21. T-Cell Mediated Diseases

Question 1

two main forms of T cell mediated-immune reactions?

Answer 1

1. phagocyte with ingested microbes in vesicles stimulates CD4+ T cell response
2. infected cell with microbes in cytoplasm stimulates CD8+ T cell (CTL) response

Question 2

activation nof macrophages from helper T cells involves what?

Answer 2

IFN-gamma from Th1 cell to macrophage IFN-gammaR

CD40L on T cell to CD40 on macrophage with ingested microbes

Question 3

responses of activated macrophages (when activated by Th1 cells)?

Answer 3

to be a better APC:

• increased expression of costim molecus (B7)
• increased expression of MHC molecs

to be a better killer:
- killing of phagocytosed microbes

to amplify activation:
- secretion of cytokines (TNF, IL-1, IL-12)

Question 4

activated Th1 cells release what cytokines (which do what)?

Answer 4

TNF - inflammation

IFN-gamma - macrophage activation (DTH = delayed type hypersensitivity)

Question 5

type IV hypersensitivities?

Answer 5

t cell-mediated, delayed-type hypersensitivity

beware, DTH is CD4/macrophage mediated…thre are other T-cell mediated diseases

Question 6

which cytokines do Th2 cells release and what do they do?

Answer 6

IL-10, IL-4, IL-13 to inhibit macrophage activation and inflammation

Question 7

The CD40L-CD40 interaction is critical for T cell-mediated activation of macrophages - explain?

Answer 7

it ensures that the APC macrophage is the one that responds most efficiently upon interaction w/T cell, thereby avoiding activation of macrophages in an indiscrete manner. Upreg of MHC and costim molecs on the surface of activated macrophages enhances the antigen presentation function of theses cells leading to amplification of the T cell response

Question 8

Th17 cells secrete which cytokine that does what?

Answer 8

IL-17, which is a pro-inflamm cytokine capable of eliciting the production of other pro-inflammatory cytokines and chemokines

Question 9

activation of CD4+ cells in the presence of what leads to differentiation into CD17?

Answer 9

TGF-beta and an inflammatory cytokine (IL-6, IL-1 and IL-23)

IL-23 (secreted by APC) helps the maintenance of Th17 cells

Question 10

which cytokines inhibit IL-17 production?

Answer 10

IFN-gamma and IL-4

Question 11

Th17 cells play an important role in mediating inflammation of the skin and GI tract, and in providing immunity vs some extracellular bacteria and fungi. But - what happens when they are over expressed/function aberrantly?

Answer 11

serve as effector T cells in some autoimmune disease like RA and MS

Question 12

what is mononuclear cell infiltration?

Answer 12

in response to an antigenic or infectious challenge, leukocytes leave the BVs at the site of the antigenic depot (thanks to orchestration of cytokines, adhesion molecules, chemokines) and accumulate in the perivascular area at that site

Question 13

the migration of effector T cells from the blood to the site of infection is antigen-_______, but their retention at that site it antigen-_______.

Answer 13

independent, dependent

Question 14

previously primed (sensitized) antigen-specific CD4+ T cells get reactivated at the site of the antigen/infection and the cytokines secreted by them in turn activate macrophages (cytokine?) and the endothelial cells of blood vessels (cytokine?) leading to vasodilation and leukocyte extravasation.

Answer 14

IFN-g, TNF-a

Question 15

what causes granuloma formation?

Answer 15

a persistent microbe (e.g., a pathogen having lipid-rich, poorly soluble components) causes continued activation of macrophages, and the resulting chronic DTH response leads to formation of nodules of inflammation called ‘granulomas’

(usually macrophages and neutrophils would destroy infectious organisms and remove dead tissues to facilitate repair after infection is controlled)

Question 16

typically, granulomas consist of what?

Answer 16

activated macrophages surrounded by a rim of helper T cells

(upon chronic activation, macrophages can change their shape to epitheloid cells and even form multinucleated Giant cells - due to fusion of macrophages)

Question 17

what actually causes tissue damage in DTH?

Answer 17

Chronic activation of macrophages leads to the continued production of microbicidal agents that diffuse into the surrounding area and inadvertently cause tissue damage. Chronic inflammatory response is followed by fibrosis that can severely compromise the function of the tissue/organ involved by replacing functional tissue with fibrotic tissue.

Question 18

the DTH response to defined antigens is used as an assay to assess what?

Answer 18

the status of cell-mediated immunity of an individual.

(the loss of DTH response to commonly encountered antigens is an indication of a deficient T cell function, and this condition = anergy)

Question 19

in leukocyte extravasation, which leukocytes extravasate first, second, last? and what are their associated endothelial adhesion molecules?

