HLA Matching Multi-Locus Standards

What is HLA matching and multilocus genotyping?

Simply put, HLA matching and multilocus genotyping is a highly accurate genetic testing technology used to determine a person's specific type at multiple key loci within their human leukocyte antigen (HLA) system.

We can break this concept down:

1.HLA (human leukocyte antigen): 

*It is not a single gene, but a whole set of very important genes in the human body, located on chromosome 6.

*This set of genes encodes proteins called "antigens," which act like "identification cards" and are located on the surface of almost all cells (especially white blood cells).

*The immune system uses these "identification cards" to distinguish between "self" and "non-self." If it's "self," it remains unaffected; if it's "non-self" (such as viruses, bacteria, or transplanted organs), the immune system launches an attack.

2.Multilocus: 

*The HLA system contains hundreds of genes, but several loci are particularly critical for transplantation. "Multilocus" refers to the simultaneous testing of these most important loci.

*Core loci typically include:

HLA-A, HLA-B, HLA-C (class I antigens, present on nearly all nucleated cells)

HLA-DR, HLA-DQ, HLA-DP (class II antigens, primarily present on immune cells such as B cells and macrophages)

*Thus, "multi-locus typing" comprehensively characterizes these three class I loci and three class II loci (a total of six).

3.Genotyping: 

*Earlier techniques (such as serological methods) could only detect a rough pattern of HLA protein levels.

*Genotyping directly examines the DNA itself, using molecular biology techniques (such as PCR-SSP, PCR-SSO, and next-generation sequencing (NGS)) to determine the precise base sequence of the HLA gene.

*This technique is extremely precise and can detect subtle differences that serological methods cannot distinguish, thus enabling more compatible donors and recipients.

Summary: HLA matching multi-locus genotyping uses high-precision DNA sequencing technology to conduct a detailed analysis of multiple HLA gene sites that are most critical in transplantation to determine the most accurate genotype.

The Role of HLA Matching Multilocus Genotyping

Its core purpose is to maximize graft survival and minimize the risk of serious post-transplant complications.

Specifically:

1.Assessing immune compatibility between donor and recipient: By comparing the HLA typing results of the donor (donor) and recipient (patient), doctors can determine how similar their "identity cards" are. The higher the match, the lower the risk that the recipient's immune system will recognize the transplanted organ as "foreign" and attack it (i.e., reject it).

2.Selecting the Best Donor: When multiple potential donors are available (such as siblings, volunteers from bone marrow banks, or cord blood banks), this is the gold standard for selecting the most compatible donor. The degree of match is one of the key factors determining the success of a transplant.

3.Predicting and Mitigating Risks:

*Reducing Graft-Versus-Host Disease (GvHD): This is particularly important in bone marrow/hematopoietic stem cell transplantation. If the transplanted hematopoietic stem cells (from the donor) recognize the recipient's body as "non-self," they will attack the recipient's tissues and organs, causing GvHD, a potentially fatal complication. A good HLA match can significantly reduce the incidence and severity of GvHD.

*Reducing rejection: In solid organ transplants (such as kidney, liver, heart, and lung transplants), a good HLA match can reduce the risk of the recipient's body rejecting the transplanted organ.

What diseases are associated with this procedure?

This technology is primarily relevant to diseases that require transplantation for treatment, rather than diseases that directly cause HLA abnormalities.

1. Diseases requiring bone marrow/hematopoietic stem cell transplantation:

*Leukemia (such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL))

*Lymphoma

*Severe aplastic anemia

*Thalassemia

*Sickle cell disease

*Severe combined immunodeficiency

*Certain inherited metabolic disorders

For bone marrow transplantation, HLA matching requirements are the highest and most stringent, typically requiring full matching (6/6, 8/8, 10/10) or the highest possible matching.

2. Diseases requiring solid organ transplantation:

*End-stage renal disease (requiring a kidney transplant)

*End-stage liver disease (such as cirrhosis and liver cancer, requiring a liver transplant)

*End-stage heart failure (requiring a heart transplant)

*End-stage lung disease (requiring a lung transplant)

*Type 1 diabetes (sometimes requiring pancreatic islet cell transplantation)

For solid organ transplantation, the importance of HLA matching varies depending on the organ. Among them, kidney and pancreas transplants are most dependent on HLA matching, with well-matched kidneys having significantly longer survival times. For liver, heart, and lung transplants, HLA matching carries a relatively lower weight due to factors such as organs' greater sensitivity to ischemic damage and higher waiting times, but it remains an important consideration.

Application Scenarios

1. Pre-transplant donor-recipient matching: This is the most core application scenario. This test is mandatory for both family-to-family transplants and for finding unrelated donors through the China Bone Marrow Bank or the Organ Allocation System.

2. Development of a Hematopoietic Stem Cell Donor Database (Bone Marrow Bank): When volunteers sign up for the Bone Marrow Bank, they undergo HLA multilocus genotyping, and their data is entered into the database. When a patient needs a donor, the database can be quickly searched for a matching donor.

3. Development of an Umbilical Cord Blood Bank: When storing cord blood, HLA typing is mandatory for cord blood samples to facilitate future access and use.

4. Auxiliary Diagnosis of Certain Diseases:

Although not directly used for diagnosis, some autoimmune diseases are strongly associated with specific HLA types. For example:

* Ankylosing spondylitis is highly associated with HLA-B27.

* Rheumatoid arthritis is associated with HLA-DR4.

* Type 1 diabetes, celiac disease, and other conditions are also associated with specific HLA types. In such cases, HLA typing can be used as a tool for auxiliary diagnosis and disease risk prediction.

5. Paternity Testing and Forensics: Due to the extremely high polymorphism of the HLA system (which varies significantly from person to person), it was once a key tool for paternity testing. Although now largely replaced by STR technology, it still has some value.

6. Pharmacogenomics: Certain HLA genotypes are associated with serious adverse reactions to specific drugs. For example, individuals with the HLA-B*15:02 allele are at increased risk for severe skin allergic reactions, such as Stevens-Johnson syndrome (SJS), when taking the antiepileptic drug carbamazepine. Therefore, HLA genetic screening is performed on specific populations before using these drugs.