Immunopathology Type IV, Immune Regulation Flashcards
Define Type IV immunopathology
T cell mediated immunity and delayed hypersensitivity (in contrast to immediate hypersensitivity), do not require antibody or B-cells, but usually disease involve both Type IV and antibody-mediated phenomena. Examples of Type IV: rejection of allografts, raft vs. host disease (the reverse of allograft rejection), a positive tuberculin skin test, resistance to Mycobacterium tuberculosis, resistance to fungal infections, contact dermatitis, etc.
Describe the cellular and molecular events following intradermal injection of tuberculin antigen into a person who has cell-mediated immunity to it. Justify calling the process ‘delayed hypersensitivity’.
a. Tuberculin skin testing (Mantoux): 0.1 mL of purified protein derivative (PPD) of M. tuberculosis antigens is injected intradermally.
b. TB antigen is taken up by local macrophages and dendritic cells (remember? APCs with Class II MHCs). The APCs “present” the antigen to Th1 cells and if the patient has an increased number of anti-tuberculosis Th1 cells, they will come and get stimulated by the APCs Th1 cells produce IFNgamma and attract more macrophages.
Characterize the cells that would be seen in a 48-hour biopsy of the TB injection site with regard to whether T cells or macrophages predominate
The PPD test is read after 48 hours. The diameter of the induration (firm raised part that represents cellular infiltrate—which is FULL of macrophages if a reaction occurred because one Th1 cell can attract 1000 macrophages) is measured and 15 mm is positive, 5-10 mm can even be positive under certain conditions (ie: immunocompromised patient).
Explain why a person usually has no observed symptoms when first exposed to poison ivy.
The initiation phase of an immune response follows the first exposure to the antigen and the person is “immunized”. They may not KNOW they have been immunized because by the time the number of T cells are increased throughout the circulation, the antigen (poison ivy oil) has usually been washed off or worn off the skin, thus no red area of inflammation occurs. Their body has done everything correctly, but it just was too slow to elicit a response to the first exposure
Discuss how a chemical or small peptide might not need to be processed through an antigen presenting cell to be presented by that cell to T cells.
Processing of antigen is required to reduce the antigen to an epitope-sized particle capable of interacting with the MHC. If the antigen is already reduced to the size of the epitope, as with small chemicals or peptides, it may associate directly with the MHC without processing. Antigens can also bind to a peptide which is then presented on an MHC
Discuss in principle how T cell immunity could be measured in the laboratory
a. Whole blood or WBCs can be incubated with antigen in cell culture and activation observed, look at cell numbers for proliferation, look at cell size for activation “blast transformation”, look at DNA synthesis using radiolabeled precursors, measure cytokines released into the media
b. QuantiFERON-TB: purified M. tuberculosis-specific (human, NOT cow like the PPD) proteins are added to sample of whole blood and after incubation the IFNgamma levels are measured in the medium with ELISA. The test will be negative in people vaccinated with BCG, allowing you to distinguish between infection and previous immunization. The test will be positive if you have sufficient T cells against human M. tuberculosis.
Explain why TB skin tests can be administered repeatedly to the same subject
The dose of PPD to elicit a positive reaction in an immune person is much lower than would be required to immunize him/her. Therefore, the TB skin test does NOT immunize a person and they can be repeated with the subject becoming positive
Differentiate between a first-set and second-set graft rejection.
This is a similar idea to memory cells during infection. In a “first-set” graft rejection, a recipient rejects a graft in 10-20 days because 5-10% of the recipient T cells recognize the graft MHCs as self MHC plus antigen, thus becoming activated. During the response anti-graft Th1 and CTLs are boosted and rejection occurs in full force. In a “second-set” graft rejection another skin graft from the same donor is placed upon the same recipient. This time the graft is rejected in 5-10 days. This quicker rejection is a result of memory T-cells recognizing the graft and being able to more quickly up-regulate a response. If another unrelated donor gave a graft, it would be rejected in 10-20 days suggesting that the response is specific
Define hyperacute rejection and indicate the mechanism
A hyperacute rejection is one in which a graft is rejected before it even has time to “heal in.” This is sometimes called a “white graft” reaction because the graft stays white and bloodless. A hyperacute rejection results from the development of antibodies against histocompatibility antigens. Hyperacute rejections are common in xenografts (from another species) because humans have a pre-existing antibody against ubiquitous carbohydrate epitopes present in many animal species, but not humans.
Discuss how autoimmunity can result from environmental exposure to tissues that cross-react with human organs.
The example presented about this concerns the brain. The brain is antigenic, but not immunogenic to its owner because during T-cell development there is not brain protein presented causing the negative selection of anti-brain T-cells. Thus, anti-brain T-cells exist in everyone’s T-cell repertoire, they just are hardly ever stimulated because the brain is well defended and well protected. However, if the T-cells were to somehow get stimulated against the brain, they would attack it. This is believed to have happened in a meat packing plant in Minnesota where several workers charged with the task of blowing the brains out of pig heads developed severe neurological problems. It is believed that the workers inhaled pig brain pieces and their own cells presented them to T-cells as antigens. Because pig brain and human brain proteins are similar, the T-cells that were activated against the pig brain cross-reacted with the human brains of the workers and caused the neurological issues. Mouse studies have shown that this is possible and some researchers believe a mechanism similar to this may be the underlying cause of MS
Discuss the three requirements for graft-versus-host disease to occur
1) The graft must contain immunocompetent T-cells (bone marrow does)
2) There must be at least one antigen in the host which the graft’s T-cells can recognize
3) The host must be relatively immunoincompetent or unable for some other reason (possibly genetic) to recognize the graft’s MHC antigens. If the host recognized the graft MHCs, the graft would be rejected too quickly for a graft vs. host reaction to occur.
Define the graft-versus-leukemia phenomenon
Studies have shown that patients who receive T-depleted allogenic marrow or marrow from themselves during a bone marrow transplant have a higher rate of leukemia relapse than those who get allogenic bone marrow that still has T-cells. Thus, it is believed that graft-versus-leukemia reactions are somehow important for the success of a bone marrow transplant. The mechanisms underlying this phenomenon are not well understood
Speculate on the role of HLA alleles in autoimmunity and chronic inflammatory diseases
It is believe that there is an association between HLA haplotype and autoimmunity. This has been shown in Type 1 diabetes and celiac disease. The HLA alleles a person inherits determine the ways in which their antigen presenting cells display materials and their T-cells recognize presented materials. Thus, if a person’s HLA has certain amino acids arranged in ways that make them more likely to recognize self as foreign (β-cells in pancreas), that person will be more likely to develop autoimmune disease. Thus, there often is a genetic element in some autoimmune disorders
