IMMUNE EFFECTOR MECHANISMS Cell-Mediated Reactions
T-Cell Cytoxicity Definition - cytotoxicity involving direct contact between CTLs and target cells, resulting in target cell lysis or apoptosis Mechanisms TCR on CD8+ CTL binds to Ag-MHC Class I complexes on target cell CTL activation results in release of granules containing perforin and granzymes Perforin can mediate pore formation, target cell lysis Granzymes together with Fas-Fas ligand interaction trigger apoptosis of target cell (programmed cell death) Cytokines released(ifn-, TNF-α) may also be cytotoxic
Cytotoxic T Cell Mechanisms Cell lysis through granule release Perforins pore formation Granzymes proteases degrade cell components Takes a few hours Downstream Caspases Caspase 8 Activation of apoptosis in target cell Triggered by Fas-Fas ligand binding Activates JUN kinase, Caspase 8 Aided by granzymes Causes destruction of mitochondria, DNA Takes 1-2 days
T-Cell Cytoxicity: Medical Aspects (Examples) Protective Viral infections Cancer - immune surveillance, recognition of TSTAs Intracellular pathogens Immunopathologic Autoimmune diseases Contact dermatitis (together with DTH) Viral exanthems (rash and fever) Allograft rejection (together with DTH)
Clinical Vignette T-Cell Cytotoxicity, from Geha and Notarangelo, Case Studies in Immunology Case 45 Acute Infectious Mononucleosis 15 yo Emma Bovary had a severely sore throat, lymphadenopathy, and 2 weeks of fever, but eventually improves with supportive therapy Fig. 45.1
CD8+ effector T cell activation by APC, CD4+ Helper cell s, Proliferation
Specific killing of virusinfected cells by cytotoxic T cells Geha and Notarangelo, Fig. 45.2
Cytotoxic T cells attacking an infected cell
Geha and Notarangelo, Fig. 45.3
MALARIA ENDOGENOUS ANTIGEN PROCESSING AND T-CTL IMMUNITY SPOROZOITES INFECTION OF HEPATOCYTES ENDOGENOUS PROCESSING CLASS I MHC CIRCUMSPORATE ANTIGEN T-CTL IL-1 T-CTL T-CTL IFN-g INDUCTION T-CTL T-CTL EXPRESSION
A. TISSUE CULTURE MONOLAYER DYING CELLS SPECIFIC T-CTL TISSUE CULTURE TARGET CELLS B. AUTOIMMUNE THYROIDITIS DYING FOLLICULAR CELLS THYROID FOLLICULAR CELLS T-CTL TO THYROID FOLLICULAR CELLS BASEMEMT MEMBRANE OF THYROID GLAND
Hashimoto s Thyroiditis
Local Reaction - Hashimoto s Thyroiditis Normal Thyroiditis Roitt 23.2
51 Chromium Release Assay Virus-infected cell monolayer 450 cpm lysis, release of 51Cr viral Ag-MHC complex 50 cpm Normal cell monolayer 25 cpm MHC No lysis, little release of 51 Cr 475 cpm
TCR α, β (Red, Yellow) Antigenic Peptide (Green) MHC I Protein (Dark Blue) β2-microglobulin (Light Blue)
Delayed Type Hypersensitivity (DTH) Definition - activation of macrophages by cytokines produced by T-DTH lymphocytes Mechanisms Exposure of CD4+ cells to Ag-Class II MHC complexes results in activation, proliferation, and differentiation Differentiated Th1 cells express IL-2, Macrophage Chemotactic Factor (MCF), IFN-, and TNF- IL-2 activates additional T cells; MCF and IFN- attract and activate macrophages Enhanced motility, phagocytic activity, and killing activity of activated macrophages permits killing of pathogens or host cells
DTH IL-2 IFN GO FOR IT! CTL ETC. HELP! ACTIVATION AH! THANKS FOR THE GOODIES
EVOLUTION OF A DTH RESPONSE (SYPHILIS) DAY 1 DAY 3 DAY 7 DAY 12 H INDUCTIVE STAGE H H H DAY 14 REACTIVE STAGE H H H H H DAY 21 LATENT (HEALED) STAGE FIBROSIS
Roitt 22.4 Langerhans Cells in Epidermis - Expression of MHC Class II
Resting Macrophages Activated, Angry Macrophages
Delayed Type Hypersensitivity (DTH): Medical Aspects (Examples) Protective Destruction of intracellular bacteria (mycobacteria), protozoa, and fungi Cancer - immune surveillance Immunopathologic (overlaps with T-CTL) Contact hypersensitivity Autoimmune diseases Acute graft rejection
Macrophage Activation and Resistance to Leishmania IFN- Treated Untreated
Clinical Vignette DTH Reactions, from Geha and Notarangelo, Case Studies in Immunology Case 53 Contact Hypersensitivity to Poison Ivy 7 yo Paul Stein develops itchy eruptions after a hiking trip which responded to corticosteroids; the lesions rebounded after the corticosteroids were stopped.