Answer 19

E-selectin: neutrophils

ICAM-1: monocytes

VCAM-1: Tcells

Question 20

Th17/IL-17 defend against what type of pathogens?

Answer 20

extracellular bacteria and fungi

Question 21

what cytokines are released by Th17 cells and what do they do?

Answer 21

IL-17:increases inflammatio and neutrophil response (acts on leukocytes and tissue cells to release, causes leukocytes to release chemokines, TNF, IL-1, IL6, and CSFs)

IL-22: increases barrier functin (acts on tissue cells)

BOTH stimulate release of antimicrobial peptides

Question 22

role of Th1, Th2, and Th17 cells in disease?

Answer 22

Th1 - IFN-gamma: autoimmune disease; tissue damage associated with chronic infections

Th2 - IL4, 5, 13: allergic disease and can serve as good regulators in autoimmune disease (control macrophage activation)

Th17 - IL-17, 22: autoimmune and inflammatory diseases

Question 23

tuberculosis

Answer 23

caused by mycobacterium tuberculosis - chronic DTH response/chronic granulomatous inflammation (caseating necrosis)

Question 24

leprosy

Answer 24

chronic DTH response occurs against mycobacterium leprae. Clinical outcome of infection with M.leprae depends on the host’s genetic make-up and the type of immune response induced: dissemitated lepromatous leprosy (LL) is associated with primarily Th2 response, where as tuberculoid leprosy (TT) is the outcome of a predominantly Th1 response

lepromin skin test (like PPD) is based on DTH response and is positive in TT but negative in LL

Question 25

leishmaniasis and Th1/Th2 balance?

Answer 25

strong Th1 response: resistant

predominantly Th2 response: leishmania infection & diffuse disease

Question 26

why would a predominantly Th2 response result in ineffective reaction vs. an infection?

Answer 26

releases IL-4, IL-10, and IL-13 which INHIBIT the microbicidal activity of macrophages

Question 27

evidence for the role of T cells in the pathogenesis of autoimmune diseases?

Answer 27

• presence of T cells and macrophages in lesions
• detection of antigen-specific T cells in the blood or affected organs
• ability of T cells derived from a diseased animal to induce (by adoptive transfer) the same clinical phenotype in a syngenic healthy recipient
• cytokine-mediated alterations in adjacent tissues as indicators of local T cell stimulation (expression of MHC II molecules on a cell that normally does not express these proteins)
• protection vs. disease by antibodies interfering w/T cell-APC interaction (anti-CD4 or anti-MHC antibodies)

Question 28

what are the self antigenic targets in RA?

Answer 28

type II collagen, HSP

Question 29

IL-17 produced by Th17 cells (also CD8 T cells, gammadelta T cells, and NKT cells) acts on synovial fibroblast-like cells and other cells to increase the production/activity of what in RA?

Answer 29

• pro-inflamm cytokines
• chemokines that attract T cells, macrophages, neutrophils and other cells into the joints
• new BVs (angiogenesis)
• osteoclasts (bone damage)

Question 30

wegener’s granulomatosis?

Answer 30

vasculitis - BV wall with granulomas

Question 31

In contact sensitivity, which immune responses participate in tissue damage and what are 2 common examples?

Answer 31

DTH and CTL participate in the damage, and relative contribution may vary depending on the antigen

eg Poison Ivy and contact dermatitis or nickel and DTH reaction

Question 32

superantigen-mediated diseases (toxic shock syndrome)

Answer 32

prototypic superantigens are present in staphylococcus aureus and streptococcus pyogenes. Superantigens cross-link MHC and T cell receptor (invariant parts o fhte T cell receptor VB), causing excessive polyclonal T cell activation (activation of many subsets of T cells of different specificities) –> inflammatory cytokines, fever, shock

Question 33

please give examples for the following immunotherapeutic approach: blocking of cytokine action either by neutralization of by interference with receptor binding

Answer 33

anti-TNF-a Ab or soluble TNF-a receptor ; antibodies vs receptors for IL-6, IL-1, or IL-17

used for RA

Question 34

please give examples for the following immunotherapeutic approach: inhibtion of T cell activation

Answer 34

costimulation blockade by CTLA-4-Ig, Anti-CD40L Ab, or anti-CD3 Ab

Question 35

please give examples for the following immunotherapeutic approach: immune deviation (eg Th1 to Th2)

Answer 35

altered peptide ligands (APL) containing a modified T cell receptor/MHC-binding residue

Question 36

please give examples for the following immunotherapeutic approach: induction of regulatory T cells

Answer 36

• priming of IL-10/TGF-B-secreting T cells by nasal/oral admin of antigen
• in vitro/in vivo expansion of CD4+CD25+ T cells (Foxp3-expressing Treg) for use in vivo