The HLA System

The HLA System

The Human Leukocyte Antigen (HLA) system is the human version of the Major Histocompatibility Complex (MHC), a set of genes encoding cell-surface proteins essential for adaptive immunity. HLA molecules present peptide antigens to T cells, enabling the immune system to distinguish self from non-self and to detect intracellular pathogens and abnormal cells.

Overview

The HLA system represents one of the most polymorphic genetic regions in the human genome. This extraordinary diversity evolved to maximize the range of pathogen-derived peptides that can be presented to T cells across a population. However, this same diversity creates challenges for transplantation and underlies many autoimmune disease associations.

Key Functions

HLA molecules serve three critical functions in adaptive immunity:

1. Antigen presentation: Displaying peptide fragments to T cells for immune surveillance
2. Self/non-self discrimination: Enabling T cells to recognize infected or abnormal cells
3. Immune regulation: Influencing T cell development, selection, and tolerance

Genomic Organization

The HLA genes are located on the short arm of chromosome 6 (6p21.3) within a ~4 megabase region containing over 200 genes. This region is divided into three classes based on structure and function.

Class I Region

The classical Class I genes encode molecules that present endogenous peptides to CD8+ cytotoxic T cells:

Non-classical Class I genes have more specialized roles:

Class II Region

Classical Class II genes encode molecules that present exogenous peptides to CD4+ helper T cells:

Each Class II molecule is a heterodimer of α and β chains encoded by separate genes (e.g., HLA-DRA and HLA-DRB1 for HLA-DR).

Non-classical Class II genes support antigen presentation:

Class III Region

Located between Class I and Class II regions, this segment contains genes involved in inflammation and complement:

• Complement components (C2, C4A, C4B, Factor B)
• Tumor necrosis factors (TNF-α, TNF-β)
• Heat shock proteins (HSP70)
• 21-hydroxylase (CYP21A2)

While not classical HLA genes, variants in this region contribute to disease susceptibility.

HLA Molecule Structure

Class I Structure

HLA Class I molecules consist of:

• Heavy chain (α chain): ~45 kDa transmembrane glycoprotein with three extracellular domains (α1, α2, α3)
• β2-microglobulin (β2m): ~12 kDa non-covalently associated protein encoded outside the HLA region (chromosome 15)

The peptide-binding groove is formed by the α1 and α2 domains, creating a cleft with a floor of eight antiparallel β-sheets and walls of two α-helices. This groove accommodates peptides of 8-10 amino acids with both ends closed.

Anchor residues: Peptides bind via specific amino acids (usually positions 2 and 9) that anchor into pockets in the groove. Different HLA alleles have different pocket structures, determining which peptides can bind.

Class II Structure

HLA Class II molecules consist of:

• α chain: ~34 kDa with two extracellular domains (α1, α2)
• β chain: ~29 kDa with two extracellular domains (β1, β2)

The peptide-binding groove is formed by the α1 and β1 domains, similar to Class I but with open ends, allowing longer peptides (12-25 amino acids) to extend beyond the groove.

Polymorphism and Nomenclature

Extreme Polymorphism

The HLA system is the most polymorphic region in the human genome:

Most polymorphisms occur in exons encoding the peptide-binding groove, affecting which peptides can be presented.

Nomenclature System

HLA alleles follow a standardized naming convention:

HLA-A*02:01:01:02N
 │   │  │  │  │  └─ Expression variant (N=null, L=low, S=secreted, Q=questionable)
 │   │  │  │  └──── Non-coding region change
 │   │  │  └─────── Synonymous coding change
 │   │  └────────── Protein sequence (unique amino acid sequence)
 │   └───────────── Allele group (serologically defined)
 └─────────────────  Gene

Common reporting levels:

• Two-digit (e.g., HLA-A*02): Allele group, roughly equivalent to serological typing
• Four-digit (e.g., HLA-A*02:01): Unique protein sequence—minimum for clinical applications
• Six-digit+: Includes synonymous variants, important for research

Haplotypes and Linkage Disequilibrium

HLA genes are inherited as haplotypes—blocks of alleles on a single chromosome that are transmitted together. Strong linkage disequilibrium means certain allele combinations occur far more frequently than expected by chance.

Common Caucasian haplotypes include:

• A1-B8-DR3: Associated with multiple autoimmune diseases
• A3-B7-DR15: Associated with multiple sclerosis
• A2-B44-DR4: Common in Northern European populations

Antigen Presentation Pathways

Class I Pathway (Endogenous/Cytosolic)

HLA Class I presents peptides derived from proteins synthesized within the cell:

1. Protein degradation: Cytosolic proteins (including viral proteins) are degraded by the proteasome
2. Peptide transport: Peptides are transported into the endoplasmic reticulum by TAP (Transporter associated with Antigen Processing)
3. Peptide loading: Peptides are loaded onto HLA Class I molecules with help from the peptide-loading complex (tapasin, calreticulin, ERp57)
4. Surface expression: Stable peptide-HLA complexes travel to the cell surface
5. T cell surveillance: CD8+ T cells scan these complexes via their TCR

This pathway enables immune surveillance against viral infections and cancer.

