MHC and Transplantation Flashcards
What actually is the MHC complex?
It is a gene complex on the short arm of chromosome 6
The proteins coded for by the MHC genes are HLA proteins
What are the different types of HLA antigens in humans?
Class I - A, B and C
Class II - DR, DQ and DP
Where are class I HLA antigens found?
They consist of 3 alpha helices and are a heterodimer
they are found on all nucleated cells
they are not present on red blood cells
WHat is meant by the HLA molecules being a heterodimer?
They are completed by something that is non-polymorphic (same in everyone)
This is B2u in humans
How are class II antigens different to class I?
They have 2 alpha helices and 2 beta pleat sheets
They are expressed more selectively on antigen presenting cells
This includes dendritic cells, langerhans cells and Kuppfer cells
Where are the MHC genes found?
On the short arm of chromosome 6
A = alpha chain
B = beta chain
What is meant by HLA molecules being highly polymorphic?
They vary between different people depending on their genetic backgrounds
Variation is around the peptide groove area as different peptides will fit in the grooves
How has the number of defined HLA alleles changed over time?
There has been a rapid increase in defined HLA alleles
This is because humans are genetically outbred - everyone is very genetically different so everyone has different HLA antigens
What is the chance that 2 siblings will have the same HLA antigens?
A sibling has a 1 in 4 chance of inheriting the same antigens from their parents
It can be hard to find a match for a bone marrow transplant if a parent or sibling is not a match, due to the extent of diversity
What is the difference in function between class I and class II MHC molecules?
Class I are important in handling intracellular foreign proteins
Class II are important in handling extracellular proteins that have been endocytosed
Complete the table for the roles of MHC I and II in different cell types
What is the relationship between HLA and infectious disease?
There are associations of protection
e.g. If you have HLA-B53, you are protected from contracting malaria
Genetic diversity prevents the whole population from dying out as some people will be able to develop an immune response and eradicate the infection
What is the association between autoimmune diseases and HLA?
Autoimmune diseases are associated with HLA polymorphisms
e.g. DR2 has an association with Goodpastures nephritis - you are 16x more likely to get the disease
What is the difference between positive and negative selection?
Positive selection:
- involves selection of T cells with an affinity for self antigens
Negative selection:
- involves selecting against T cells that have too much affinity for self-antigens
- this would lead to autoimmune disease
What is meant by allorecognition?
Anyone with a different genetic background to you that appears foreign to your immune system
How is rejection mediated in an allogeneic transplantation?
Rejection is mediated by lymphocytes
This is against HLA molecules
Why does rejection occur in allogeneic transplantation?
APC migration
Foreign cells from the donor migrate to the inguinal lymph nodes and are recognised by lymphocytes in the recipient as foreign
There is a reaction between APCs and CD4+ T cells
This excites a vigorous immune response
What molecules are missing from the immunological synapse?
Costimulation is needed for full immunological activation
What are the effector functions of the allogeneic APC?
- CD4 T cell gets activated and generates B cells that generate antibodies
- CD8 T cells will destroy any cells with a class I molecule on them
- CD4 produce delayed type hypersensitivity reaction
What is the purpose of tissue typing?
What is meant by haplotype?
Matching HLA types avoids rejection
You receive one haplotype from the mother and one from the father
a haplotype is a copy of the short arm of chromosome 6
there is a possibility of 4 different combinations
What are the 2 different types of HLA typing?
Serological:
- cell based
Molecular:
- extraction of DNA
- amplification
- detection of sequence polymorphisms
Why do people do HLA typing?
- Less rejection episodes
- better graft survival
- less sensitisation
- to establish relationships - e.g. paternity testing as one haplotype must come from the father
What are the missing stages in the renal transplant pathway?
Every 3 months on dialysis, the patient is screened to make sure they do not have HLA antibodies
Why may someone acquire HLA antibodies whilst waiting for a transplant?
- If they have had a previous transplant
- In pregnancy as the women is exposed to the HLA antigens of the male so may generate antibodies
- In a blood transfusion as white cells contaminate blood and perform the sensitisation
What will happen if the patient has HLA antibodies at the time of transfusion?
Hyperacute reaction
the transplant turns black and is rejected immediately
Why is antibody detection important and carried out?
- Prevents hyperacute reaction
General antibody detection:
- this is against many HLA types
Specific antibody detection:
- this is against the donor
- pretransplant cross match either living or cadaveric
- Avoids aborted transplant
What is meant by complement dependent cytotoxicity test?
It detects complement fixing IgG/IgM HLA and non-HLAs
- Recipient serum is added to a Petri dish containing donor T cells (with class I antigens on the surface)
- If the recipient has antibodies, they will bind and complement is added
- There is cell lysis if antibodies are present
What are the disadvantages of complement dependent cytotoxicity test?
- Limited sensitivity
- Subjective
- Non-complement fixing antibodies
- Non-HLA antibody interference
What is a more modern way of performing CDC?
Luminex screening
Beads have recombinant HLA molecules on their surface
if there is fluorescence, this shows that the patient has antibodies to the HLA molecule
What are the 3 types of rejection?
- Acute antibody mediated rejection
- Acute cellular rejection
- Chronic antibody mediated rejection
When does hyperacute rejection occur?
It happens if you have pre-existing antibodies at the point the transplant goes in
blood flows in from the renal artery, antibodies bind and activate clotting cascade and complement
What are the 3 important types of pre-formed antibodies?
Blood group:
- if you have blood group A, you will have anti-blood group B antibodies
HLA molecules:
- high levels can lead to immediate rejection
- this comes from transfusion, pregnancy or previous transplant
Animals of lower species:
- this prevents pseudotransplantation
- all humans have antibodies against carbohydrates from lower mammals
How does hyperacute rejection occur?
Anti-HLA antibodies bind to endothelial cells and activate them
they may bind the antigen and activate the complement cascade
any cell with Fc portion will bind and set off inflammation
What are the properties of acute cellular rejection?
It is T cell dependent
It typically occurs 7-10 days after transplant
the reaction is directed against foreign HLA molecules as a result of HLA mismatch
What is the treatment for acute cellular rejection?
Invasion of lymphocytes means that patients are kept on immunosuppressant drugs and steroids
a large dose of Methylprednisolone is used to treat rejection
Why are antibody tests performed after transplant?
Antibodies are a bio marker of poor outcome
