Lecture 5 Effector Mechanisms

1. Lecture 5Effector Mechanisms

2. Host Defense Inborn independent of previous experience Innate after natural exposure to a foreign agent Active Defense Mechanisms Naturally acquired placental transfer Passive immune cells in colostrum immune cells in colostrum Adoptive Acquired Specific immunization Active Artificially acquired administration of preformed antibodies Passive Bone marrow transplant Adoptive

3. Effector Mechanisms • Antibody-mediated • Neutralizing • Opsonization • Complement activation • Receptor-mediated • Antibody-dependent cellular cytotoxicity • Cell-mediated • Direct cytotoxicity (induction of apoptosis) • Cytokines • Regulatory

4. T-cell Mediated Cytotoxicity • Necrosis • Programmed cell death or apoptosis

5. Cytokines • Polypeptides produced by a variety of cell types including T lymphocytes used for communications between cells. • Cytokine production is triggered by specific receptor binding and subsequent signal transduction pathways • Cytokine repertoire is dependent on cell type triggered, receptors present on that cell type. • Cytokines act on cells that possess receptors for them. • Play role similar to hormones (messengers of the endocrine system) • Hormones usually act at a distance • Cytokines act locally • Play an important role in both innate and adaptive immunity

6. Properties of cytokines • Proteins • Low molecular weight • Bind to receptor on either cell which produced it or another cell • Receptor binding triggers a signal • Signal results in altered pattern of gene expression • Are not antibodies

7. Lymphocyte Migration, Activation, and Effector Function Depends on Cell-Adhesion Molecules • A variety of cell surface polypeptides serve as receptors to ensure appropriate cell-cell interactions. These polypeptide include: • Selectins • Integrins • Immunoglobulin Superfamily • Mucin-like Vascular Addressins

8. Cytokine nomenclature • Interleukins (1-18) • Interferons (a,b,g) • Others (common names)

9. Cytokine -mediated effects • Cell growth • Cell differentiation • Cell death • Induce non-responsiveness to other cytokines/cells • Induce responsiveness to other cytokines/cells • Induce secretion of other cytokines

10. How can non-specific cytokines act specifically? • Only cells expressing receptors for specific cytokines can be activated by them • Many cytokines have very short half-lives • Only cells in close proximity will be activated • High concentrations of cytokines are needed for activation • Only cells in close proximity will be activated • May require cell-to cell contact

11. Alert to infection.tumor/etc. Recruit cells to site Specify type of immune response Immune effector phase Immune down-regulation Immune memory and resetting the system Early mediators (IFNa/b) Chemokines (MIP-1a) Early & late mediators (IL-2, IFNg, IL-4, IL-5) Down-regulators (IL-10, TNFg) Maintenance of cytokines, etc. (GM-CSF, IL-3, IL-7, etc.) Cytokines in the immune response

12. Cytokine secretion and biological activities of TH1 and TH2 Subsets Type 1 Type 2 Cell-mediated Immune response (intracellular Organisms) Humoral response (parasites) T cell IL-2 IFN-g TNF IL-4 IL-5

13. Role of TH1/TH2 balance in determining disease outcomes • Balance of two subset determines response to disease • Leprosy • Tuberculoid (TH1, CMI response, patient lives) • Lepromatous (TH2, humoral response, patient dies)

14. Cytokine-related diseases • Bacterial septic shock • Blood pressure drops, clots form, hypoglycemia ensues, patient dies • LPS triggers results in TNF release • TNF induces IL-1 which induces IL-6 and IL-8 • Bacterial toxic shock and related diseases • Superantigens trigger large numbers of T cells which release massive amounts of cytokines (Super antigens are bacterial toxins that bridge CD4 T cell receptors and the MHC class II molecules on APC’s, bypassing the need for antigen) • Lymphoid and myeloid cancers • Some cancer cells secrete cytokines • Chagas’ disease • Trypanosoma cruzi infection results in sever immune suppression • Depression of IL-2 receptor production

15. Infectious agents that target cytokines • Epstein-Barr virus foster the generation of T helper cells that do not produce IL-2. • EBV produces an analog of IL-10 that favors TH2 cells, rather than TH1. • Parasites such as tape worms induce high levels of IgE, an immunoglobulin induced by TH2 cells. • Since TH1 cells mediate inflammation, this may be a protective ploy to avoid destructive inflammatory processes.

16. Immunosuppressive effects of oral bacteria on immune function • Impairment of B and T cell function (P. intermedia, P. asaccharolytica, P. endodontalis, P. melaninogenica) • Production of specific toxins that kill monocytes (A. actinomycetemcomitans) • Provoke the release of peroxide, prostaglandins and other mediators capable of inhibiting lymphocyte function (T. denticola) • Modulate expression of cytokines

17. Cytokine-inducing components of Gram-positive bacteria

18. Interferon Action • Viral replication stimulates the infected host cell to produce interferon. • Interferon induces uninfected cells to • produce antiviral proteins that prevent translation of viral mRNA • degrade viral nucleic acid • Viral replication is blocked in uninfected cells

19. Interferon Action

20. Therapeutic uses of cytokines • Modulation of TH activation • Interfere with receptor function • Interfere with cytokine • Make it unable to bind to receptor • Make it unable to act

21. Examples of therapeutic uses • Soluble T-cell receptor • Anti-IL-2R • Interleukin analogs which bind receptor, but do not trigger activation (ties up receptor) • Toxins conjugated to cytokines which kill activated T-cells • Administration of cytokines to enhance immunity (side effects/ short half lives) • Allergies

22. Summary • Effector cells and antibodies play critical roles in almost all adaptive immune responses • Antigen-presenting cells play critical role in processing and presenting antigen to T cells • Cytokines are released by a variety of cell types and regulate a variety of biological effects • T-cell mediated cell death is largely via apoptosis

23. What’s the bottom line? • Innate immunity is a function of anatomical, mechanical and biochemical factors. • No requirement for prior exposure/memory • Biochemical response may involve pattern recognition • Lacks the specificity of the adaptive immune system • Adaptive immune system recognizes foreign agents via receptors and develops memory. • Triggering the adaptive immune response results in activated T cells and antibodies specific for the substance (antigen) that triggered it. • Antibodies react with antigen • Block or neutralize • Activate complement system • Bind to Fc receptors on cells providing specificity to the effector activity of those cells • Activated T cells • Cytotoxic against foreign agent (tumor cell, transplant, virus-infected cell) • May influence other cells (Helper/Suppressor T cells, cytokines)

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