What are Human Leukocyte Antigen (HLA) variants?

Human Leukocyte Antigen (HLA) Variants

HLA variants are genetic polymorphisms in the human leukocyte antigen genes that encode proteins critical for immune system function, particularly in antigen presentation and immune response regulation. 1

Structure and Organization of HLA Variants

• HLA genes are located in the Major Histocompatibility Complex (MHC) region on chromosome 6p21

• HLA variants are organized into:

  • Class I molecules (HLA-A, HLA-B, HLA-C): Present peptides to CD8+ T cells
  • Class II molecules (HLA-DR, HLA-DQ, HLA-DP): Present peptides to CD4+ T cells 1, 2

• Each individual inherits up to 6 HLA class I variants (maternal and paternal copies of HLA-A, HLA-B, and HLA-C) and multiple HLA class II variants 3

HLA Nomenclature System

HLA variants follow a standardized four-field nomenclature system:

1. Field 1 (first two digits, e.g., HLA-DRB1*01): Describes the serological type
2. Field 2 (e.g., HLA-DRB1*01:01): Corresponds to unique amino acid sequence
3. Field 3 (e.g., HLA-DRB1*01:01:01): Reflects synonymous nucleotide substitutions
4. Field 4 (e.g., HLA-DRB1*01:01:01:01): Reflects polymorphisms in non-coding regions 1

Alternative nomenclatures include:

• G group: HLA alleles sharing the same nucleotide sequence in the peptide-binding domain
• P group: HLA alleles sharing the same protein sequence in the peptide-binding domain 1

Functional Significance of HLA Variants

• HLA variants determine which peptides can be presented to T cells, influencing immune responses
• Each HLA variant has its own repertoire of presented peptides with specific sequence motifs 3
• Different HLA variants show preferences for presenting proteins with specific molecular functions:
  • Some preferentially present membrane and receptor proteins
  • Others preferentially present ribosomal and DNA-binding proteins
  • Most show reduced presentation of extracellular matrix and collagen proteins 3

Clinical Significance

Disease Associations

• HLA variants are associated with over 100 different diseases, including:

  • Autoimmune disorders: Type 1 diabetes, rheumatoid arthritis, psoriasis
  • Infectious diseases: HIV, tuberculosis, hepatitis B/C, COVID-19 2, 4, 5

• Specific examples:

  • HLA-DRB104-DQA103:01-DQB103:02 (DR4-DQ8) and HLA-DRB103-DQA105:01-DQB102:01 (DR3-DQ2.5) are strongly associated with type 1 diabetes
  • HLA-DQB1*06:02 has a protective effect against diabetes onset in children 2

Pharmacogenetics

• HLA-B*5701 testing is recommended before initiating abacavir therapy to prevent hypersensitivity reactions
• Patients carrying the HLA-B*5701 allele have a significantly increased risk of developing a potentially fatal hypersensitivity reaction to abacavir 6

HLA Haplotypes and Inheritance

• HLA genes are inherited as complete haplotypes from each parent
• Recombination between HLA loci is rare due to their close proximity on chromosome 6
• Frequent haplotypes in human populations often contain combinations of HLA variants with complementary peptide presentation preferences, providing broader immune coverage 2, 3

HLA Typing Methods

• Traditional methods:

  • Sequence-based typing (SBT)
  • Sequence-specific oligonucleotide probe hybridization (SSOP)

• Modern approaches:

  • Next-generation sequencing (NGS)
  • HLA imputation from genotype data using reference panels 1

• Solid phase bead arrays containing purified HLA molecules can be used to determine antibody specificity for individual HLA proteins 7

Clinical Applications

• Organ and bone marrow transplantation compatibility assessment
• Predicting disease susceptibility and progression
• Guiding pharmacological therapy (e.g., abacavir)
• Vaccine development and personalized immunotherapy 2, 6

HLA typing has revolutionized our understanding of immune responses and disease mechanisms, though its routine clinical use should be targeted to specific scenarios where it provides clear diagnostic or therapeutic value.