Regulation of The Immune System

1. Regulation of The Immune System

2. Introduction • 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

3. Overview of Immune System

4. Innate and Adaptive Immune Responses

5. The inter-talk between innate immunity and acquired immunity

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

7. ImmunologicaLTolerance • 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

8. 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 • ClonalAnergy- • Suppression of responses may occur by production of regulatory T cells • Ignorance to some self antigens may also exist

9. (Absence of Co-stimulation) Central and Peripheral Tolerance

10. Central toleranceT lymphocyte • 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)

11. Differentiation of thymocytes apoptosis CD4+ precursor thymocyte mature naive T cells 95% 5% export to the periphery CD4+8+ CD4-8- CD8+ Single pos small, resting thymocyte double neg large & active thymocyte double pos small resting thymocyte negative selection cortex medulla positive selection

12. Peripheral Tolerance 1. ClonalAnergy-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

13. TCR MHC II B7 CD28 T cell activationThe Two Signal Hypothesis for T-cell Activation Signal 1 Mature Dendritic cell APC Activated TH cell TH cell Signal 2

14. Resting B-cell APC TH0 cell CD28 Tolerance (anergy or apoptosis) from lack of signal 2 Hypothetical mechanism of tolerance in mature T cells Signal 1 Tolerant T cell

15. Pathways to Peripheral Tolerance Proliferation & differentiation Activated T cells NormalResponse B7 CD28 Antigen Recognitionwithout co-stimulation FunctionallyUnresponsive Anergy CTL4-B7 interaction CTLA4 B7 Fas Activation induced cell death Fas-FasL interaction Apoptosis FasL Inhibition of proliferation & effector action Cytokine-mediated suppression Cytokine regulation cytokines

16. Definition of Regulatory T cells • 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).

17. Treg cell mediated phenomenon • 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

18. Suppression mechanisms of Treg cells • Treg cell influence other T cells • Treg cell alter APCs • T cell derived suppression molecules

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

20. Alter the differentiation of naïve CD4+T cell into IL-10/TGF-b secreting T cells • 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

21. Treg cell alter APCs • 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)

22. Regulatory T cells Production of IL-10 or TGF-b FunctionallyUnresponsive T cell RegulatoryT cell

23. Functions of Treg cells • 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

24. Concepts of B cell tolerance • Centeral tolerance: • Apoptosis • Receptor editing…… • Peripheral Tolerance • Anergy • Apoptosis

25. 2.Which type of immune response must be activated? 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)

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

28. Th1 versus Th2 Balance Disease Th1 Th2 Experimental Cure Progression Leishmaniasis Experimental autoimmune Progression Preventionencephalomyelitis Tuberculosis Cure/Prevention Progression Atopy Prevention? Progression Type 1 Diabetes (NOD) Progression Prevention

29. 3.Homeostasis of Immune System

30. 3.Homeostasis of Immune System 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

31. 3.Homeostasis of Immune System • CTLA-4 may also act as a terminator for immune response • Fas-Fasligand

32. 3.Homeostasis of Immune System • Regulation by Antibody • Antibody exerts feedback inhibition on its own production. • There are two explanations for antibody-mediated suppression. • Circulating antibody competes with antigen-reactive B cells for antigen inhibiting the clonalexpansion of the B cells. • Binding of antigen-antibody complexes by Fc receptors on B cells reduces signaling by the B-cell-receptor complex. • Vaccine production

33. 3.Homeostasis of Immune System • 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

34. Factors Affecting Tolerance Induction A. Age: Young immunologically immature animals show tolerance antigen exposure. 1. Immature B cells lack surface IgD and fail to resynthesizeIgM 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.

35. 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

36. Inappropriate Immune Response 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).

37. Inappropriate Immune Response • 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).

38. Inappropriate Immune Response • 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.

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

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

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