The field of histocompatibility and immunogenetics can be very intimidating, especially to the non-scientist. This section is designed to be a simplified view of the HLA system and its importance in transplantation and transfusion medicine.
HLA stands for Human Leukocyte Antigen. HLA molecules are found on all cells in the body, with the exception of red blood cells. They were originally discovered on white blood cells or leukocytes. HLA molecules play an important role in your own immune system’s ability to determine what is self and what is foreign and to be able to attack what is foreign.
The HLA system includes many different types or groups of HLA antigens that are identified by different letters (ex. HLA-A and HLA-B). For solid organ transplants, the HLA antigen groups that are considered for matching the HLA-A, B, and DR antigens. In platelet transfusions, the groups of importance are only the HLA-A and B. For bone marrow or stem cell transplants, the groups of importance may include HLA-A, B, C, DR, DP, and DQ. Specific HLA antigens are designated by their group (A, B, or DR), then by a number to distinguish antigens from the same group. For example, you may have an HLA-A1, B8, DR17 while someone else has an HLA-A2, B7, DR15.
HLA antigens can also be separated into Class I and Class II molecules. These classes differ structurally and by their function in the immune system. Class I molecules include the HLA-A, B, and C antigens and are found on nearly all cells in the body. Class II molecules include the HLA-DR, DP, and DQ antigens and are typically only found on cells of the immune system although all cells with a nucleus have the ability to express these molecules.
The genes that code for the HLA antigens are found on chromosome 6. This area of chromosome 6 is called the Major Histocompatibility Complex (MHC). Since you have two copies of chromosome 6, you also have two copies of the HLA-A, B, and DR molecules. Each set of HLA antigens is referred to as a “haplotype” and every person inherits one haplotype from each parent. Therefore, you will share an HLA-A, B, and DR antigen with each of your parents. Due to the inheritance patterns of these genes, it is possible to determine the probability of sharing HLA types with a sibling, as shown below. You have a ¼ chance of being HLA identical, a ¼ chance of being completely non-identical, and a ½ chance of sharing a haplotype with your siblings.
An important characteristic of the HLA system is the enormous number of HLA types that are possible. Each person has 2 each of the HLA-A, B, and DR antigens. There are roughly 25 different HLA-A antigens, 40 different HLA-B antigens and 20 different HLA-DR antigens. Most of these antigens can be further distinguished if the molecular typings are compared. That is, the DNA sequence that codes for each antigen. When HLA antigens are typed using molecular typing methods, there are several hundred HLA antigens at each locus. Therefore, it is not an exaggeration to say that there are potentially millions of possible HLA types in the population.
HLA and Transplantation
In the case of transplants, when HLA molecules of the donor are different from recipient, the recipient’s immune system can build antibodies against the foreign HLA molecules on the transplanted organ. If the immune system is not suppressed, the recipient’s immune system may eventually destroy the transplanted organ.
Today’s immunosuppressive drugs have allowed for the successful transplantation of completely HLA mismatched organs. This is because the drugs prevent the recipient’s immune system from building a response against the transplanted organ. It is important to note, however, that the better the HLA match, the better the long-term survival of the transplant.
An individual may build antibodies against foreign HLA molecules if they are exposed to them through pregnancy, transfusion, or transplantation. An individual who has had any of these events is considered “sensitized”. For these patients, it is important to first determine if they have built any anti-HLA antibodies and if so, what specific HLA molecule(s) they are against. If a patient has antibodies against a specific HLA molecule, any donor that has that antigen expressed on their cells will be considered unsuitable.
Antibody screening is performed in the laboratory to look for anti-HLA antibodies in the patient’s serum, or liquid portion of the blood. The result of this test is expressed as a Percent/Panel Reactive Antibody or PRA. This value is calculated as the number of cells in a panel that the patient’s serum contained antibodies against divided by the total number of cells tested. It is used as a rough estimate of the percentage of donors that a patient will NOT be compatible with. In other words, a patient with a low PRA has a greater chance of finding a compatible donor than a patient with a high PRA.
The laboratory also attempts to identify the specificity of any antibody present. If a patient has a positive PRA (greater than 0%), the laboratory will perform further testing in order to identify unacceptable antigens, that is, the specific HLA target of the antibodies. Any unacceptable antigens identified for a patient are used to rule out potential donors that will be incompatible by crossmatch, and therefore unsuitable.
Due to the large degree of diversity in the HLA system, it is not practical for all solid organ transplants to be from HLA matched donors. Instead, transplants must be from HLA compatible donors. This means that the patient does not have antibodies specific to the HLA antigens on the donor’s cells. The crossmatch is the last test performed prior to transplantation. The crossmatching techniques used in the HLA laboratory at INBC are very sensitive and can detect very low levels of antibodies.
- Antibody – proteins present in serum that can be specific for anything from pathogens to foreign HLA molecules.
- Crossmatch – a laboratory assay that looks for patient antibodies directed against a potential donor’s cells.
- Haplotype – a set of HLA antigens that are inherited from each parent.
- HLA (Human Leukocyte Antigens) – proteins found on the surface of cells, also called histocompatibility or tissue antigens.
- Leukocyte – term used to describe white blood cells, including lymphocytes, monocytes, and granulocytes.
- MHC (Major Histocompatibility Complex) – genetic region on chromosome 6 that codes for HLA molecules.
- Molecular HLA typing –an HLA typing that was determined by looking at the gene that codes for the protein expressed on the surface of the cell.
- PRA (Percent/Panel Reactive Antibody) –the amount of anti-HLA antibody in a patient’s serum.
- Sensitization – exposure to foreign HLA molecules through pregnancy, transfusion, or transplant (called sensitizing events).
- Unacceptable Antigens (UA) – Specific HLA molecules that a patient has built antibodies against.