lecture 5 effector mechanisms. host defense defensemechanisms innate inborn independent of previous...
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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)