Human Leukocyte Antigen-DR, or HLA-DR, is a protein found on the surface of specialized cells. These molecules are part of the human leukocyte antigen system, a family of proteins that helps the immune system distinguish the body’s own proteins from those of foreign invaders like viruses and bacteria. HLA-DR is classified as a Major Histocompatibility Complex (MHC) class II molecule and is encoded by genes on chromosome 6. These proteins are expressed on antigen-presenting cells, including macrophages, B cells, and dendritic cells, where they help initiate defensive responses against pathogens.
The Function of HLA-DR in the Immune System
HLA-DR functions within the adaptive immune system, which provides long-lasting protection. Its primary role is to present fragments of proteins from outside the cell to specialized immune cells called T-helper cells. Antigen-presenting cells (APCs) constantly sample their environment. When an APC engulfs a bacterium, it breaks the invader down into smaller pieces called peptides.
These peptide fragments are loaded into a specific groove on the HLA-DR molecule. The HLA-DR molecule then transports the peptide to the cell surface, acting like a display case to show the foreign peptide to T-helper cells. This presentation signals that an invasion has occurred.
The interaction between the HLA-DR-peptide complex and a T-helper cell’s receptor triggers the next phase of the immune response. The activated T-helper cell multiplies and sends out chemical signals, called cytokines, that orchestrate a targeted attack. These signals stimulate B-cells to produce antibodies and activate other immune cells to destroy infected cells, tailoring the defense to the specific pathogen.
Genetic Diversity of HLA-DR
The genes encoding HLA-DR proteins are among the most variable, or polymorphic, in the human genome. This genetic diversity means there are hundreds of different versions, known as alleles, of the HLA-DR genes. The result is that each person, except for identical twins, has a nearly unique set of HLA-DR molecules. This diversity is an evolutionary advantage, ensuring the human population can respond to a vast array of pathogens.
Most of this variability is centered in one of the genes that codes for the HLA-DR molecule. The specific combination of HLA-DR alleles an individual inherits determines the shape of the peptide-binding groove on their HLA-DR proteins. This shape dictates which pathogen fragments their immune system can display to T-helper cells.
A laboratory process known as HLA typing is used to identify a person’s specific HLA-DR alleles. Modern DNA-based techniques provide high-resolution typing that can precisely determine the alleles present. This testing has direct clinical applications in disease risk and transplantation.
The Role of HLA-DR in Autoimmune Conditions
The HLA-DR system can be involved in autoimmune diseases, which occur when the immune system mistakenly attacks the body’s own healthy cells. Associations have been established between certain HLA-DR variants and an increased risk for specific autoimmune conditions. For example, the HLA-DR4 allele is associated with a higher risk of rheumatoid arthritis. The HLA-DR2 allele is associated with multiple sclerosis, while HLA-DR3 is linked to systemic lupus erythematosus and Type 1 diabetes.
It is thought that certain HLA-DR variants have a binding groove structure more likely to present a “self-peptide”—a fragment of one of the body’s own proteins. When a self-peptide is presented by these HLA-DR molecules, it can be recognized by a T-helper cell, initiating an inappropriate immune response. This misdirected activation leads to inflammation that damages healthy tissues, causing the symptoms of autoimmune disease.
HLA-DR in Organ and Stem Cell Transplantation
The genetic diversity of HLA-DR is a consideration in organ and hematopoietic stem cell transplantation. A recipient’s immune system is programmed to attack foreign tissue, using the donor’s HLA proteins to identify it as non-self. A mismatch in HLA-DR molecules between the donor and recipient is a trigger for transplant rejection.
To prevent rejection, extensive HLA typing is performed on both the donor and recipient to find the closest possible match. This is particularly important for the HLA-DR, HLA-A, and HLA-B genes. The recipient’s T-helper cells will identify mismatched donor HLA-DR proteins and initiate an immune assault on the transplanted tissue.
In kidney transplantation, an HLA-DR mismatch is a primary factor for rejection. For stem cell transplants, a close match is needed to prevent both graft rejection and graft-versus-host disease (GVHD), where donor immune cells attack the recipient’s body. The closer the HLA-DR match, the higher the likelihood of long-term transplant success.