Lecture 5Lecture 5Effector MechanismsEffector Mechanisms

Host Host DefenseDefense

Defense Defense MechanismsMechanisms

InnateInnate

Inborn independent Inborn independent of previous of previous experienceexperience

AcquiredAcquired

Naturally Naturally acquired acquired

ActiveActive

AdoptiveAdoptive

PassivePassive

ActiveActive

AdoptiveAdoptive

PassivePassive

after natural after natural exposure to a foreign exposure to a foreign

agent agent

placental transferplacental transfer

immune cells in immune cells in colostrum colostrum

Artificially Artificially acquired acquired

Specific Specific immunization immunization

administration of administration of preformed antibodies preformed antibodies

Bone marrow Bone marrow transplant transplant

immune cells in immune cells in colostrum colostrum

Effector MechanismsEffector Mechanisms Antibody-mediatedAntibody-mediated

NeutralizingNeutralizing OpsonizationOpsonization Complement activationComplement activation Receptor-mediatedReceptor-mediated

Antibody-dependent cellular cytotoxicityAntibody-dependent cellular cytotoxicity Cell-mediatedCell-mediated

Direct cytotoxicity (induction of apoptosis)Direct cytotoxicity (induction of apoptosis) CytokinesCytokines RegulatoryRegulatory

T-cell Mediated CytotoxicityT-cell Mediated Cytotoxicity NecrosisNecrosis Programmed cell death or apoptosisProgrammed cell death or apoptosis

CytokinesCytokines Polypeptides produced by a variety of cell types including T Polypeptides produced by a variety of cell types including T

lymphocytes used for lymphocytes used for communicationscommunications between cells. between cells. Cytokine production is triggered by specific receptor binding Cytokine production is triggered by specific receptor binding

and subsequent signal transduction pathwaysand subsequent signal transduction pathways Cytokine repertoire is dependent on cell type triggered, Cytokine repertoire is dependent on cell type triggered,

receptorsreceptors present on that cell type. present on that cell type. Cytokines act on cells that possess Cytokines act on cells that possess receptorsreceptors for them. 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 Hormones usually act at a distancedistance Cytokines act Cytokines act locallylocally

Play an important role in both innate and adaptive immunityPlay an important role in both innate and adaptive immunity

Properties of cytokinesProperties of cytokines

ProteinsProteins Low molecular weightLow molecular weight Bind to receptor on either cell which produced it or Bind to receptor on either cell which produced it or

another cellanother cell Receptor binding triggers a signalReceptor binding triggers a signal Signal results in altered pattern of gene expressionSignal results in altered pattern of gene expression Are Are notnot antibodies antibodies

Lymphocyte Migration, Activation, and Effector Lymphocyte Migration, Activation, and Effector Function Depends on Cell-Adhesion MoleculesFunction Depends on Cell-Adhesion Molecules

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

Cytokine nomenclatureCytokine nomenclature

Interleukins (1-18)Interleukins (1-18) Interferons (Interferons ()) Others (common names)Others (common names)

Cytokine -mediated effectsCytokine -mediated effects Cell growthCell growth Cell differentiationCell differentiation Cell deathCell death Induce non-responsiveness to other Induce non-responsiveness to other

cytokines/cellscytokines/cells Induce responsiveness to other cytokines/cellsInduce responsiveness to other cytokines/cells Induce secretion of other cytokinesInduce secretion of other cytokines

How can non-specific cytokines How can non-specific cytokines act specifically?act specifically?

Only cells expressing receptors for specific cytokines Only cells expressing receptors for specific cytokines can be activated by themcan be activated by them

Many cytokines have very short half-livesMany cytokines have very short half-lives Only cells in close proximity will be activatedOnly cells in close proximity will be activated

High concentrations of cytokines are needed for High concentrations of cytokines are needed for activationactivation Only cells in close proximity will be activatedOnly cells in close proximity will be activated May require cell-to cell contactMay require cell-to cell contact

Cytokines in the immune responseCytokines in the immune response

Alert to Alert to infection.tumor/etc.infection.tumor/etc.

Recruit cells to siteRecruit cells to site Specify type of immune Specify type of immune

responseresponse Immune effector phaseImmune effector phase Immune down-Immune down-

regulationregulation Immune memory and Immune memory and

resetting the systemresetting the system

Early mediators (IFNEarly mediators (IFN)) Chemokines (MIP-1Chemokines (MIP-1)) Early & late mediators Early & late mediators

(IL-2, IFN(IL-2, IFN, IL-4, IL-5), IL-4, IL-5) Down-regulators (IL-10, Down-regulators (IL-10,

TNFTNF)) Maintenance of Maintenance of

cytokines, etc. (GM-CSF, cytokines, etc. (GM-CSF, IL-3, IL-7, etc.)IL-3, IL-7, etc.)

Cytokine secretion and biological Cytokine secretion and biological activities of Tactivities of THH1 and T1 and THH2 Subsets2 Subsets

Type 1Type 1 Type 2Type 2

IL-2IL-2IFN-IFN-TNFTNF

IL-4IL-4IL-5IL-5

Cell-mediatedCell-mediatedImmune responseImmune response(intracellular(intracellularOrganisms)Organisms)

Humoral Humoral responseresponse(parasites)(parasites)

T cellT cell

Role of TRole of THH1/T1/THH2 balance in determining 2 balance in determining

disease outcomes disease outcomes

Balance of two subset determines response Balance of two subset determines response to diseaseto disease

LeprosyLeprosy Tuberculoid (TTuberculoid (THH1, CMI response, patient lives)1, CMI response, patient lives)

Lepromatous (TLepromatous (THH2, humoral response, patient 2, humoral response, patient

dies)dies)