Poison Oak Exanthem (Rash) Blistering accumulation of fluid at epidermisdermis junction Mononuclear infiltrate CD4 + T cells and macrophages
Clinical Vignette DTH Reactions, from Rosen and Geha, Case Studies in Immunology Case 48 Lepromatous Leprosy Ursula Iguaran has leprosy, and develops disseminated lesions with large numbers of M. leprae due to a Th1-Th2 imbalance and a resulting poor DTH response
Appearance of Activated Lymphocytes (Blasts) Roitt 22.16
Blast Transformation Assay Add mitogen or antigen Activation Add *Thymidine 1 day 2-5 days Proliferation * * * * * ConA Added * Thymidine Incorporated Donor lymphocytes added Nothing added Time (days)
Granulomatous Reactions Definition - space-occupying lesion consisting of a mononuclear infiltrate at the site of deposition of a poorly degradable antigen Mechanisms Usually, CD4+ T cell-mediated; can also be nonspecific or antibody-mediated A poorly degraded or persistent Ag (e.g M. tuberculosis) activates a DTH response Because the Ag is not eliminated, large numbers of lymphocytes and macrophages accumulate, causing a granuloma Epithelioid cells, multinucleate giant cells form, and tissue displacement, necrosis, and fibrosis cause pathology
GRANULOMATOUS REACTIONS INSOLUBLE ANTIGEN C1->C3b OPSONIZATION MACROPHAGE IgG ANTIBODY + C3a, C5a, C5-7 CHEMOTAXIS T-DTH SENSITIZED CELLS GRANULOMA - SPACE OCCUPYING MASS LYMPHOKINES ACTIVATED MACROPHAGES CLINICAL CONDITIONS TUBERCULOSIS LEPROSY PARASITIC INFECTIONS SARCOIDOSIS GRANULOMATOSES
Granulomatous Reactions: Medical Aspects (Examples) Both protective and immunopathologic Mycobacterial infections (tuberculosis and leprosy) Parasitic infections (Wucheria bancrofti (filariasis) elephantiasis) Immunopathologic Sarcoidosis: granulomas of unknown etiology Crohn's disease: granulomatous reactions in bowel
Roitt 22.21 Chest X-Ray: Tuberculosis
Caseating Granuloma (Microscopic View) Roitt 22.22 multinucleate giant cell caseous (cheese-like) necrosis Epitheloid macrophages CD4 + Th1 cells + macrophages
Roitt 22.19 Borderline Leprosy
Granulomatous Reaction to Ova Schistosoma mansoni Ovum Ovum Roitt 17.6
Roitt 22.24 Sarcoidosis - Lung
Roitt 22.23 Microscopic View - Sarcoidosis
Clinical Vignette Granulomatous Disease, from Rosen and Geha, Case Studies in Immunology Case 26 Chronic Granulomatous Disease Randy Johnson (not the pitcher) develops granulomas and is unable to ward off Aspergillus and other opportunistic pathogens due to inability of his phagocytes to produce H 2 O 2 and superoxide anion.
Keep in mind that responses to any infectious agent or antigen are rarely, if ever, of a single type. For example, mycobacterial infections produce strong DTH responses, but may also generate CTL reactions; antiviral responses often include antibody, DTH and CTL components.
Emerald Pool, Yellowstone National Park