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37 Cards in this Set
- Front
- Back
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What is immunologic tolerance?
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Lack of response to antigens induced by exposure to these antigens
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Central vs Peripheral Tolerance:
Location Cells Involved Deletion/Anergy |
Central Tolerance: when developing lymphocytes encounter antigen in the primary (central) lymphoid organs: thymus, bone marrow
Lymphoid precursor exposed to self-antigen, if immature lymphocyte has receptor for self-Ag, it is deleted (undergoes apoptosis). If not, maturation of clones not specific for self-Ag pass to peripheral lymphoid tissues. Peripheral: when mature lymphocytes encounter antigen in the peripheral (secondary) lymphoid organs Mature lymphocytes exposed to self-Ag, if responsive, cell undergoes apoptosis or anergy (non-reactive). If non-reactive, they wait for the right foreign Ag. |
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How is negative selection carried out? (Cells involved)
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Negative Selection: When cells that react too strongly with Ag's are induced to undergo apoptosis
Double positive thymocyte is exposed to an APC with self-antigen; if the CD4+8+ cell exhibits strong recognition, it undergoes apoptosis |
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Function of AIRE?
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AIRE = Autoimmune Regulator
Protein responsible for expression of peripheral proteins in thymus; increases exposure of developing T cells to normal proteins from throughout body Facilitates T cell education Note: All self-Ag's from throughout the body are NOT presented in thymus or BM (we don't just rely on Central Tolerance!) |
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What is anergy? When does it occur?
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Functional inactivation of T cells
Occurs when Ag is recognized without co-stimulation |
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Where do Regulatory T Cells arise?
What differentiates them from other T cells? What is their role? How is this carried out? (2 ways) |
Tregs arise in thymus and peripheral lymphoid organs
Characterized by CD25 and FoxP3 expression Ensure effector T cells aren't reacting to self-Ag 1) Contact Dependent Suppression: CD25 will bind IL-12 being released by APC's (Naive T Cell won't bind it) 2) Cytokine-Mediated Suppression: Treg (from thymus!) releases IL-10, TGF-beta which inhibits Th1 cells (prevents them from activating macs) |
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APC-Naive T Cell Signals Required for:
Clonal Expansion Anergy (2 ways) |
Clonal Expansion (Normal Response):
APC binds with MHC-Ag, B7 binds T cell's CD28 Anergy: 1)APC presents MHC-Ag, but not co-stimulation 2) APC presents MHC-Ag, B7 binds CLTA-4 receptor on T Cell |
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APC-Naive T Cell Signals Required for:
Clonal Expansion Deletion (2 ways) |
Clonal Expansion:
APC with MHC-Ag and co-stim binds Naive T Cell and releases IL-2-->Anti-apoptotic Protein produced-->CLONAL EXPANSION Death Receptors: APC with MHC-Ag, NO CO-STIM binds Act'd T Cell, IL-2 release-->Fas and FasL expression-->APOPTOSIS Pro-Apoptotic Proteins: APC with MHC-Ag, NO CO-STIM binds Naive T Cell, pro-apoptotic protein expressed-->APOPTOSIS |
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How do expression of CD8 T Cell populations and Fas-receptors correlate during the onset of adaptive immune response?
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Slow, steady rise of CD-8's
Much more rapid Fas-receptor expression, begins decline when CD8 cells reach peak |
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Describe the molecular events following binding of FasL to FasR.
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FasL binds FasR and forms FADD (Death Complex)
Stimulates Caspase 8 Cleaves Caspase 3 Cleaves PARP (DNA repair TF) Cell Death |
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Describe the molecular events following IFN-alpha binding IFNR.
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IFNalpha binds IFNR
Pi JAK Pi STAT Results in Gene Transcription |
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What is the effect of IFNalpha release on cell apoptosis?
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IFNalpha inhibits Fas Signaling; it provides protection from apoptosis
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Tolerogenic Self Antigens vs Immunogenic Foreign Antigens:
Presence in Generative Organs Presentation with Second Signals Persistence of Antigen |
Self-Ag's:
Present in Primary Lymphoid to induce negative selection and Tregs No co-stimulation; deficiency of second signals lead to anergy or apoptosis Long-lived; repeated T cell activation induces apoptosis Microbe: Not presence in PRIMARY lymphoid organs; concentrated in PERIPHERAL lymphoid organs Yes, microbes usually present with secondary sygnals to promote lymphocyte survival and activation Usually short-lived bc immune system eliminates Ag |
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Where does B cell CENTRAL tolerance occur? How does it differ from T cell central tolerance?
Under what conditions would apoptosis be induced? |
B cell Central Tolerance occurs in Bone Marrow
Differs because receptors can undergo editing when self-Ag is encountered If immature B cell exhibited strong recognition of self-Ag, it'd undergo apoptosis |
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Where does B cell PERIPHERAL tolerance occur?
