Immunogenetics and transplantation Flashcards
Histocompatibility
What is it?
The term is used to describe the outcome of grafts of living tissues between two individuals; they are histocompatible if the graft is accepted for a long time, and otherwise histoincompatible.
What is an MHC?
How are HLA loci expressed?
The HLA gene you inherit from one parent is called the ___2___.
Codominatly, meaning that genes encoding these molecules from both parental chromosomes are expressed.
2- Haplotype
What HLA correspond to MHC Class I loci?
In what type of cells are they present?
HLA-DR is DIFFERENT FROM HLA-A and HLA- B. HLA-A and – B (and – C), the ‘original’ transplantation antigens, were fairly simple to study because they are on all nucleated cells and antisera to them were quite easily obtained.
►They are the human Class I MHC loci
Why is the Mixed Leukocyte Reaction important to understand in transplantation?
What is a one-way MLR?
MIXED LEUKOCYTE REACTION , or MLR.
T cells were recognizing, and being stimulated to proliferate by, antigens on the foreign white cells that Bach did not have antisera against.
-Further studies identified these antigens as Class II MHC (which are on APCs). The MLR in this form doesn’t help us know how strongly the recipient’s T cells are responding against donor Class II, because the recognition is bidirectional.
But for transplanting what we want to know is: How strongly do the recipient’s T cells recognize the Class II of this potential donor as compared to that one?
►So we create a ‘one - way’ MLR , in which the cells from the donor are treated (DNA synthesis inhibitors or radiation) to prevent their division (after all, you really want to know, can the recipient recognize the donor’s MHC?). What you then observe is recipient’s Th cells dividing in response to the donor’s Class II MHC (on monocytes/macrophages). A strong reaction may preclude doing the transplant. 1
MHC antigen structure:
What are MHC antigens composed of? How many polypeptide chains?
Class I antigens have an ________ chain and an invariant chain called the _________.
Both Class II chains are______.
Do MHCs I and II, and immunoglobulins and T cell receptors arouse from the same ancestral gene?
Which HLA type is the most significant in solid organ transplantation?
Both class I and class II antigens are glycoproteins composed of two polypeptide chains.
Class I antigens consist of an allelically variable chain associated with an invariant chain called beta 2 -microglobulin.
-Both of the class II chains (α and β) are variable.
There is enough sequence homology between classes I and II, and immunoglobulins and T cell receptors, to indicate that they all arose from a common ancestral gene, the famous immunoglobulin domain.
–It’s fascinating to consider that the molecule that does the recognizing, and the molecule that’s recognized, originated in the same early structure. What might its function have been?
HLA-A and -B (and -C) produce molecules which are very similar in structure and function, and one arose from the other by gene duplication. Humans have triplicated (at least) Class II loci as well, so that we have DR , DP , and DQ. We often just say ‘ HLA-D ’ when we’re thinking Class II; in most cases we really mean HLA-DR, the most significant in solid organ transplantation.
What is a minor histocompatibility antigen?
They can lead to what kind of rejection?
The H-Y is encoded for in what chromosome?
On what MHC class is the H-Y expressed?
Why would males accept female grafts without rejection?
There are about 30 minors, mismatch at any of which may cause slow (chronic) rejection.
-One is H- Y, coded for on the Y chromosome:
_-_It’s not a transmembrane surface molecule, but an internal protein whose peptides are displayed on MHC Class I (only on male cells, of course).
Because of H-Y, male skin grafts will be slowly rejected, even by fully syngeneic inbred females, while males accept female grafts without fuss (since females don’t have a Y chromosome).
1- Grafts between genetically identical individuals are called_________.
2- Grafts between non-identical memebers of the same species are called_________.
3- Grafts between members of different species are called___________.
4- Grafts from one individual to himself (hair transplant) are called________.
1- Grafts between genetically identical individuals (e.g., inbred mice, identical twins) are called syngeneic or isografts.
2- Between non-identical members of the same species (e.g., people) are allogeneic or allografts.
