HLA-DRB5

Human leukocyte antigens (HLAs) are proteins encoded by genes on chromosome 6 that help the immune system recognize and respond to foreign threats. As part of the major histocompatibility complex (MHC), HLAs including HLA-DRB5 play critical roles in immune defense, organ transplantation, and disease susceptibility.

What Are HLAs?

The human leukocyte antigen (HLA) system is a group of genes found on chromosome 6 that helps the immune system recognize and respond to foreign substances like viruses and cancer cells. HLAs are the human version of a larger group of proteins called the major histocompatibility complex (MHC).

There are three main types of HLA genes:

Class I (HLA-A, -B, -C)

Class I HLA proteins are found on almost all cells in the body and present pieces of proteins (called peptides) to CD8+ T cells, a type of immune cell that can destroy infected or damaged cells. 

Class II (HLA-DR, -DP, -DQ)

Class II HLAs are found on immune cells like B cells and macrophages, and participate in immune system activation by presenting peptides to CD4+ helper T cells. HLA-DRB5 is part of the Class II group of proteins. 

Class III

Class III genes make proteins involved in other immune functions, but they don't present peptides.

HLAs are highly variable between individuals, which makes them essential for immune defense—but also makes organ matching for transplantation more complicated.

What Is HLA-DRB5?

HLA-DRB5 is part of the human leukocyte antigen (HLA) system—a group of genes on chromosome 6 that play a central role in immune defense. Specifically, HLA-DRB5 belongs to the HLA class II region, which helps the immune system recognize and respond to foreign proteins.

HLA Class II Molecules

HLA class II molecules are made of two chains: an alpha (α) chain from the DRA gene, and a beta (β) chain from one of the DRB genes (like DRB1, DRB3, DRB4, or DRB5). 

These molecules are found on antigen-presenting cells (APCs) such as B cells, macrophages, and dendritic cells, where they present peptides to CD4+ T helper cells, initiating adaptive immune responses.

HLA-DRB5 Specificity and Expression

HLA-DRB5 is a secondary DRB gene that is not present in all individuals. It is typically co-inherited with specific DRB1 alleles, most notably DRB115 and DRB116, as part of the extended HLA-DR2 haplotype. 

The DRB5 gene encodes the β-chain of the DR51 antigen, contributing to the diversity of peptides presented to CD4+ T cells and thereby influencing immune recognition. 

Although DRB5 is expressed at lower levels than the primary DRB1 gene, its expression is detectable and may have functional implications depending on an individual's genetic background.

When Is HLA-DRB5 Testing Relevant?

HLA-DRB5 testing may be relevant in the following clinical scenarios: 

Transplantation

HLA-DRB5 typing is not a primary match target but is relevant in high-resolution HLA matching for organ and bone marrow transplants.

In hematopoietic stem cell transplantation, mismatches in the DRB5 antigen recognition domain (ARD) have been associated with:

• Increased non-relapse mortality (HR 1.35)
• Reduced overall survival (HR 1.25) in otherwise matched donors.

Including DRB5 in extended HLA typing can improve donor selection, particularly in older or high-risk patients.

Autoimmune Disease Associations

HLA-DRB5 has been linked with the following autoimmune conditions:

Multiple Sclerosis (MS)

DRB5 is part of the well-known DR2 haplotype (DRB501–DRB115–DQB10602) associated with MS in European populations. However, in an Iranian study, DRB5 was not associated with MS susceptibility but did correlate with more severe disease and non-relapsing MS subtypes.

Immune Thrombocytopenia (ITP)

In immune thrombocytopenia (ITP) models, HLA-DRB5 is notably upregulated in macrophages, where it appears to play a key role in disease pathogenesis. Its expression promotes the activation of CD8+ cytotoxic T cells, which contribute to platelet destruction. 

Experimental knockdown of DRB5 in mice restored platelet counts, highlighting its potential clinical relevance both as a biomarker for T cell–driven ITP and as a possible therapeutic target.

Alzheimer's Disease (AD)

Genome-wide studies have identified HLA–DRB5–DRB1 as a risk locus for late-onset AD.

The exact mechanism is unclear, but findings support a role in neuroinflammation and immune dysregulation.

HLA Typing: Test Procedures

HLA typing is performed to identify a patient's human leukocyte antigen profile for transplantation matching, disease association studies, and antibody screening. There are three main types of HLA testing. 

Serologic Testing

Serologic typing is the classical method, using peripheral blood lymphocytes as the sample. 

In this approach, lymphocytes are exposed to a panel of HLA-specific antisera in microplates, and the presence of antigen-antibody binding is determined by complement-mediated cell lysis. 

Molecular HLA Typing

Molecular HLA typing is now the standard, providing high-resolution identification of specific HLA alleles. 

It uses DNA extracted from blood or buccal cells. It involves techniques such as sequence-specific oligonucleotide probes (SSOP), sequence-specific primers (SSP), or direct DNA sequencing to detect allele-level differences, particularly important in bone marrow and stem cell transplantation. 

HLA Antibody Screening and Crossmatching

HLA antibody screening and crossmatching detect preformed antibodies that may interfere with transplantation. 

This testing uses the patient's serum and is typically performed using microlymphocytotoxicity assays, flow cytometry, or Luminex®-based bead technology. Together, these tests support donor matching, predict immune compatibility, and reduce the risk of transplant rejection.

What Does the Presence or Absence of HLA-DRB5 Mean?

HLA-DRB5 may carry the following significance:

Presence of HLA-DRB5

This suggests the individual carries a DRB1 allele linked to DRB5 (e.g., DRB115 or 16). It may influence antigen presentation, autoimmune risk, or transplant compatibility.

Absence of HLA-DRB5

The absence of HLA-DRB5 indicates the person carries other DRB-linked genes (e.g., DRB3 or DRB4). The absence alone has no direct clinical impact unless specific transplant or immune contexts apply.

Key Takeaways for Clinicians

HLA-DRB5 is a polymorphic class II gene that contributes to the diversity of antigen presentation in the immune system. 

It is typically co-inherited with specific DRB1 alleles and, although not routinely typed in standard clinical settings, holds significant relevance in certain contexts. These include extended HLA haplotype matching for transplantation, autoimmune risk profiling—particularly in conditions like multiple sclerosis (MS) and immune thrombocytopenia (ITP)—and broader immunogenetic research. 

Including DRB5 in HLA typing panels may improve transplant compatibility assessments and help identify patients at increased risk for more severe autoimmune or neurodegenerative diseases.