How are self-antigen recognizing cells weeded out? (2 ways) |
Occurs in peripheral lymphoid tissues
Ag recognition without help! If Mature B Lymphocyte recognizes a self-Ag it is inactivated (Anergy) B cells that are partially activated by recognition of self-Ag's may be excluded from lymphoid follicles and die by apoptosis bc deprived of survival stimuli |
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How could self-reactive lymphocytes destroy tissue during time of infection?
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Cytokines released cause influx of lymphocytes, activation of self-reactive lymphocytes, and subsequent tissue destruction (autoimmune disease)
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Which gene mutations are most associated with self-reactive lymphocytes?
Give an example of such a gene and diseases its associated with. |
MHC Genes: HLA alleles
HLA D4: Rheumatoid arthritis, IDDM, Pemphigus Vulgaris |
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Disease Association for C2, C4 (complement) mutations?
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Lupus-like disease
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Disease Association for Fas, FasL mutations?
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Autoimmune Lymphoproliferative Syndrome (ALPS) via defective elimination of self-reactive T and B lymphocytes
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Disease association for FoxP3 mutations?
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Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (also lymphoproliferative diseases) due to deficiency of Tregs
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Disease Association for AIRE mutations?
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Autoimmune Polyendocrinopathy due to defective elimination of self-reactive T cells in thymus (defect in central tolerance)
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How is autoimmunity achieved by molecular mimicry?
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Microbial antigen looks enough like self-antigen that when presented to Self-Reactive T cell (along with second signal), T cell becomes activated and destroys self tissue
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How is autoimmunity achieved by induction of costimulators on APCs?
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Microbes may activate the APCs to express costimulators(B7) and when these APCs present self-ag's, the self-reactive T cells are activated (B7 attaches to CD28 receptor), rather than being rendered tolerant.
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In order to trigger immunity, tumor antigens must be recognized as non-self. List three ways this can be achieved.
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Mutations
Over-expression Aberrant expression (expressed at a location or time when they shouldn't be) |
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What is the effect of immunodeficiencies on tumor development?
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Immunodeficient individuals have an increased incidence of some tumor types--suggests that immune system protects against growth of tumors (immune surveillance)
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What is the effect of inflammation on tumor development during chronic infection? Provide 2 examples.
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Chronic inflammation leads to tolerization of Ag's, which contributes to the development of cancer.
Ex: Hep B: hepatocellular carcinoma H. pylori: gastric carcinoma |
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Ras, Bcr/Abl are examples of ______________
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oncogene products recognized by CD8+ CTL's
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2 examples of an oncogenic virus.
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HPV
EBV |
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Are tumor antigens intracellular or extracellular?
Which class of MHC molecule are they presented on? |
Intracellular
MHC I |
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How is induction of a CD8+ T Cell against tumors achieved?
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Cross-priming (cross-presentation):
Tumor cells or antigens taken up by DC's, processed, presented to T cells B7 costimulation provide second signal to CD8's May also stimulate CD4+ T Cells which release cytokines for dx/dy of CD8's Dx/Dy'd CTLs kill tumor cells without requirement for costimulation or T cell help (Effector Phase) |
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How does vaccination against tumor antigens enhance anti-tumor immunity?
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Engages APC's
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How does combining chemotherapy with immunotherapy enhance anti-tumor immunity?
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Chemo will damage vasculature and improve access for immune cells
Inflammation will help engage APC's Initial tumor cell death will 'feed' APC's |
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What are three ways tumor cells evade the immune system?
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1) Antigen-loss variant of tumor cell (fails to produce tumor Ag)
2) Class I MHC-deficient tumor cell (mutations in MHC genes or genes needed for Ag processing) 3) Production of immunosuppressive proteins or expression of inhibitory cell surface proteins (inhibition of T cell activtn, ex: IL-10, TGF-beta) |
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What are three vaccination methods that result in enhanced anti-tumor immune response?
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1) Vaccinate with tumor antigen-pulsed (incubated) DC
2) Vaccinate with DNA plasmid containing cDNA for tumor antigen to express antigen or transfect DC's 3) Vaccinate with tumor cell expressing costimulators (B7) or IL-12 (B7 will stimulate tumor-specific T cell, IL-2 will enhance proliferation and dx/dy of tumor-specific T cells) |
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Role of EGFR in Non-Small Cell Lung Cancer?
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Epidermal GF Receptor expressed on NSCLC to help them multiply in body
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EGFRBi vs EGFRBi-Armed ATC
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EGFRBi: bispecific Ab made of two Ab's, anti-CD3 and anti-EGFR that are chemically joined together so can bind both T cells and EGFR+ cancer cells
EGFRBi-Armed ATC: activated T Cell coated with EGFRBi so they specifically target and kill EGFR+ tumor cells (Note: ATC achieved by exposing T cells to IL-2) |
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What is leukapheresis?
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Blood transfusion that only selects WBC's, returns all other cells to donor
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