The human leukocyte antigen-DR (HLA-DR) protein complex is a central component of the immune system, playing a fundamental role in distinguishing between the body’s own cells and foreign invaders. This molecule is part of the Major Histocompatibility Complex (MHC), a gene family. The HLA-DR complex functions as an immune surveillance tool, presenting protein fragments to immune cells to initiate a coordinated defense against pathogens. Its presence is mandatory for the adaptive immune system to launch a specific and targeted response.
Structure and Cellular Placement
The HLA-DR molecule is structurally a heterodimer, composed of two different protein chains: an alpha (\(\alpha\)) chain and a beta (\(\beta\)) chain, which are non-covalently linked. Both chains are anchored within the cell membrane and contain extracellular domains. They form a specialized groove on the cell surface designed to hold and display a short peptide fragment, typically ranging from 9 to 30 amino acids in length.
This complex is classified as a Major Histocompatibility Complex (MHC) Class II molecule. The genes encoding HLA-DR are located on chromosome 6. Unlike other immune markers found on nearly all cells, HLA-DR expression is restricted, primarily found on professional antigen-presenting cells (APCs). These specialized cells include B-cells, macrophages, and dendritic cells, which engulf and process foreign material. The molecule’s placement on the surface of these specific cells dictates its function, enabling it to act as the primary communicator to the adaptive immune system.
Mechanism of Antigen Presentation
The core function of HLA-DR is to present antigens derived from outside the cell to the immune system. This process begins when an antigen-presenting cell (APC) internalizes foreign material, such as bacteria or a virus particle, often through phagocytosis. Once inside the APC, the foreign proteins are contained within specialized vesicles (endosomes or phagolysosomes) and broken down into smaller peptide fragments by lysosomal enzymes.
Concurrently, newly synthesized HLA-DR molecules, initially blocked by the invariant chain protein, are transported toward these endosomal compartments. Inside the vesicle, the invariant chain is removed, and the peptide fragments are loaded into the HLA-DR’s binding groove. The resulting complex is then transported to the cell’s outer surface for display. This display is designed to interact with and activate CD4+ T-helper cells, which possess T-cell receptors that recognize the presented peptide. This interaction triggers the adaptive immune response, leading to the proliferation of T-cells and the subsequent coordination of B-cells to produce targeted antibodies against the invading pathogen.
The Role of Genetic Variation
The genes that encode HLA-DR exhibit an extraordinary level of genetic diversity, a feature known as polymorphism. Within the human population, there are hundreds of different variants, or alleles, for the genes that determine the structure of the HLA-DR molecule. This high degree of variation ensures that humans, as a species, can collectively respond to a vast and constantly evolving array of pathogens.
An individual inherits a set of HLA genes from each parent, and these genes are expressed co-dominantly. Co-dominance means that the HLA-DR molecules inherited from both parents are present and functional on the cell surface. This creates a unique “immune signature” for every person—a combination of alleles that dictates which specific peptides their immune system can effectively present and recognize. This genetic variability is thought to be maintained through evolutionary pressure, increasing the likelihood that some individuals in a population will be able to mount an effective defense against a new infection.
Impact on Autoimmunity and Transplantation
The immense genetic variation in HLA-DR has significant clinical consequences, particularly in autoimmunity and transplantation medicine. In autoimmune disease, certain HLA-DR alleles are strongly associated with increased genetic susceptibility to specific conditions, such as rheumatoid arthritis and Type 1 Diabetes. The current understanding suggests that some HLA-DR types may possess binding grooves prone to mistakenly presenting a fragment of a person’s own protein as a foreign invader. This misidentification triggers an inappropriate immune attack against the body’s own tissues.
In transplantation, differences in HLA-DR types between a donor and a recipient are a major cause of graft rejection. The recipient’s immune system, specifically its T-cells, recognizes the donor’s HLA-DR molecules as non-self, perceiving them as foreign antigens. This recognition initiates a powerful immune response intended to destroy the foreign tissue, manifesting as acute rejection. Therefore, matching the HLA-DR types between donor and recipient is a crucial step in pre-transplant evaluation to minimize the risk of rejection and improve the long-term success of the transplant.