3- Between members of different species (e.g., baboon hearts into babies) are xenogeneic or xenografts.
4- Grafts from one individual to himself (e.g., hair transplants) are autografts.
Grafts are usually rejected by what cells?
Do antibody and complement play an important role in graft rejection? When could they cause a problem?
What is a hyperacute rejection?
What is a white graft? How can you avoid it?
Grafts are rejected by T cell mechanisms with which you are already familiar, the most important being Th1 cells (via their lymphokines and the monocyte/macrophage inflammatory response) and CTL. Macrophage-derived inflammatory cytokines makes the reaction even more intense. As we have developed better immunosuppression regimens and drugs, graft survival has increased and morbidity decreased; but it’s almost never been possible to taper and stop a patient’s drugs without rejection.
- Some biological graft materials (pig heart valves, demineralized bone matrix, tissue-cultured skin) either have no living cells, or they are gradually replaced by the recipient’s own cells while serving as a supporting matrix.
- Antibody and complement are not thought to be important:
►except in hyperacute rejection. In this case, a graft is given to a patient who has preexisting antibody, IgG or IgM, to it (either to its HLA, because of a prior graft or transfusions, or, in a mismatch, to ABO blood group antigens).
–>Antibody immediately binds to the endothelial cells of the graft’s blood vessels. Complement is activated and vasospasm results, via anaphylatoxins and histamine; the organ may never even become perfused with blood (a ‘white graft’). This catastrophe can be avoided by making sure there are _no cytotoxic (_complement-activating) antibodies in the serum of the recipient when tested on the donor’s leukocytes.
T cells interaction in rejection of grafts:
in rejection what is the first thing that happens?
Th1 proliferation is measures in ?
What lymphokine is secreted by Th1 to attact macrophages for an inflammatory response?
CTL recognize _____ and ______ in which cells? What do they require to become fully activated?
In a viral immune response, an antigen(peptide) + MHC is required to active it, in graft rejection, you need a foreign_______.
Th1 recognize foreign MHC antigens of the Class II, HLA-DR loci; killer T cells (CTL) recognize foreign MHC antigens of the Class I, HLA-A and HLA -B loci.
In rejection, what first happens is that Th1 cells recognize foreign HLA-DR on graft cells.
Remember, not all cells express HLA-DR; the cells which do so are primarily macrophages and dendritic cells (which are APCS), of which most grafts have plenty. The Th1 proliferate (the phenomenon which is measured in the mixed leukocyte reaction).
–They will also secrete lymphokines (like IFN-gamma) that attract a macrophage inflammatory response. The macrophages will mostly be the graft recipient’s, because there are more of them.
Meanwhile, CTL nearby are recognizing foreign HLA-A and HLA-B, which are on all the graft cells; this recognition is usually insufficient to activate them, though; they also require Th1- derived interleukins (IL-2, probably others) as a second signal. Once activated, the CTL become highly cytotoxic; they may proliferate although they don’t have to, and they start killing cells in the graft.
► You have recognized, I hope, that this whole sequence of events is exactly parallel to the recognition of antigen in a normal immune response, for example to a virus. The difference is that in a normal response, it’s peptide plus self - MHC that’s recognized; in rejection, it’s foreign MHC.
How can a rejection be minized?
If the donor and recipient are identical at class I but DIFFERENT at class II, what cells will be activated and in term of time, what kind of reaction would it produce?
A match of what type of MHC is more important to decrease tissue rejection?
In bone marrow transplant, who attacks who?
►(1) If the donor and recipient are identical at Class I but different at Class II, Th1 will be activated; but no CTL will be activated, because there is no Class I difference for them to see. The graft will still be rejected, but since only Th1 and not CT L would be involved, rejection may be slower.
►(2) If the donor and recipient are different at Class I but identical at Class II, there will be no Th1 activated, no IL-2 will be generated, and so few CTL will be activated.
►Therefore a good Class II match is the most important thing .
