Immunogenetics and Transplantation Flashcards
Define the human Major Histocompatibility Complex. Distinguish between HLA-A and HLA-B antigens and the HLA-D
a. Major Histocompatibility Complex: a family of genes, coded for on a single chromosome, that code for histocompatibility antigens, some of which are expressed on the surfaces of all nucleated cells. MHC in humans is HLA (Human Leukocyte Antigen). The most important loci within the HLA are HLA-A, HLA-B and HLA-D, of which HLA-DR is the most interesting for transplanters.
Distinguish between HLA-A and HLA-B antigens on the one hand, and the HLA-D group on the other, in terms of: which associate with foreign antigens for recognition by helper T cells; which, in association with foreign antigens, are the targets for killer T cells.
- HLA-A and HLA-B code for Class I MHC and so they are on all nucleated cells and are recognized by cytotoxic
- HLA-D (DP, DQ and DR) code for Class II MHC and are on antigen presenting cells only (macrophages, dendritic cells, etc), they are recognized by T helper cells.
Define haplotype
combination of alleles (DNA sequences) at adjacent locations (loci) on the chromosome that are transmitted together. The MHC gene set that you inherited from your parents is called a haplotype.
Define alloantigen
antigen that is a part of an animal’s self-recognition system. e.g., Major histocompatibility complex molecules. When injected into another animal, they trigger an immune response aimed at eliminating them. Therefore, it can be thought of as an antigen that is present in some members of the same species, but is not common to all members of that species. If an alloantigen is presented to a member of the same species that does not have the alloantigen, it will be recognized as foreign. They are the products of polymorphic genes
Distinguish Class I and Class II histocompatibility antigens.
- Class I histocompatibility antigens: present on all nucleated cells (and platelets)
- Class II histocompatibility antigens: present on antigen presenting cells (B cells, macrophages and DCs)
Identify the chromosome on which the MHC is found in humans
6p
Discuss HLA-A and B typing in terms of how many antigens a person expresses at each locus; given two unrelated parents’ haplotypes, predict their children’s phenotypes.
-Like most genes, each of these loci are expressed codominantly, so that at the HLA-A locus you have both paternal and maternal alleles expressed.
Father HLA phenotype: A1, A3, B5, B7, DR9, DR11. Mother HLA phenotype: A2, A4, B6, B8, DR10, DR12. Child: A1, A4, B6, B7, DR11, DR12. The haplotypes are as follows:
—-Child: A1, B7, DR11 and A4, B6, DR12
—-Mother: A4, B6, DR12 and A2, B8, DR10
—Father: A1, B7, DR11 and A3, B5, DR9
Name the best probable donors of tissues or bone marrow to an individual, and discuss the reasons for your choices.
a. HLA-DR (Class II) matching is the most important thing T helper cells won’t be stimulated. In terms of Class I matching, HLA-A and HLA-B are the most importantkiller T cells won’t be stimulated but Th1 cells will be.
b. The best probably donor will be an identical twin, followed by a sibling, there is a 25% chance that two siblings will have identical haplotypes and will therefore be accepted as tissue/bone marrow donations.
c. Parents will always be ½ different from their child so they are not good donors. Likewise, children are ½ different from their parents, so they are not good donors.
d. You can also use volunteer donor if they match via HLA.
e. For bone marrow, you look for matches at A, B, C, DR and DQ. A 10/10 match is desired.
Describe the one-way mixed leukocyte reaction (MLR) and discuss its use.
To answer the question: How strongly do the recipient’s T cells recognize the Class II of this potential donor versus that one?
Cells from the donor are treated with DNA synthesis inhibitors or radiation (kills lymphocytes, but not APCs like macrophages) to prevent their division. You want to know if the recipient can recognize the donor’s MHC. Then the cells from donor and recipient are mixed together to see if recipient’s Th cells divide in response to the donor’s HLA-D (mostly DR, on monocytes). A strong reaction (burst of cell division) may preclude the transplant.
Distinguish between “HLA-D” and HLA-DR, -DP, -DQ
HLA-D are all Class II MHC, but HLA-DR has to do with transplantation, which HLA-DQ and HLA-DP have to do more with autoimmune diseases
Explain the interaction of T cells recognizing antigen plus HLA-D and T cells recognizing antigen plus HLA-A or B in the generation of killer T cells. Include the roles of cytokines in your discussion.
- If the donor and recipient are identical at HLA-A and HLA-B, but different at HLA-DR: you will activate Th1, but no CTL will be generated. You will still reject the graft but since only Th1 and not CTL are involved, rejection will be slower.
- If the donor and recipient are different at HLA-A and HLA-B, but identical at HLA-DR, you will get no MLR/no Th1 activation/no IL-2 generation and few CTL will be activated. Therefore, a good HLA-DR match is the most important.
Describe the cellular and molecular events which go on during graft rejection, both of the usual type and hyperacute rejection, including cytotoxic T cells, Th1 cells, angry macrophages, and antibody + complement.
a. Th 1 cell recognizes foreign HLA-DR (not on all cells, just the APC’s like macrophages and DCs) on graft cells. Th1 proliferates (this is what the MLR measures) and secrete lymphokines like IFNgamma to attract a macrophage inflammatory response. The macrophages product pro-inflammatory cytokines like TNF-alpha and the graft is destroyed. Meanwhile, CTL’s recognize foreign HLA-A and HLA-B which are on all cells (including macrophages and DCs). This recognition is insufficient to activate them; they also require Th1-derived interleukins as a 2nd signal. Once activated the CTL’s become highly cytotoxic. Exactly parallels what happens in normal immune response (like a virus) except that in a normal response a peptide + self-MHC is recognized, in rejection its foreign MHC.
b. In hyperacute rejection graft tissue is rejected almost immediately because there was circulating antibody against the graft’s tissue (from a previous failed graft) or against the graft’s residual blood in the tissues endothelium. The antibodies attached to endothelium and activate lots and lots of complement –> anaphylatoxin (C3a, C4a, C5a) from mast cells –> vasospasm, constricting vessels and tissue ischemia. COMPLEMENT MEDIATED IS FAST REJECTION
Discuss how T cells selected to recognize “self + X” also recognize foreign MHC (allorecognition).
- The recognition of foreign MHC is a chance cross-reaction; the receptors are actually selected to recognize self-MHC and antigen.
- T cells are selected to see something that is not quite “you”: you + foreign peptide. 5-10% of T cells also will response in a one-way MLR against foreign cells (it is like they were immunized, but they have never seen it before).
- 5% of T cells will bind a foreign MHC strong enough to cause activation. But none of the T cells that see MHC + foreign peptide will also see foreign MHC + peptide, since they were selected for a specific MHC (not the foreign MHC). This is why we can’t give T cells to other people.
Give an example of a disease whose incidence is tightly linked to a particular HLA allele. Speculate on the mechanism which might explain the linkage.
- Ankylosing spondylitis: arthritic condition in which there is inflammation of the insertions of tendons into bones –> calcification of joints and they become inflexible (ankylosed). 92% of people with this are HLA-B27. Your risk of getting this disease is 90x greater if you are B27 than if you are not. Unknown association but some ideas are: unknown pathogen with a surface antigen that so closely resembles the B27 molecule that B27+ people can’t recognize it as foreign OR antigen may cross react with B27 so that a response to the foreign antigen might lead to autoimmunity OR cross-reaction between B27 and Klebsiella OR unknown ankylosing spondylitis gene to the left of HLA-B that is in strong linkage disequilibrium with B27.
- Association between HLA-DR3 and –DR4 and juvenile diabetes
