Lecture 24 Type 4 Hypersensitivities Flashcards
Give the quick highlights of type 4 hypersensitivities
- Cell-mediated type hypersensitivity
- Delayed-type hypersensitivity (usually 48-72 hours)
- Mediated by Th1 cells and cytokines, macrophages
- Common presentations: contact dermatitis, graft rejection
What is being pictured here?
Contact dermatitis
In this case, the disease resulted from a type 4 hypersensitivity to poison ivy.
When is the immune system’s cell-mediated immunity (CMI) response usually most important?
In response to intravesicular pathogens and cytokines.
Th1 response.
Key cytokines: IL2, TNF, IFN gamma
Learning Objective 1
Explain why antibody does not provide protective immunity for some diseases and what type of immunity can provide protection for those diseases.
Antibody cannot enter cells to reach intravesicular pathogens or intracellular viruses.
In these cases, cell-mediated immunity (CMI) is the most important mode of protection.
Learning Objective 2
Define type IV hypersensitivity and give an overview of the cells and mediators involved. – include cells, cytokines, and any other important mediators (e.g. macrophage products)
Cell-mediated, delayed-type hypersensitivity
- Th1 cells are sensitized to antigens and release IL2, TNF, and IFN gamma in response to the antigen.
- IFN gamma activates macrophages to M1 “angry” macrophages
- If antigen is presented on MHC 1 through the endogenous pathway, CTLs will that encounter the antigen will induce apoptosis.
- Main cellular infiltrate: lymphocytes and macrophages.
How does an animal become sensitized to an antigen in type 4 hypersensitivities?
- Process takes 1-2 weeks
- Antigen captured by dendritic cell (Langerhans cell), which drains to regional lymph node.
- Presentation of antigen on MHC2 to T cells and secrete IL12.
- Th1 cells clonally expand.
- If antigen is presented on MHC1 through the endogenous pathway, will cause clonal expansion of CTLs.
Learning Objective 3
Give a brief explanation for why this hypersensitivity is delayed – 24-72 hours.
Memory lymphocytes have to circulate through the blood stream to reach the site of the antigen. Once there, they need to produce and secrete cytokines to attract and activate macrophages.
All of this takes time.
You perform an intradermal TB skin test on a cow. What would you expect the result to look like and when would you expect to see it?
Raised, hardened nodule (an induration) on skin resulting from influx of lymphocytes and macrophage.
Expect to see results in 48-72 hours.
What does a negative tuberculin skin test suggest?
Suggests that memory T cells are not responding to the antigens injected into the skin.
Note: there can be false negative results. These occur in the case of recent infections where memory T cells have not had time to form, immunosuppression, etc.
Learning Objective 4
Describe the series of events that occurs to result in a positive intradermal skin test for tuberculosis and what it means.
- Tuberculin injected into dermis. Antigen is taken up by APCs and presented on MHC2 through the exogenous pathway.
- If memory T cells are present, they will recognize the presented antigen and release their cytokines.
- Cytokines cause upregulation of addressin molecules on endothelium and activation of macrophages to M1 macrophages, resulting in inflammation.
- A positive result indicates that the animal has memory T cells to TB and is thus currently infected or was previously infected.
Learning Objective 5
Define induration, granuloma, or abscess
Induration - a hardened skin nodule resulting from mononuclear cell accumulation. Example: positive TB skin test.
Granuloma - a large nodule that is a sign of chronic inflammation. Mononuclear cells found at the periphery, and the centers are often necrotic.
Abscess - accumulation of purulent material resulting from the activity of neutrophils. Suggests actue inflammation.
Learning Objective 6
Compare and contrast the intradermal skin test for allergies and the intradermal skin test for type IV hypersensitivity.
Both involve injections directly into the dermis
Allergy test
- Symptoms result from mast cell degranulation, arachidonic acid derivatives, and cytokines. Takes 15-30 minutes.
Tuberculin skin test
- Symptoms result from memory Th1 cytokines and accumulation of mononuclear cells. Takes 24-72 hours.
Where is the tuberculin skin test administered in a cow?
Caudal tail fold
Learning Objective 7
Describe the “gamma” test for tuberculosis.
Recall that when a memory Th1 cell encounters its antigen, it releases IFN gamma.
- Take peripheral blood sample and purify out monocytes and lymphocytes. Monocytes will differentiate to macrophages.
- Add TB antigen, which is taken up by macrophages and presented on MHC2.
- If memory Th1 cells are present, they will release IFN gamma in response to the antigen. IFN gamma in solution indicates a positive test.
What is a hapten and how can a hapten like urushiol (poison ivy molecule) cause contact dermatitis?
Haptens are molecules that are not antigenic by themselves but become antigenic when bound with other proteins.
Urushiol enters the body and binds to self proteins. If it binds extracellularly, it will be taken up by APCs and presented on MHC2, resulting in CD4+ activation. If it binds intracellularly, it will be presented on MHC1 and cause CD8+ activation.
Because of resulting memory cell formation, future exposure to urushiol will result in contact dermatitis.