Class II Pathway (Exogenous/Endosomal)

HLA Class II presents peptides derived from extracellular proteins:

1. Antigen uptake: Professional APCs internalize antigens via endocytosis, phagocytosis, or receptor-mediated uptake
2. Processing: Proteins are degraded in acidic endosomal/lysosomal compartments
3. Class II assembly: HLA Class II molecules are assembled in the ER with invariant chain (Ii) blocking the peptide groove
4. CLIP exchange: In endosomal compartments, Ii is degraded to CLIP; HLA-DM catalyzes exchange of CLIP for antigenic peptide
5. Surface expression: Peptide-loaded Class II molecules are displayed on the cell surface
6. T cell recognition: CD4+ T cells recognize peptide-HLA Class II complexes

This pathway coordinates adaptive immune responses against extracellular pathogens.

HLA and Disease

Autoimmune Disease Associations

Certain HLA alleles confer dramatically increased risk for specific autoimmune diseases:

Protective Alleles

Some HLA alleles confer protection against disease:

Infectious Disease

HLA diversity within populations provides collective protection against pathogens:

• Different alleles present different pathogen peptides
• Population-level polymorphism ensures some individuals can respond to any pathogen
• Heterozygosity advantage: individuals with different alleles on each chromosome can present more diverse peptides

HLA in Transplantation

Matching Requirements

HLA compatibility between donor and recipient is critical for transplant success:

Graft Rejection

HLA mismatches drive rejection through:

1. Direct allorecognition: Recipient T cells recognize intact donor HLA molecules
2. Indirect allorecognition: Recipient T cells recognize processed donor HLA peptides on self-APCs
3. Antibody-mediated rejection: Pre-existing or de novo anti-HLA antibodies attack donor tissue

Graft-versus-Host Disease (GVHD)

In hematopoietic stem cell transplantation, donor T cells can attack recipient tissues expressing “foreign” HLA. Even single HLA mismatches significantly increase GVHD risk.

HLA Typing Methods

Serological Typing (Historical)

Based on antibody reactivity patterns. Now largely replaced by molecular methods but still defines allele groups (e.g., HLA-A2).

Molecular Typing Methods

High-resolution typing (4+ digits) is increasingly standard for clinical applications.

Clinical Testing Indications

Transplantation

• Donor-recipient matching
• Antibody screening and crossmatching
• Epitope-level matching for sensitized patients

Disease Association

• HLA-B*27 for ankylosing spondylitis diagnosis
• HLA-DQ2/DQ8 for celiac disease risk assessment
• HLA typing before immunotherapy (abacavir hypersensitivity screening for HLA-B*57:01)

Drug Hypersensitivity

Certain HLA alleles predict severe drug reactions:

Pharmacogenomic screening is now standard of care for these drugs.

Key Concepts

1. HLA molecules present peptide antigens to T cells, enabling adaptive immune responses against pathogens and abnormal cells

2. Class I molecules (HLA-A, -B, -C) present endogenous peptides to CD8+ T cells; Class II molecules (HLA-DR, -DQ, -DP) present exogenous peptides to CD4+ T cells

3. Extreme polymorphism in HLA genes maximizes peptide presentation diversity across populations but creates challenges for transplantation

4. Disease associations reflect the central role of HLA in immune responses—certain alleles predispose to autoimmunity while others protect against infection

5. HLA matching is essential for successful transplantation, with requirements varying by organ type

6. Pharmacogenomic screening for specific HLA alleles prevents severe drug hypersensitivity reactions

Related Articles

• Antigen Presentation — The pathways of peptide loading and display
• T Cell Receptor Structure — How TCRs recognize peptide-HLA complexes
• T Cell Development — Thymic selection and HLA restriction
• Immune Tolerance — How HLA shapes self-tolerance
• Autoimmune Disease — HLA associations and mechanisms

References

1. Robinson J, et al. (2020). IPD-IMGT/HLA Database. Nucleic Acids Research, 48(D1):D829-D834.

2. Trowsdale J, Knight JC. (2013). Major histocompatibility complex genomics and human disease. Annual Review of Genomics and Human Genetics, 14:301-323.

3. Dendrou CA, et al. (2018). HLA variation and disease. Nature Reviews Immunology, 18:325-339.

4. Petersdorf EW. (2017). Role of major histocompatibility complex variation in graft-versus-host disease after hematopoietic cell transplantation. F1000Research, 6:617.