Lecture 5 Effector Mechanisms

Host Defense DefenseMechanisms Innate Inborn independent of previous experience Acquired Naturallyacquired Active Adoptive Passive Active Adoptive Passive after natural exposure to a foreign agent placental transfer immune cells in colostrum Artificiallyacquired Specificimmunization administration of preformed antibodies Bone marrow transplant immune cells in colostrum

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

T-cell Mediated Cytotoxicity Necrosis Necrosis Programmed cell death or apoptosis Programmed cell death or apoptosis

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

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

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: A variety of cell surface polypeptides serve as receptors to ensure appropriate cell-cell interactions. These polypeptide include: Selectins Selectins Integrins Integrins Immunoglobulin Superfamily Immunoglobulin Superfamily Mucin-like Vascular Addressins Mucin-like Vascular Addressins

Cytokine nomenclature Interleukins (1-18) Interleukins (1-18) Interferons (  ) Interferons (  ) Others (common names) Others (common names)

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

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

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

Cytokine secretion and biological activities of T H 1 and T H 2 Subsets Type 1 Type 2 IL-2 IFN-  TNFIL-4IL-5 Cell-mediated Immune response (intracellularOrganisms)Humoralresponse(parasites) T cell

Role of T H 1/T H 2 balance in determining disease outcomes Balance of two subset determines response to disease Balance of two subset determines response to disease Leprosy Leprosy Tuberculoid (T H 1, CMI response, patient lives) Tuberculoid (T H 1, CMI response, patient lives) Lepromatous (T H 2, humoral response, patient dies) Lepromatous (T H 2, humoral response, patient dies)

Cytokine-related diseases Bacterial septic shock Bacterial septic shock Blood pressure drops, clots form, hypoglycemia ensues, patient dies Blood pressure drops, clots form, hypoglycemia ensues, patient dies LPS triggers results in TNF release LPS triggers results in TNF release TNF induces IL-1 which induces IL-6 and IL-8 TNF induces IL-1 which induces IL-6 and IL-8 Bacterial toxic shock and related diseases 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) 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 Lymphoid and myeloid cancers Some cancer cells secrete cytokines Some cancer cells secrete cytokines Chagas’ disease Chagas’ disease Trypanosoma cruzi infection results in sever immune suppression Trypanosoma cruzi infection results in sever immune suppression Depression of IL-2 receptor production Depression of IL-2 receptor production

Infectious agents that target cytokines Epstein-Barr virus foster the generation of T helper cells that do not produce IL-2. 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 T H 2 cells, rather than T H 1. EBV produces an analog of IL-10 that favors T H 2 cells, rather than T H 1. Parasites such as tape worms induce high levels of IgE, an immunoglobulin induced by T H 2 cells. Parasites such as tape worms induce high levels of IgE, an immunoglobulin induced by T H 2 cells. Since T H 1 cells mediate inflammation, this may be a protective ploy to avoid destructive inflammatory processes. Since T H 1 cells mediate inflammation, this may be a protective ploy to avoid destructive inflammatory processes.

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

Cytokine-inducing components of Gram- positive bacteria

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

Interferon Action

Therapeutic uses of cytokines Modulation of T H activation Modulation of T H activation Interfere with receptor function Interfere with receptor function Interfere with cytokine Interfere with cytokine Make it unable to bind to receptor Make it unable to bind to receptor Make it unable to act Make it unable to act

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

Summary Effector cells and antibodies play critical roles in almost all adaptive immune responses 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 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 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 T-cell mediated cell death is largely via apoptosis

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