In general transplant surgeons take the immunology less seriously than immunologists do; they figure that a perfect match is impossible anyway, taking minor antigens into account, so they might as well rely on immunosuppressive drugs. It is true that, given the intensive drug therapy that is used, the goodness of HLA matching becomes less important. Nevertheless, kidney grafts identical at 6/6 alleles (HLA-A, B, DR) do better than those with 2/6 matches, which is the average quality of match in the USA.
For bone marrow transplantation, where the graft can attack the recipient, we look for matches at A, B, C, DR, and DQ: A 10/10 match is desirable.
Antigen recognition and allorectivity:
Why cannot we give T cells from one person to another?
Th cells normally see MHC Class II + peptide; they also are the ones that see foreign MHC Class II.
CTL normally see peptide + Class I, and they also can see foreign Class I.
-The recognition of foreign MHC is a chance cross-reaction; the receptors are actually selected to recognize self-MHC + antigen (Figure 4, below). In fact, if you make a cloned T cell line specific for the donor’s own HLA plus antigen X, the same cells can quite often be shown to also react with some foreign HLA (probably loaded with a different peptide, antigen Y).
My T cells were selected to see something that isn’t quite me; it’s me plus a foreign peptide.
► What else could look like not-quite-me? You. In fact, whoever you are, about 5 or 10% of my T cells will respond in a one-way MLR against your leukocytes. That ’s a lot , so even if I’ve never seen you before, I behave as though I’m immunized against you.
Here’s the paradox: Maybe 5% of my T cells will bind your MHC strongly enough to cause activation. But essentially none of my T cells that see me plus peptide X will also see you plus peptide X, since they were selected on my MHC, not yours. For these two reasons, we can’t give one person’s T cells to another.
Ankylosing spondylitis
what is it?
With what HLA allele is associated with?
Why does this association happens?
This is an arthritic condition in which there is inflammation of the insertions of tendons into bones, and the fibrous joints of the spine and pelvis, followed eventually by calcification so that affected joints may become inflexible (ankylosed).
- About 92% of people with ankylosing spondylitis are HLA-B27 (8% of people in the USA without the disease are B27).
- Your risk of getting the disease is 90 times greater if you are B27 than if you are not. Rats made transgenic for the human HLA-B27 gene develop arthritis similar to ankylosing spondylitis.
Why the association?
Is there an as-yet unknown pathogen with an antigen that so closely resembles the B27 molecule that B27+ people can’t recognize it as foreign? Alternatively, the antigen might cross-react with B27, so that a response to the foreign antigen might somehow lead to autoimmunity There is some intriguing evidence of cross-reaction between certain Klebsiella bacteria and B27 (the ‘arthritogenic peptide’ hypothesis). Finally, HLA -B27 protein is prone to misfolding; could this, like a prion, cause inflammation?
The second most-relevant risk locus is the ERAP1 gene, coding for an endopeptidase that affects how HLA-B27 loads with endogenous peptides; this could be seen as supporting the misfolding idea.
Which HLAs are associated with type I diabetes?
Another interesting association is between HLA-DR3 and -DR4 and Type 1 juvenile (insulin-dependent) diabetes.
The relative risk factor is 5 if a child has one of these antigens. HLA-DR2 seems to protect against Type 1 diabetes. In all these cases, the real culprit seems to be certain HLA-DQ alleles which are in strong linkage disequilibrium with those HLA-DR alleles.
Modifications of self-proteins could be related to creation of “neoantigents” that could cross react with the normal protein and lead to what two specific diseases?
A growing body of evidence suggests that modifications of self-proteins (citrullination and deamidation in rheumatoid arthritis (RA) and celiac disease, respectively) may create novel epitopes that associate strongly with certain MHC alleles; the cells that respond to these ‘neoantigens’ cross-react with the normal protein. These modifications are probably more environmental than genetic; RA is associated with airborne pollution and smoking, and celiac with consumption of the grain protein group called gluten.
HLA associatiosn with disease:
