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

Caspase 8

DownstreamCaspases

Cytotoxic T CellMechanismsCell lysis through granule release• Perforins – pore

formation• Granzymes –

proteases degrade cell components

• Takes a few hours

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

,Proliferation

s

Specific killing of virus-infected cells by cytotoxic T cells

Geha and Notarangelo, Fig. 45.2

Cytotoxic T cells attacking an infected cell

Geha and Notarangelo, Fig. 45.3

T-CTL

T-C

TL

T-CTL

T-CTL

T-CTL

SPOROZOITES

CLASS I MHC

IFN-gIL-1

ENDOGENOUS ANTIGEN PROCESSING AND T-CTL IMMUNITY

MALARIA

ENDOGENOUSPROCESSING

INFECTION OF HEPATOCYTES

INDUCTIONEXPRESSION

CIRCUMSPORATEANTIGEN

SPECIFIC T-CTL

TISSUE CULTURE TARGET CELLS

DYING CELLS

A. TISSUE CULTURE MONOLAYER

DYING FOLLICULARCELLS

BASEMEMT MEMBRANE OF THYROID GLAND

T-CTL TO THYROID FOLLICULAR CELLS

THYROIDFOLLICULARCELLS

B. AUTOIMMUNE THYROIDITIS

Hashimoto’s Thyroiditis

Local Reaction - Hashimoto’s Thyroiditis

Normal Thyroiditis

Roitt 23.2

Virus-infected cell monolayer

lysis, releaseof Cr

25 cpm

viral Ag-MHC complex

No lysis, little release of Cr

MHC

450 cpm

50 cpm

475 cpm

Normal cell monolayer

Chromium Release Assay

51

51

51

TCR α, β(Red, Yellow)

Antigenic Peptide (Green)

β2-Microglobulin(Light Blue)

MHC I Protein(Dark 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

IL-2

IFN

ETC.CTL

DTH

GO FOR IT

!

HELP!

AH! THANKS FOR THE GOODIES

ACTIVATION

HH

HH

H

HH

H

DAY 1DAY 7 DAY 12

DAY 14

DAY 21

H

DAY 3

EVOLUTION OF A DTH RESPONSE (SYPHILIS)

INDUCTIVE STAGE

REACTIVE STAGE

LATENT (HEALED) STAGE

FIBROSIS

Langerhans Cells in Epidermis -Expression of MHC Class II

Roitt 22.4

‘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 LeishmaniaIFN- 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 epidermis-dermis 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. lepraedue to a Th1-Th2 imbalance and a resulting poor DTH response

Appearance of Activated Lymphocytes (Blasts)

Roitt 22.16

Add mitogenor antigen

Activation

Proliferation

1 day 2-5 days

Add *Thymidine

*

*

*

*

**

Thym

idin

e In

corp

orat

ed

Time (days)

ConA Added

Donor lymphocytesadded

Nothing added

Blast Transformation Assay

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

T-DTH

C1->C3bOPSONIZATION

C3a, C5a, C5-7CHEMOTAXIS

LYMPHOKINESACTIVATED

MACROPHAGES

IgG ANTIBODY

SENSITIZEDCELLS

+

INSOLUBLE ANTIGEN

GRANULOMA - SPACE OCCUPYING MASS

TUBERCULOSISLEPROSYPARASITIC INFECTIONSSARCOIDOSISGRANULOMATOSES

CLINICAL CONDITIONS

GRANULOMATOUS REACTIONS

MACROPHAGE

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

Chest X-Ray: Tuberculosis

Roitt 22.21

Caseating Granuloma (Microscopic View)

Roitt 22.22CD4+ Th1 cells+ macrophages

‘Epitheloid’macrophages

caseous(cheese-like)necrosis

multinucleategiant cell

Borderline Leprosy

Roitt 22.19

Granulomatous Reaction to Ova – Schistosoma mansoni

Roitt 17.6

Ovum Ovum

Sarcoidosis - Lung

Roitt 22.24

Microscopic View - Sarcoidosis

Roitt 22.23

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 Aspergillusand other opportunistic pathogens due to inability of his phagocytes to produce H2O2 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