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Molecular Biology

Histocompatibility

Let’s talk about the body’s ultimate security system, the gatekeeper of “self” versus “other.” This is the world of histocompatibility, and it’s governed by a fascinating and wildly complex set of genes

At its core, histocompatibility is the study of tissue compatibility—how can we put tissues or cells from one person into another without the recipient’s immune system launching an all-out attack? The answer lies in a special set of proteins found on the surface of our cells called the Human Leukocyte Antigens (HLA)

You can think of HLA proteins as your body’s cellular ID card. Every one of your nucleated cells presents this ID card on its surface. Your immune system’s security guards—the T-cells—are constantly patrolling and checking these IDs. If they see an ID card that matches the ones they were trained on (your own “self” IDs), they move along. But if they see a foreign ID card—from a donated organ, a bone marrow transplant, or even a virally infected cell presenting a strange peptide—the alarms go off, triggering a massive immune response

Our job in the molecular histocompatibility lab is to be expert ID checkers. We read the DNA blueprint that codes for these HLA ID cards to determine a person’s specific “HLA type.” This information is absolutely critical for several life-saving applications

The HLA Genes: A Barcode of Uniqueness

The HLA genes are located in a dense cluster on chromosome 6 known as the Major Histocompatibility Complex (MHC). What makes them so special is that they are the most polymorphic genes in the human genome. This means there isn’t just one version of the HLA-A gene; there are thousands of different versions, or alleles, in the human population. This incredible diversity is great for us as a species—it ensures that some people will always be able to fight off any new pathogen—but it makes finding a matching donor for a transplant incredibly challenging

The HLA genes are divided into two main classes:

  • Class I (HLA-A, HLA-B, HLA-C): Found on all nucleated cells. Their job is to present peptides from inside the cell to the immune system. Think of it as showing the security guard what’s happening inside the building
  • Class II (HLA-DR, HLA-DQ, HLA-DP): Found only on professional “antigen-presenting cells” like macrophages and B-cells. Their job is to present peptides they have picked up from outside the cell. This is like the security guard analyzing trash from outside the building to see if there are any threats nearby

Clinical Applications: Why We Type

Solid Organ Transplantation (Kidney, Heart, Lung, etc.)

The primary goal here is to prevent rejection. We want to find a donor whose HLA “ID cards” are as similar to the recipient’s as possible to minimize the chance of the recipient’s immune system attacking the new organ. While a perfect match is the holy grail, it’s often not possible. We prioritize matching the most important genes: HLA-A, HLA-B, and HLA-DRB1. Molecular typing gives us a precise, DNA-level match, which has largely replaced older, less accurate serological methods

Hematopoietic Stem Cell (HSC) Transplantation

This is also known as a bone marrow transplant. Here, the stakes are even higher, and the need for a perfect match is paramount. We aren’t just worried about the recipient rejecting the donor cells; we are even more worried about the opposite, a devastating condition called Graft-versus-Host Disease (GVHD). In GVHD, the new, donor-derived immune system (the graft) sees the recipient’s entire body (the host) as foreign and launches a systemic attack. To prevent this, we need a very high-resolution match at multiple loci, typically including HLA-A, -B, -C, and -DRB1. Modern labs use Next-Generation Sequencing (NGS) to get the most detailed and unambiguous HLA type possible

Disease Association

Decades of research have shown that carrying certain HLA alleles dramatically increases a person’s risk for specific autoimmune diseases. The HLA allele doesn’t cause the disease, but it creates a genetic susceptibility. It’s like having a faulty lock that a specific “key” (an environmental trigger) can more easily open

  • HLA-B27: Strongly associated with Ankylosing Spondylitis, an inflammatory arthritis of the spine
  • HLA-DQ2 and HLA-DQ8: The two key risk alleles for Celiac Disease. If a person with symptoms does not have either of these alleles, Celiac Disease can essentially be ruled out

Pharmacogenomics: Predicting Drug Hypersensitivity

This is a critical safety application. For some people, a specific drug can bind to their specific HLA protein, changing its shape. The immune system’s T-cells see this altered “ID card” as a dangerous foreign threat and trigger a massive, sometimes fatal, reaction. HLA typing can identify patients at high risk before they ever receive the drug

  • HLA-B*57:01: A person with this allele has a >50% chance of a severe hypersensitivity reaction to the HIV drug abacavir. The FDA requires testing for this allele before prescribing the drug
  • HLA-B*15:02: Strongly associated with a life-threatening skin reaction (Stevens-Johnson Syndrome) when taking the anti-seizure drug carbamazepine, particularly in Southeast Asian populations

Key Terms

  • HLA (Human Leukocyte Antigen): The proteins on the surface of cells that act as markers of “self” and are responsible for regulating the immune response
  • MHC (Major Histocompatibility Complex): The region on chromosome 6 that contains the highly variable cluster of HLA genes
  • Polymorphism: The state of having many different forms or versions (alleles) of a particular gene within a population. This is the hallmark of the HLA system
  • Haplotype: A set of HLA alleles that are located close together on a single chromosome and are therefore inherited together as a block from a parent
  • HLA Typing: The laboratory process of identifying which specific HLA alleles an individual possesses
  • Graft-versus-Host Disease (GVHD): A serious complication of allogeneic stem cell transplantation in which the donor’s immune cells (the graft) attack the recipient’s tissues (the host)
  • High-Resolution Typing: A detailed level of HLA typing (e.g., specifying HLA-A*02:01) that distinguishes between alleles that differ by even a single nucleotide, which is essential for HSC transplantation