HLA-DRB4

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 such as HLA-DRB4 play critical roles in immune defense, organ transplantation, and disease susceptibility.

Introduction: 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.

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-DRB4?

HLA-DRB4 is part of the human leukocyte antigen (HLA) system—a group of genes on chromosome 6 that helps the immune system tell the difference between self and non-self. These genes belong to the major histocompatibility complex (MHC), which plays a key role in immune defense.

HLA Class II Molecules

HLA-DRB4 encodes a beta chain of the HLA class II protein, which pairs with an alpha chain (from the DRA gene) to form a molecule that displays antigens to CD4+ helper T cells. These class II molecules are found on antigen-presenting cells like B cells, macrophages, and dendritic cells and are essential for activating immune responses.

HLA-DRB4 Specificity

Unlike the primary DRB1 gene, which is expressed in everyone, HLA-DRB4 is only present in individuals with certain DRB1 alleles, especially DRB1*04, *07, or *09. It contributes to immune diversity by adding to the range of peptides presented to T cells.

When is HLA-DRB4 Testing Relevant?

HLA-DRB4 testing may be recommended in the following scenarios: 

Transplantation

HLA-DRB4 typing helps match donors and recipients in hematopoietic stem cell and organ transplantation. 

Although DRB1 is the primary match target, DRB4 mismatches—especially in the antigen recognition domain (exon 2)—have been linked to increased risk of graft-versus-host disease and non-relapse mortality.

Autoimmune Disease Risk

Type 1 Diabetes & Celiac Disease: DRB4*01:03:01 is strongly associated with children who develop both conditions, especially when part of the DR4-DQ8 haplotype.

Multiple Sclerosis: certain DRB4 alleles are more frequent in MS patients and contribute to disease susceptibility when co-inherited with other HLA-DRB alleles.

Immunotherapy

In non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors, HLA-DRB4 positivity was associated with:

• Longer overall survival (26.3 vs. 10.2 months)
• Higher risk of endocrine immune-related adverse events (e.g., thyroiditis, adrenal insufficiency)

Research and Risk Stratification

DRB4 typing enhances research into autoimmune mechanisms, immunotherapy response, and transplant outcomes. Its presence provides insight into extended HLA haplotypes relevant to immune regulation.

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 of HLA-DRB4 Mean?

The presence of HLA-DRB4 indicates co-inheritance with specific DRB1 alleles and expanded antigen-presenting ability. In clinical contexts, it may:

• Inform transplant donor selection
• Indicate increased risk for certain autoimmune diseases
• Predict stronger responses or toxicity in immunotherapy

What Does the Absence of HLA-DRB4 Mean?

If HLA-DRB4 is absent, the individual carries other DRB-linked genes (like DRB3 or DRB5). By itself, the absence may have no clinical impact unless HLA matching or autoimmune profiling is involved. Routine screening is not necessary in the general population.

Key Takeaway for Clinicians

HLA-DRB4 is a non-primary but clinically meaningful HLA class II gene. 

It is relevant to transplant compatibility and autoimmune disease risk (especially T1D and MS) and is emerging as a biomarker for immunotherapy response and toxicity. 

Extended HLA typing that includes DRB4 may improve clinical decision-making in high-risk or precision medicine settings.