TYPE IV IMMUNOPATHOLOGY

Question 1

Type IV

Answer 1

T-cell mediated. Do not require antibody or B cells.

Question 2

Initiation

Answer 2

phase of an immune response following first exposure to the antigen. (immunization phase). Poison Ivy example. urushiol compound is what causes it. MHC gets the antigen. Common in contact immune responses. MHC on dendritic cells (either by binding directly to MHC, or by binding peptides which then get presented on MHC). The dendritic cell travels to the draining lymph nodes, where it presents its MHC plus antigen to the appropriate Th0 precursors, which develop into Th1 and Th17 cells.

Question 3

elicitation

Answer 3

of a reaction in a person who is already immunized (effector phase). memory T cells from the expanded clones are throughout the body, and get activated. They secrete interferon-γ which attracts and activates a large number of macrophages. , because of all the cellular events that need to take place, begins to be visible in 6 to 12 hours, and peaks at 24 to 48 hours, thus earning the label ►delayed- type hypersensitivity. Th1 –> IGN-Gamma–> M1. NOTE: 1 th1 can recruit 1000 macrophages!

Question 4

Memory T cells

Answer 4

are persisting cells in a clone that was expanded by contact with antigen. key thing is that there are more of them than in a naïve person. They also ►have a lower activation threshold, so that it takes less antigen for elicitation of a reaction than it did to immunize in the first place.. Tho–>Th1, so more easily triggered.

Question 5

Tuberculin skin testing

Answer 5

The Mantoux skin test is most commonly used in the USA. In it, 0.1 mL of PPD—purified PROTEIN derivative, a standardized preparation of M. tuberculosis antigens—is injected intradermally. (It is necessary to see a skin “bubble,” because if not the injection has gone subcutaneously, and will diffuse away before the reaction can get established.) The antigen is taken up by local macrophages and dendritic cells, and presented on MHC Class II. If the subject has an expanded number of anti-tuberculosis Th1 memory cells, they will come by and get stimulated, produce IFNγ, and attract macrophages. The test is read at 48 hours, and the diameter of the induration (firm raised part) is measured; 15 mm is always positive, and 10 or even 5 mm can be called positive under certain conditions, for example if a person is partly immunosuppressed. TB skin tests are not immunizing, and they can be repeated regularly without the subject becoming positive since it is a miniscule dose. In some countries kids get vaccined with Bacill Calmette Guerin (BCG)

Question 6

Immunization to TB antigens

Answer 6

normally happens during a primary infection, which is usually unapparent to the patient, so a positive routine skin test usually comes as a surprise

Question 7

T-Cell mediated immunity in Vitro

Answer 7

TESTING: Whole blood or isolated white blood cells (you need both T cells and APCs like monocytes) may be incubated with antigen in cell culture, and activation observed: one could count cell numbers for proliferation, look at cell size for activation (“blast transformation”), or at DNA synthesis using radiolabeled precursors.

Question 8

T-cell testing quantiferon-TB GOLD

Answer 8

test is new, very nice, and is preferred (2010, CDC) to skin testing when the subject has had BCG immunization. Purified M. tuberculosis (human-specific) proteins are added to a sample of whole blood, and after incubation, interferon-γ is measured in the medium by an ELISA assay. Unlike the skin test, it remains NEGATIVE in people vaccinated with BCG, (no cross-reactive antigen with BCG,) allowing you to distinguish infection from previous immunization.

Question 9

Cytotoxic T lymphocytesin DTH

Answer 9

They probably take part in many manifestations of T cell-mediated immunity, and are quite important in many autoimmune diseases, tumor immunity, and transplant rejection

Question 10

Contact dermatitis

Answer 10

Also called contact hypersensitivity or contact sensitivity or, INCORRECTLY, contact allergy; ‘allergy’ should be reserved for IgE-mediated events. The classic example of this is poison ivy, but many other chemicals can cause it; the main requirements are that they pass through intact skin to reach antigen-presenting cells, and they associate with MHC Class II. Treat with avoidance, and topical steroid creams or ointments. Example LATEX gloves are starting to go away in clinics.

Question 11

HLA and T cell Reactions

Answer 11

HIV example and learning objective) Up to 8% of people who are given ABACAVIR, a nucleoside reverse transcriptase inhibitor, for HIV, develop abacavir hypersensitivity syndrome which is quite awful and difficult to diagnose correctly. Nearly all people with the syndrome are HLA-B*5701. We now TEST for this allele before offering the drug, a good example of “personalized medicine”. This is a Class I proble and the syndrom is actualy a drug induced autoimmune reaction

Question 12

Graft rejection

Answer 12

Rejection is a complex phenomenon eventually involving most or all of the specific immune and nonspecific amplifying elements of the immune system. Allograft immunity shows specificity and memory:. First (10-20 days) and SECOND set reactions (5-10 days). Point it is faster the second time!

Question 13

Hyperacute or “white graft” reactions

Answer 13

If you keep putting A grafts onto B, eventually they will rejected even before they heal in, that is, they stay white and bloodless. This is due to the development of antibodies to histocompatibility antigens. Common with xenografts. DUE TO PREEXISTING ANTIBODY.