Cytokine-related diseasesCytokine-related diseases

Bacterial septic shockBacterial septic shock Blood pressure drops, clots form, hypoglycemia ensues, patient diesBlood pressure drops, clots form, hypoglycemia ensues, patient dies LPS triggers results in TNF releaseLPS triggers results in TNF release TNF induces IL-1 which induces IL-6 and IL-8TNF induces IL-1 which induces IL-6 and IL-8

Bacterial toxic shock and related diseasesBacterial toxic shock and related diseases Superantigens trigger large numbers of T cells which release massive amounts Superantigens trigger large numbers of T cells which release massive amounts

of cytokines of cytokines (Super antigens are bacterial toxins that bridge CD4 T cell receptors and the MHC class II (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)molecules on APC’s, bypassing the need for antigen)

Lymphoid and myeloid cancersLymphoid and myeloid cancers Some cancer cells secrete cytokinesSome cancer cells secrete cytokines

Chagas’ diseaseChagas’ disease Trypanosoma cruzi infection results in sever immune suppressionTrypanosoma cruzi infection results in sever immune suppression Depression of IL-2 receptor productionDepression of IL-2 receptor production

Infectious agents that target cytokinesInfectious agents that target cytokines

Epstein-Barr virus foster the generation of T helper cells Epstein-Barr virus foster the generation of T helper cells that do not produce IL-2. that do not produce IL-2.

EBV produces an analog of IL-10 that favors TEBV produces an analog of IL-10 that favors THH2 cells, 2 cells, rather than Trather than THH1.1.

Parasites such as tape worms induce high levels of IgE, Parasites such as tape worms induce high levels of IgE, an immunoglobulin induced by Tan immunoglobulin induced by THH2 cells. 2 cells.

Since TSince THH1 cells mediate inflammation, this may be a 1 cells mediate inflammation, this may be a protective ploy to avoid destructive inflammatory protective ploy to avoid destructive inflammatory processes.processes.

Immunosuppressive effects of oral Immunosuppressive effects of oral bacteria on immune functionbacteria on immune function

Impairment of B and T cell function (Impairment of B and T cell function (P. intermedia, P. P. intermedia, P. asaccharolytica, P. endodontalis, P. melaninogenicaasaccharolytica, P. endodontalis, P. melaninogenica))

Production of specific toxins that kill monocytes (Production of specific toxins that kill monocytes (A. A. actinomycetemcomitansactinomycetemcomitans))

Provoke the release of peroxide, prostaglandins and Provoke the release of peroxide, prostaglandins and other mediators capable of inhibiting lymphocyte other mediators capable of inhibiting lymphocyte function (function (T. denticolaT. denticola))

Modulate expression of cytokinesModulate expression of cytokines

Cytokine-inducing components of Cytokine-inducing components of Gram-positive bacteriaGram-positive bacteria

Interferon ActionInterferon Action

Viral replication stimulates the infected host cell to Viral replication stimulates the infected host cell to produce interferon. produce interferon.

Interferon induces uninfected cells to Interferon induces uninfected cells to produce antiviral proteins that prevent translation of viral produce antiviral proteins that prevent translation of viral

mRNAmRNA degrade viral nucleic aciddegrade viral nucleic acid

Viral replication is blocked in uninfected cellsViral replication is blocked in uninfected cells

Interferon ActionInterferon Action

Therapeutic uses of cytokinesTherapeutic uses of cytokines

Modulation of TModulation of THH activation activation Interfere with receptor functionInterfere with receptor function Interfere with cytokineInterfere with cytokine

Make it unable to bind to receptorMake it unable to bind to receptor Make it unable to actMake it unable to act

Examples of therapeutic usesExamples of therapeutic uses Soluble T-cell receptorSoluble T-cell receptor Anti-IL-2RAnti-IL-2R Interleukin analogs which bind receptor, but do not Interleukin analogs which bind receptor, but do not

trigger activation (ties up receptor)trigger activation (ties up receptor) Toxins conjugated to cytokines which kill activated T-Toxins conjugated to cytokines which kill activated T-

cellscells Administration of cytokines to enhance immunity (side Administration of cytokines to enhance immunity (side

effects/ short half lives)effects/ short half lives) AllergiesAllergies

SummarySummary

Effector cells and antibodies play critical roles in Effector cells and antibodies play critical roles in almost all adaptive immune responsesalmost all adaptive immune responses

Antigen-presenting cells play critical role in Antigen-presenting cells play critical role in processing and presenting antigen to T cellsprocessing and presenting antigen to T cells

Cytokines are released by a variety of cell types Cytokines are released by a variety of cell types and regulate a variety of biological effectsand regulate a variety of biological effects

T-cell mediated cell death is largely via apoptosisT-cell mediated cell death is largely via apoptosis

What’s the bottom line?What’s the bottom line? Innate immunity is a function of anatomical, mechanical and Innate immunity is a function of anatomical, mechanical and

biochemical factors. biochemical factors. No requirement for prior exposure/memoryNo requirement for prior exposure/memory Biochemical response Biochemical response maymay involve pattern recognition involve pattern recognition Lacks the specificity of the adaptive immune systemLacks the specificity of the adaptive immune system

Adaptive immune system recognizes foreign agents via receptors and Adaptive immune system recognizes foreign agents via receptors and develops memory.develops memory.

Triggering the adaptive immune response results in activated T cells Triggering the adaptive immune response results in activated T cells and antibodies specific for the substance (antigen) that triggered it.and antibodies specific for the substance (antigen) that triggered it.

Antibodies react with antigenAntibodies react with antigen Block or neutralizeBlock or neutralize Activate complement systemActivate complement system Bind to Fc receptors on cells providing specificity to the effector activity of Bind to Fc receptors on cells providing specificity to the effector activity of

those cells those cells Activated T cellsActivated 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)