W7L8 - Human Leucocyte Antigen (HLA) Flashcards
HLA
Cell surface proteins encoded by genes within the MHC
Called HLA antigens (MHC antigens) in context of transplantation
Inherited co-dominantly
Minor Histocompatibility Antigens (mHAgs)
Other surface proteins can act as antigens in transplantation
mH antigens - non HLA antigens associated with graft rejection
Complete matching for HLA often lead to graft rejection (requirement for immunosuppressive therapy)
MHC Class 1 and 2
MHC divided into classes related to structure, function and location within MHC
Three independent genes in class 1
- HLA-A, HLA-B, HLA-C (also E, F, G, H, J, K, L)
Three sets of genes in class 2
- HLA-DR, HLA-DQ, HLA-DP (also DM and DO, not expressed on surface)
Class III genes made of a variety of genes most related to immune function
- complement, tumour necrosis factor (TNF)
- LMP and TAP found within class 2 region but are class 3
MHC Class 1
Single gene coding for transmembrane glycoprotein (α or heavy chain) forming three globular domains
- α1, α2, and α3
Linked to β2-microglobulin
Sequence differences between alleles are limited to α1 and α2
The α1 and α2 domains form a peptide binding groove
- 8-9 amino acids peptides
Variation in α1 and α2 domains determine peptide binding and antigenicity
MHC Class 2
Consists of two transmembrane glycoproteins coded for by separate genes
- α and β
Form four domains:
α1 and β1
- most distant from cell membrane, forms binding groove, polymorphic region
- binds 12-17 amino acid peptides
α2 and β2
- Nearest to cell membrane, less variation, bind to CD4 cells
What is HLA typing?
Test used to identify certain individual variations in a person’s immune system
HLA Inheritance Example
Since HLA is inherited co-dominantly, if mother has A1 and A23 and father has A2 and A3, then there are 4 different haplotypes
- A1 and A2
- A1 and A3
- A23 and A2
- A23 and A3
Linkage Disequilibrium
Mendelian genetics suggests that the frequency of one locus is not influenced by another
So what is inherited at HLA-A should be independent of what is inherited at HLA-DR
But this is not true for HLA
Some HLA antigens are found in higher frequencies with other HLA antigens
HLA Types
HLA antigens extremely polymorphic
- many variations of same proteins
Expressed on all cells (class I) so HLA typing is referred to as “tissue typing”
3 class I (A, B, C) and 3 class II (DR, DQ, DP)
- total of 12 antigens per person
Many allelic variation of HLA antigens
In transplantation these are recognised by recipient as being foreign
HLA Nomenclature
Starts with HLA
Then locus - name of specific locus (e.g. DR)
- for molecular typing of class 2 the region is added (e.g. DRB1)
Number - refers to allele within locus
- HLA-DR3 = HLA-DR03
- HLA-DR17 = HLA-DR0301
- HLA-DR18 = HLA-DR0302
For class I (only one gene, region not added): HLA-A1 (serology), HLA-A0101 to 0109
Transplantation
Graft - a piece of living tissue that is transplanted surgically
Recipient has an immune system that will recognise graft as foreign
- self vs non-self
- graft rejection
Most rejection is due to differences in HLA (some mHAg) due to large numbers of possible alleles
Types of Transplantations
Autograft (autologous graft)
- transplant of tissue from one area to another area of same individual
- e.g. skin graft
Isograft (syngeneic graft)
- transplant from one individual to another who is genetically identical (syngeneic)
- e.g. kidney transplant between identical twins
Allograft
- most common
- transplantation between individuals of the same species
- MHC polymorphism will lead to probable rejection (immunosuppressive therapy required)
Xenograft
- transplantation across species
Allograft Rejection - Hyperacute Rejection
Occurs few minutes or hours of transplantation
There are pre-existing humoral antibodies
Blood group incompatibility (ABO)
Pre-sensitisation to class I MHC (blood transfusion, previous transplant, pregnancy)
Symptoms:
- complement activation
- thrombosis
- swelling
- interstitial haemorrhage
- fibrinoid necrosis
Cell mediated immunity not involved
Allograft Rejection - Acute Rejection
Occurs few days after transplant (complete loss 10-14 days)
Predominately mediated by T cells
- direct recognition of alloantigens on donor cells by recipient
Antibody binding of graft cells
- antibody mediated cellular cytotoxicity
- antibody binding blood vessel of graft with complement activation
HLA mismatch, insufficient immunosuppression
Allograft Rejection - Chronic Rejection
Some month of years after transplantation
Both antibody and cell mediated immunity
Rate, extent and mechanism may vary with tissue/organ
Immune injury already taken place so immunosuppressive therapy of no use
