HLA and Transplantation

This week's PATH3304 lecture was mainly about HLA (Human Leukocyte Antigen), also known as MHC (Major Histocompatibility Antigen). I practically spent my entire semester in Canada blogging about MHC, so most of this post will probably consist of links to previous posts that I wrote while abroad.

Understand the normal structure and function of HLA class I and II molecules
Understand the inheritance of HLA haplotypes

See previous post: The Major Histocompatibility Complex (MHC)

One thing not covered in the above post is that recombination can occur during inheritance. For example, your mum's copies of the MHC genes may cross over, resulting in some mixing of MHC alleles. The same could happen with your dad's copies of those genes. However, your mum's genes won't cross over with your dad's genes, so you won't receive a chromosome that has a mix of genes from both of your parents. (Hope that made sense.)

Define the following terms: allele vs. locus, polymorphism, linkage disequilibrium, HLA haplotype, HLA genotype

• Allele vs. locus: A locus is a region of a chromosome in which a certain gene can be found (e.g. DQ gene). An allele is the specific form of that gene that a patient might have (e.g. DQ2 or DQ3).
• Polymorphism: A term that basically means that there is more than one allele in a population (e.g. there are over 400 alleles for DQ).
• Linkage disequilibrium: Multiple loci are inherited together more frequently than you would expect by random chance alone, suggesting that they are linked together somehow.
• HLA haplotype: The combination of alleles on the same chromosome.
• HLA genotype: The combination of haplotypes found in an individual (one from the mother, one from the father).

Develop a basic understanding of HLA nomenclature

To explain HLA nomenclature, I'll give you an example: HLA-B*08:01. The HLA stands for HLA (amazing...), the B stands for the B gene, and the 08:01 refers to a specific allele. The * indicates that this particular allele was identified via DNA sequencing. Serological recognition methods (i.e. using antibodies to detect a particular allele) are also used, but they tend to be less accurate (so the same allele might only be identified as HLA-B8 using this method).

Understand that HLA matching is important in all forms of transplantation: HSCT (haematopoietic stem cell transplantation) vs. solid organ transplantation

See previous post: Immune Responses to Transplants

HLA matching is very important for many reasons. Well-matched HLA types can extend the life of the transplanted organ and reduce the need for immunosuppressive drugs, which in turn reduces the risk of infection and extends the life of the patient. HLA matching may even reduce the risk of lymphoma (which is usually associated with Epstein-Barr Virus reactivation).

HLA matching is particularly important in HSCT (haematopoietic stem cell transplantation), which includes things like bone marrow transplants. That is because the graft, which contains leukocytes, can attack and really damage the host (Graft vs. Host Disease). As such, more loci are considered in matching for HSCT compared to other solid organ transplants (in which usually only HLA-A, HLA-B and HLA-DR are considered). In order to find a perfect match, HSCT transplants are matched with donors all over the world, whereas solid organ transplants may only be matched nation-wide.

Describe some common HLA disease associations (non-transplant related)

Certain HLA alleles have also been implicated in drug sensitivity reactions and in autoimmune diseases. For example, the drug abacavir can interact with the binding site of some HLA types, causing a conformational change. The conformational change induced by abacavir may then allow HLA to bind to peptides that it wouldn't normally bind to, which may or may not provoke a reaction from the immune system.

Coeliac disease is an example of an autoimmune disease that may be linked to HLA type. When gluten is taken up, glutamine residues are converted into glutamic acid. The modified peptide can then bind to certain HLA types, which may or may not provoke an immune response. Other immune diseases that may be affected by HLA type include ankylosing spondylitis, rheumatoid arthritis and multiple sclerosis.