Question 14

Autoimmune diseases

Answer 14

any conditions are clearly autoimmune, and T cells are involved in the pathogenesis. Some of these conditions also involve autoantibodies, and thus there is both Type II and Type IV immunopathology

Question 15

Multiple sclerosis

Answer 15

the demyelinating disease in which T cell (t1/t17) reactivity to an autoantigen (myelin basic protein) was first shown, responds to therapies directed at T cells, such as the humanized monoclonal antibody natalizumab. But it also responds to the B cell-depleting monoclonal rituximab.

Question 16

Molecular mimicry

Answer 16

Using the information to scan a database of microbial proteins they have found several cases where a viral peptide, whose sequence is not necessarily the same as the MBP sequence, but which has close structural similarity, that is, distribution of charges and hydrophobicity, acts as a strong stimulator of clones of T cells derived from MS patients.

Question 17

Hashimoto thyroiditis

Answer 17

is characterized by a destructive attack by T cells on thyroid antigens. ►Almost 1.5 million people in the US have the disease, the most common cause of hypothyroidism. Like many autoimmune diseases, it has a familial tendency; and families with it also have increased incidence of other autoimmune diseases, like type 1 diabetes, vitiligo, and gluten-sensitive enteropathy (celiac disease)

Question 18

Sjogren syndrom

Answer 18

said to be the second most common autoimmune disease, but that’s only an estimate as it is difficult to diagnose; symptoms are highly variable until the characteristic dry eyes and mouth develop, which can take years. It is an autoimmune reaction against exocrine glands, especially those that secrete tears and saliva; little is known about its etiology, and pathogenesis seems to involve CTL

Question 19

Juvinile diabetes

Answer 19

Autoimmunity is strongly implicated in Type 1, or juvenile, or insulin-dependent diabetes mellitus (T1D). Depending on the technique used, antibody to -cells
(the islet cells that produce insulin) can be detected in the serum of over 90% of patients at the time of diagnosis (normals, fewer than 2%).

Question 20

HLA association with T1D

Answer 20

association between T1D and HLA-DR3 or HLA-DR4. These are in linkage disequilibrium with HLA-DQ2 and HLA-DQ8, respectively. The DQ genes are thought to be the problem; they have unusual amino acids placements in the antigen-binding groove that allows ready presentation of islet cell-associated peptides.

Question 21

Graft Vs. Host Reactions

Answer 21

If a non-identical graft contains T cells (and, except for corneas, they usually do, because they contain blood or have tissue spaces where leukocytes can be hiding) there is a perfectly good possibility that these cells will recognize HLA antigens of the recipient (host) as foreign, and so the graft will try to reject the host.

Question 22

For graft v host disease (GvHD) to result the following 3 conditions must be met:

Answer 22

1. The graft must contain immunocompetent T cells (even bone marrow has mature T cells in it).
2. There must be at least one antigen in the host which the graft’s T cells can recognize (so, no worries with identical twins.)
3. The host must be relatively immunoincompetent or unable for genetic reasons to recognize the graft’s MHC antigens, otherwise the graft would be rejected too rapidly.

Question 23

Acute GvHD

Answer 23

This develops in 2 to 10 weeks after bone marrow transplantation in humans. The symptoms include a nasty maculopapular skin rash; diarrhea; hepatic inflammation with jaundice; and infections (probably due to immunosuppression, as Tregs try to control the raging immune activation.) The treatment is with anti-inflammatory drugs like corticosteroids and, paradoxically, with immunosuppressives.

Question 24

Chronic GvHD

Answer 24

This develops in months to years, even in patients with a perfect HLA match; therefore it is probably against minor histocompatibility antigens. With a lot of chronically activated T cells pouring out cytokines, regulation is compromised and autoimmunity can become an issue.

Question 25

Graft versus leukemia reaction

Answer 25

For leukemia that has stopped responding to conventional therapy, one treatment is to give patients large doses of drugs or radiation, which would in themselves probably be fatal. One then can take marrow from the best matched allogeneic donor one can find, and give it to the patient after the high-dose (“myeloablative,” because it destroys all the bone marrow) therapy. MEANS a transplant regiment that produces the LEAST amount of graft vs host, but provides the best treatment.

Question 26

Th2 Cells in Immunopathology

Answer 26

Activated Th2 cells are found in the periphery in certain inflammatory and infectious states, ►especially asthma and chronic worm infestation. They activate macrophages (alternatively activated or M2) which produce fibrosis under these chronic conditions; and ►also attract eosinophils which, in excess, make inflammation more intense. So although this raises the question of whether allergy and asthma might really be T cell diseases, for now most people refer to asthma as a Type I condition because of the role played by IgE.

Question 27

Delayed type hypersensitivity

Answer 27

is an old term for T cell-mediated events that are considered undesirable or injurious.

Question 28

Brain story

Answer 28

Activated T cells can get through blood brain barrier. They need exposure to “brain” in lymph nodes.