens are eliminated returning the immune system to its basal resting state During the immune response: Antiapoptic proteins…….BCL family Co –stimulator Survival signals Cytokines  Apoptosis

CTLA-4 may also act as a terminator for immune response Fas-Fas ligand

Regulation by Antibody Antibody exerts feedback inhibition on its own production. There are two explanations for antibody-mediated suppression. 1. Circulating antibody competes with antigen-reactive B cells for antigen inhibiting the clonal expansion of the B cells. 2.Binding of antigen-antibody complexes by Fc receptors on B cells reduces signaling by the B-cell-receptor complex. Vaccine production

Network hypothesis Another means of regulation that has been proposed is the idiotypic network hypothesis(idiotypes reflect the antigen binding specificity of any particular antibody molecule). This theory suggests that the idiotypic determinants of antibody molecules are so unique that they appear foreign to the immune system and are, therefore, antigenic. Thus, production of antibody in response to antigen leads to the production of anti-antibody in response, and anti-anti- antibody and so on. Eventually, however, the level of [anti] n - antibody is not sufficient to induce another round and the cascade ends

Factors Affecting Tolerance Induction A. Age: Young immunologically immature animals show tolerance antigen exposure. 1. Immature B cells lack surface IgD and fail to resynthesize IgM receptors after capping. 2. Antigen is poorly localized and presented in immature animals B. Route of exposure: i.v. or oral exposure favors tolerance. S.c. or intradermal favors immunity. Intramuscular favors Th2. C. Dose of antigen: High doses favor tolerance; however, repeated low doses can also cause tolerance D. Associated antigens: Coupling of antigens to self Ig or self cells enhances tolerogenicity. 1. Coupling nucleosides to self carriers can prevent anti-DNA in genetically autoimmune mice.

Tolerance can be broken Tolerance can be broken – New clones of T and B cells appear in the absence of antigen – Viral infection can create a cytokine milieu to turn on quiescent (anergic) cells – New epitopes are introduced by viral modification

Failure to regulate the immune response: 1- Hypersensitivity (exaggerated) 2- Immune tolerance (no response) 3- Autoimmunity (to self) 4- Immune deficiency (absent or functionally defective host defense).

Hypersensitivity reactions: Harmful immune responses that produce tissue injury and may cause serious diseases. The antigen itself may not be harmful. Four types: Allergy (type I): The most serious (IgE- mediated). Type II: IgG- mediated Serum sickness, Arthus reaction (type III)- IgG mediated). Delayed type (type IV)- Specific T cells-mediated).

Autoimmunity: - Specific immunity to self antigens. -Initiated by responses involving T cells. -T cells help to initiate a harmful Ab response. -It is not known what triggers autoimmunity. -Strong association bet. infection & autoimmunity -Susceptibility to autoimmunity is controlled by environmental & genetic factors. -MHC class II more than MHC class I.

Some examples of autoimmune diseases Multiple sclerosis Myasthenia Gravis Coeliac disease Psoriasis Crohn’s disease Lupus erythematosus Rheumatoid Arthritis

Primary (Genetically determined): Early in life (6-24 months). Rare, can be adaptive or innate. Eg thymic hypoplasia (DiGeorge syndrome) Secondary (Acquired) Malnutrition, infection, cancer, renal disease, sarcoidosis, ageing, chemotherapy, autoimmunity.