BL - Immunopathology Type IV Immune Regulation

Question 1

Type IV immunopathology definition

Answer 1

Also “T cell-mediated immunity” & “delayed hypersensitivity”; pathological outcomes of normal or abnormal T cell responses including helper and cytotoxic cells. Only type of immunopathology which does not require antibody or B cells

Question 2

Delayed hypersensitivity in TB skin testing

Answer 2

1. Small dose of TB protein injected intradermally 2. PPD antigen taken up by local macrophages/dendritic cells and presented on MHCII
2. Patients with anti-TB Th1 memory cells will be stimulated to produce IFN-y and attract macrophages
3. Macrophages will be the predominant cell in a positive (raised) PPD skin test

Question 3

Reason for absence of reaction after first poison ivy exposure

Answer 3

1) initiation: toxin associated with MHC on dendritic cells which stimulate Th1/Th17 but by the time there are lots in circulation, toxin has been worn off the skin and there is no reaction (T-cell maturation took days and now the antigen is no longer present)
2) elicitation: second exposure to toxin/antigen. Now your circulating memory T-cells encounter the epitope, bind it, and get activated. Secrete IFN-y which attracts/activates macrophages. Inflammation is visible within 6-12 hours and peaks 24-48 hours (delayed-type hypersensitivity).

Question 4

How is T cell immunity measured in laboratory?

Answer 4

Place T cells with antigens and measure T cell proliferation (cell numbers for proliferation, cell size for activation/blast transformation). Measure DNA synthesis using radiolabeled precursors. Can quantify cytokines released into medium.
Most commonly ordered test: QuantiFERON-TB Gold test.

Question 5

Explain why TB can be administered repeatedly to same subject

Answer 5

TB skin test does not have a sufficient dosage; it is NOT IMMUNIZING because a larger dose is required to immunize than to elicit reaction in a previously exposed person; can give multiple skin tests without them turning positive

Question 6

First-set vs. Second-set graft rejection

Answer 6

First set: skin graft from mouse strain A to strain M is rejected in 10-20 days. Recipient has 5-10% of their T-cells able to react with foreign MHC, because some foreign MHCs look like self MHC + peptide. These cells cause graft reaction in 10-20 days. As this process proceeds, recipient’s response to A histocompatibility antigens is boosted – develops more anti-A Th1 and CTL.
Second set: another A skin graft placed on same M recipient. Rejected in 5-10 days. This is a secondary response; results from T-cell memory developed during first exposure, which is specific (graft from unrelated strain C will be rejected in 10-20 days).

Question 7

Hyperacute rejection definition & mechanism

Answer 7

If you keep putting A grafts onto B, eventually they will be rejected even before they heal in (stay white and bloodless, never get perfused). Subsequent grafts will be rejected faster and faster (eventually “on the operating table”).

Question 8

Autoimmunity resulting from environmental exposure to tissues cross-reacting with human organs

Answer 8

Ex. Multiple sclerosis and progressive inflammatory neuropathy from cow brains. Brain removed from one mouse, mixed with innate-immunity stimulating adjuvant, injected into similar mouse: recipient develops experimental autoimmune encephalitis. If you make brain into an immunogen by presenting its antigens to your immune response (so it can be picked up by DCs and carried to lymph nodes) – then you will make activated T cells which will have no trouble entering and attacking corresponding organ. In mice, brain-infecting virus can trigger MS-like autoimmunity.

Question 9

3 requirements for Graft-versus-host disease

Answer 9

1) graft must have immunocompetent T cells
2) at least one antigen in host which graft’s T cells can recognize
3) host doesn’t fight back: must be relatively immunocompetent or unable to recognize graft’s MHC antigens, otherwise graft would be rejected too rapidly

Question 10

Graft-versus-leukemia phenomenon

Answer 10

After large doses of chemotherapy or radiation (myeloablative treatment), marrow from the best matched donor can be administered to patient.
Leukemia patients who receive self-bone marrow or T-depleted allogenic marrow have fewest GvH symptoms but higher leukemic relapse rate.
Don’t get GvH response because T-cells are developed then from donated clone

Question 11

HLA alleles and DTH reactions

Answer 11

1. HLA-B-57 (abacavir reaction in HIV treatment)
2. HLA-B-15 (Stephens-Johnson Syndrome, CTL forms of Type IV immunopathology)
3. Link between type 1 diabetes and HLA-DR3 or HLA-DR4

Question 12

Characteristics of Cytotoxic T Lymphocytes in DTH

Answer 12

less well studied; target cell (normal cells can be soaked in a epitope-sized peptide which associates directly w/MHC w/out having to be processed) mixed w/patient T cells and target cell death is measured

Question 13

HLA alleles and autoimmunity

Answer 13

T1 Diabetes and HLA-DR3 or HLA-DR4 (linkage disequilibrium w/HLA-DQ2 and HLA-DQ8)

Question 14

TB vaccine response

Answer 14

People who have been immunized with BCG vaccine will test “positive” to TB test, because the test can’t tell if you have been immunized or if you have been exposed to TB.
Quantiferon test used - add antigen from human TB (not known to crossreact with cow TB) to patient’s blood sample