21. T-Cell Mediated Diseases Flashcards
two main forms of T cell mediated-immune reactions?
- phagocyte with ingested microbes in vesicles stimulates CD4+ T cell response
- infected cell with microbes in cytoplasm stimulates CD8+ T cell (CTL) response
activation nof macrophages from helper T cells involves what?
IFN-gamma from Th1 cell to macrophage IFN-gammaR
CD40L on T cell to CD40 on macrophage with ingested microbes
responses of activated macrophages (when activated by Th1 cells)?
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)
activated Th1 cells release what cytokines (which do what)?
TNF - inflammation
IFN-gamma - macrophage activation (DTH = delayed type hypersensitivity)
type IV hypersensitivities?
t cell-mediated, delayed-type hypersensitivity
beware, DTH is CD4/macrophage mediated…thre are other T-cell mediated diseases
which cytokines do Th2 cells release and what do they do?
IL-10, IL-4, IL-13 to inhibit macrophage activation and inflammation
The CD40L-CD40 interaction is critical for T cell-mediated activation of macrophages - explain?
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
Th17 cells secrete which cytokine that does what?
IL-17, which is a pro-inflamm cytokine capable of eliciting the production of other pro-inflammatory cytokines and chemokines
activation of CD4+ cells in the presence of what leads to differentiation into CD17?
TGF-beta and an inflammatory cytokine (IL-6, IL-1 and IL-23)
IL-23 (secreted by APC) helps the maintenance of Th17 cells
which cytokines inhibit IL-17 production?
IFN-gamma and IL-4
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?
serve as effector T cells in some autoimmune disease like RA and MS
what is mononuclear cell infiltration?
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
the migration of effector T cells from the blood to the site of infection is antigen-_______, but their retention at that site it antigen-_______.
independent, dependent
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.
IFN-g, TNF-a
what causes granuloma formation?
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)
typically, granulomas consist of what?
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)
what actually causes tissue damage in DTH?
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.
the DTH response to defined antigens is used as an assay to assess what?
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)
in leukocyte extravasation, which leukocytes extravasate first, second, last? and what are their associated endothelial adhesion molecules?
E-selectin: neutrophils
ICAM-1: monocytes
VCAM-1: Tcells
Th17/IL-17 defend against what type of pathogens?
extracellular bacteria and fungi
what cytokines are released by Th17 cells and what do they do?
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
role of Th1, Th2, and Th17 cells in disease?
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
tuberculosis
caused by mycobacterium tuberculosis - chronic DTH response/chronic granulomatous inflammation (caseating necrosis)
leprosy
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
leishmaniasis and Th1/Th2 balance?
strong Th1 response: resistant
predominantly Th2 response: leishmania infection & diffuse disease
why would a predominantly Th2 response result in ineffective reaction vs. an infection?
releases IL-4, IL-10, and IL-13 which INHIBIT the microbicidal activity of macrophages
evidence for the role of T cells in the pathogenesis of autoimmune diseases?
- 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)
what are the self antigenic targets in RA?
type II collagen, HSP
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?
- pro-inflamm cytokines
- chemokines that attract T cells, macrophages, neutrophils and other cells into the joints
- new BVs (angiogenesis)
- osteoclasts (bone damage)
wegener’s granulomatosis?
vasculitis - BV wall with granulomas
In contact sensitivity, which immune responses participate in tissue damage and what are 2 common examples?
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
superantigen-mediated diseases (toxic shock syndrome)
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
please give examples for the following immunotherapeutic approach: blocking of cytokine action either by neutralization of by interference with receptor binding
anti-TNF-a Ab or soluble TNF-a receptor ; antibodies vs receptors for IL-6, IL-1, or IL-17
used for RA
please give examples for the following immunotherapeutic approach: inhibtion of T cell activation
costimulation blockade by CTLA-4-Ig, Anti-CD40L Ab, or anti-CD3 Ab
please give examples for the following immunotherapeutic approach: immune deviation (eg Th1 to Th2)
altered peptide ligands (APL) containing a modified T cell receptor/MHC-binding residue
please give examples for the following immunotherapeutic approach: induction of regulatory T cells
- 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
