Jada Bascom Foundation
2
30-35 minutes

How Matching Works: HLA & Genetics

Understand the high-level genetics of HLA matching and why finding compatible donors can be challenging.

Learning Objectives

  • Explain the function of HLA in the immune system
  • Understand why HLA matching is more complex than blood type matching
  • Analyze how inheritance patterns affect finding matches within families vs. unrelated donors
  • Recognize why genetic diversity affects match probability for different populations

Materials

  • Whiteboard for inheritance diagrams
  • Note-taking materials

Lesson Content

Review: Why Not Just Blood Type? (3 min)

  • "Blood type matching involves 8 common types—relatively simple."
  • "But for transplanting living cells that will become part of the immune system, we need much more precise matching."
  • "Enter HLA—the human leukocyte antigen system."

What Is HLA? (8 min)

  • Function: HLA proteins sit on cell surfaces and present antigens to the immune system—they're how your body distinguishes "self" from "non-self."
  • Location: HLA genes are found in the MHC region on chromosome 6.
  • Key genes: HLA-A, HLA-B, HLA-C (Class I) and HLA-DR, HLA-DQ, HLA-DP (Class II) are most important for matching (Source: NMDP / Be The Match, HLA basics).
  • The challenge: Each of these genes has thousands of known alleles worldwide (Source: IPD-IMGT/HLA Database, 2025).
  • Example: HLA-B alone has well over 10,000 known alleles catalogued in the IPD-IMGT/HLA database. The number of combinations across all HLA loci is astronomical (Source: IPD-IMGT/HLA Database, accessed 2025).

Inheritance of HLA (10 min)

  • Haplotype inheritance: HLA genes are close together on chromosome 6 and typically inherited as a unit (haplotype).
  • One from each parent: You receive one haplotype from your mother and one from your father.
  • Sibling matching (Source: NMDP / Be The Match, "Likelihood of finding a matching donor"):
    • 25% chance of being a perfect match (same haplotypes from both parents)
    • 50% chance of being a half-match (sharing one haplotype)
    • 25% chance of no match (different haplotypes)
  • Why only ~30% find family matches: Not everyone has siblings, and not all siblings match (Source: NMDP, 2024).

Probability Example:

If a patient has 3 siblings, the probability that at least one is a full match is: 1 − (0.75)³ ≈ 1 − 0.42 ≈ 0.58 (about 58%). Still a significant chance no family match exists.

Finding Unrelated Donors (7 min)

  • Registry searching: When no family match exists, doctors search registries for unrelated donors.
  • Match criteria: Ideally matching at 8/8 or 10/10 key HLA markers; some mismatches may be acceptable (Source: NMDP HLA matching guidelines).
  • Ancestry factor: Because HLA patterns evolved in different populations, people with similar ancestry are more likely to share HLA types.
  • Diversity reality: If most registry donors are of one ancestry, patients of different ancestries have fewer potential matches.
  • Mixed ancestry: Patients with mixed heritage may have unusual HLA combinations, making matches even rarer.

Consequences of Mismatching (3 min)

  • Rejection: Patient's immune system may attack donor cells.
  • Graft-versus-Host Disease (GvHD): Donor immune cells may attack patient's tissues.
  • Balance: Some GvHD may actually help fight remaining cancer cells (the graft-versus-leukemia effect), but severe GvHD can be life-threatening (Source: NIH National Cancer Institute, GvHD overview).

Closing (2 min)

  • "HLA diversity is a triumph of human evolution—it protects populations from disease."
  • "But it creates a matching challenge for transplantation."
  • "Next lesson: We'll examine how this genetic reality translates into health disparities."

Activity: HLA Inheritance Problem

Problem:

A patient needs a stem cell transplant. Their HLA haplotypes are: A1-B8-DR3 / A2-B44-DR7. They have two siblings.

  1. What are the possible HLA combinations their siblings could have inherited?
  2. What is the probability that each sibling is a full match?
  3. What is the probability that at least one of the two siblings is a full match?
  4. If neither sibling matches, what factors will affect finding an unrelated donor?
HLA (Human Leukocyte Antigen)
A set of genes on chromosome 6 that encode cell surface proteins crucial for immune recognition.
MHC (Major Histocompatibility Complex)
The genetic region containing HLA genes; essential for distinguishing self from non-self.
Polymorphism
The existence of multiple allele variations at a genetic locus in a population.
Haplotype
A set of alleles inherited together from one parent; for HLA, typically inherited as a block.
Graft-versus-Host Disease (GvHD)
A complication where donor immune cells attack the recipient's tissues.

Discussion Questions

  • Why do you think HLA has so many variations in the human population? What evolutionary advantage might this provide?
  • How does the HLA matching challenge differ from organ transplants like kidney or heart?
  • If you were designing a registry to maximize matches, what strategies might you consider?

Optional Extension

Research topic: Investigate haploidentical transplantation—a newer approach using half-matched family donors. What makes this possible now when it wasn't before?

Sources