What does HLA (Human Leukocyte Antigen) stand for in immunology?

HLA Stands for Human Leukocyte Antigen

HLA stands for Human Leukocyte Antigen, which represents the human version of the major histocompatibility complex (MHC) system 1.

Core Definition and Location

• HLA is encoded by the HLA gene complex located on the short arm of chromosome 6 (position 6p21) 1
• This genomic region spans approximately 3.6 Mb and represents the most gene-dense and polymorphic region of the human genome 1, 2
• The locus contains more than 200 genes, with at least 132 protein-coding genes involved in immune regulation 1, 2

Functional Classification

HLA molecules are divided into three main classes based on their structure, distribution, and function 1, 3:

Class I HLA Molecules

• Classical class I antigens include HLA-A, HLA-B, and HLA-C 1, 3
• These molecules are expressed on nearly all nucleated somatic cells 1
• They present intracellular peptides (self-antigens or cytosolic pathogens) to CD8+ T cells 1, 4
• The class I molecule consists of an α-chain encoded in the MHC region and a β2-microglobulin chain encoded on chromosome 15 1

Class II HLA Molecules

• Classical class II antigens include HLA-DP, HLA-DQ, and HLA-DR 1, 3
• Specific genes include HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1 (among others) 1
• These molecules are expressed primarily on antigen-presenting cells 1
• They present processed extracellular pathogens to CD4+ T cells 1

Class III Region

• Contains genes for complement components and other immune-related molecules 1, 3
• Includes complement component 4 (C4), which plays roles beyond classical antigen presentation 1

Primary Biological Function

The main function of HLA molecules is to present antigenic peptides to T cells, thereby regulating immune surveillance, tolerance, and response 1, 5. This process involves:

• Influencing thymic selection during T cell development 1
• Activating appropriate immune responses to pathogens 1, 5
• Maintaining immune tolerance to self-antigens in healthy conditions 4, 5

Clinical Significance

Disease Associations

• The HLA locus is associated with more complex diseases than any other locus in the human genome 1
• In many diseases, HLA explains more heritability than all other known genetic loci combined 1
• Associated with over 100 different diseases, including autoimmune conditions (type 1 diabetes, rheumatoid arthritis, psoriasis), infectious disease susceptibility, and even schizophrenia 1, 2

Transplantation Medicine

• HLA typing is essential for assessing donor-recipient immune compatibility in organ and tissue transplantation 1, 6
• Accurate HLA matching, particularly for HLA-A, HLA-B, and HLA-DR (the "haplotype"), significantly improves transplant outcomes 6
• Anti-HLA donor-specific antibodies (DSAs) are critical biomarkers for antibody-mediated rejection and allograft survival 1

Unique Polymorphism

• HLA genes exhibit extreme polymorphism, with thousands of known alleles 1
• This diversity is population-specific and reflects pathogen-driven natural selection over human evolutionary history 1
• The polymorphic nature makes HLA the most variable genetic system in humans 1, 2

Important Caveats

• HLA-C is the most recently evolved HLA class I molecule, present only in humans and great apes, and serves as a natural ligand for killer-cell immunoglobulin-like receptors (KIRs) on natural killer cells 4
• The HLA region exhibits unique long-range linkage disequilibrium, meaning variants across the entire MHC region are inherited together more often than expected 1
• HLA molecules can activate the immune system through both direct and indirect pathways of T cell activation, making them particularly immunogenic 5