The Human Leukocyte Antigen system — and the cells that carry it.

The human leukocyte antigen (HLA) system, also known as the major histocompatibility complex (MHC), is a complex of genes located on chromosome 6 that encode cell-surface proteins responsible for regulating the immune system. The HLA system is central to the body's defense against disease, helping the immune system distinguish self from non-self. Mutations in HLA genes have been linked to autoimmune diseases including type 1 diabetes and celiac disease, and the HLA complex is the principal determinant of organ-transplant compatibility.

The HLA system is divided into two classes: HLA class I (HLA-A, -B, -C) and class II (HLA-DR, -DP, -DQ). HLA glycoproteins are decisive contributors to the defense against foreign antigens and control the immunological identity of an individual. This is the genetic system Paul Ehrlich postulated at the beginning of the 20th century to be responsible for the differentiation between "self" and "non-self" — between tolerance toward one's own tissue and active immune defense against foreign invaders.

HLA-typed cancer cells from Cytion

Cytion aims to provide diverse HLA haplotypes to medical and immunological research organizations, representing an individual's unique HLA complex. This is achieved by collecting B-LCLs and various human tumor cell lines and performing high-resolution NGS HLA typing. Our collection includes a wide range of HLA-typed cancer cells from different organs, used to test potential therapies and detect cross-reactions. With 272 HLA-typed cell lines readily available, you can eliminate the need for in-house cell HLA typing.

Location and structure

The HLA gene complex is located on the short arm of chromosome 6, at position 21.3, and spans a 3 Mbp stretch. The complex includes genes that encode various cell-surface proteins, including HLA class I and II molecules and components of the complement system. The HLA system is highly polymorphic, with many alleles for each HLA gene, allowing for a diverse array of antigen presentations.

Polymorphism

HLA genes are highly polymorphic, meaning they have many alleles that allow fine-tuning of the adaptive immune system. This diversity is essential to disease defense — the chance of two unrelated individuals being identical at all HLA loci is extremely low. Polymorphism is also a key factor in organ transplantation, where matching donors and recipients for HLA types is crucial to prevent rejection.

Relationship to MHC

The HLA system is the human version of the major histocompatibility complex (MHC) found in many animals. MHC genes are involved in immune response, and the HLA system encodes the MHC molecules in humans. The HLA system includes genes that encode for both HLA class I and II molecules, presenting peptides from inside and outside the cell.

Function

HLA class I molecules are encoded by three HLA genes: HLA-A, HLA-B, and HLA-C. These molecules present peptides from inside the cell, allowing the immune system to identify and destroy infected or abnormal cells. HLA class I molecules are critical for cell-mediated immunity, which involves T-cells recognizing and destroying abnormal or infected cells.

Peptide presentation

HLA class I molecules present peptides produced from proteins broken down in proteasomes. The resulting peptides are typically 8–10 amino acids in length, although recent research has shown that longer peptides (11–14 amino acids) can also be presented on MHC I molecules. Foreign antigens presented by MHC class I attract cytotoxic T-lymphocytes that destroy the presenting cell.

Role in the immune system

HLA class I molecules play a critical role in identifying and destroying infected or abnormal cells. When a cell is infected by a virus, HLA class I molecules display fragments of viral protein on the cell surface, allowing CD8+ T-cells to recognize and eliminate the infected cell. This process is vital to the body's defense against intracellular pathogens and malignancy.

Killer T-cells

Killer T-cells, also called CD8-positive or cytotoxic T-cells, are T-lymphocytes that recognize and destroy cells displaying foreign antigens. These cells are critical for cell-mediated immunity and play a vital role in defense against infectious disease. HLA class I molecules are central to activating killer T-cells and directing them to destroy infected or abnormal cells.

Function

HLA class II molecules present peptides derived from outside the cell, allowing the immune system to recognize and respond to extracellular pathogens. Class II molecules stimulate the multiplication of T-helper cells, which in turn drive antibody production by B-cells.

Peptide presentation

HLA class II molecules present antigens from outside of the cell to T-lymphocytes. These antigens stimulate the multiplication of T-helper cells, which then drive antibody-producing B-cells to generate antibodies specific to that antigen. Regulatory T-cells suppress responses to self-antigens.

Role in the immune system

HLA class II molecules play a critical role in identifying and responding to extracellular pathogens. By presenting antigens to T-helper cells, class II molecules drive antibody production by B-cells, which in turn neutralize extracellular pathogens. This process is vital to the body's humoral defense.

T-helper cells

T-helper cells (CD4-positive T-cells) are T-lymphocytes that recognize antigens presented by HLA class II molecules. These cells are critical for stimulating antibody production by B-cells, which neutralize extracellular pathogens. HLA class II molecules are central to activating T-helper cells and orchestrating the humoral response.

Function

HLA class III molecules are encoded by genes that produce components of the complement system, the arm of innate immunity that helps destroy foreign invaders. The complement system consists of proteins that cooperate to kill bacteria and viruses, forming a membrane attack complex that punctures the cell membrane of the invading microbe.

Role in disease defense

HLA class III molecules are essential in disease defense, playing a critical role in activating the complement system. The complement system is integral to the body's protection against infectious disease and destroys bacteria and viruses. HLA class III genes encode the proteins that comprise the complement system, making them essential for proper immune function.

Relationship to organ transplant rejection

HLA class III molecules are also involved in organ transplant rejection. In addition to class I and class II molecules, class III molecules contribute to the immune response against transplanted tissue. The proteins encoded by class III genes participate in the inflammatory response that can lead to transplant rejection.

Other functions

HLA class III molecules have also been linked to other biological processes, including apoptosis (programmed cell death) and regulation of the immune response. Research has suggested that specific class III alleles may be associated with increased risk of certain diseases, such as Alzheimer's and various autoimmune disorders.

Relationship between HLA and autoimmune disease

HLA molecules are inherited, and certain HLA types are connected with autoimmune disorders. People with specific HLA antigens are more likely to develop autoimmune conditions including type 1 diabetes, ankylosing spondylitis, rheumatoid arthritis, celiac disease, systemic lupus erythematosus, myasthenia gravis, inclusion body myositis, Sjögren syndrome, and narcolepsy.

Relative risk

Different HLA alleles are associated with different autoimmune disorders, and the relative risk varies by HLA type. The HLA-B27 allele increases the risk of ankylosing spondylitis, reactive arthritis, and acute anterior uveitis. The HLA-DR2 allele is associated with increased risk of systemic lupus erythematosus. The HLA-DR3 allele is associated with increased risk of autoimmune hepatitis, primary Sjögren syndrome, and type 1 diabetes.

HLA typing in diagnosis and treatment

HLA typing is used as a tool in the diagnosis and treatment of autoimmune diseases. For celiac disease and type 1 diabetes, HLA typing has substantially improved diagnostic certainty. In celiac disease, HLA typing is the only effective means of discriminating between first-degree relatives at risk and those not at risk before the appearance of sometimes-irreversible symptoms.

HLA and cancer

HLA-mediated diseases are also involved in the promotion of cancer. Gluten-sensitive enteropathy is associated with an increased prevalence of enteropathy-associated T-cell lymphoma, and DR3-DQ2 homozygotes are within the highest risk group — nearly 80% of gluten-sensitive enteropathy-associated T-cell lymphoma cases occur in this background.

Importance of HLA typing

HLA typing is a laboratory test that determines a person's HLA antigens. It is essential for matching donors and recipients for organ transplantation, predicting risk of certain diseases, and informing treatment choices for autoimmune conditions.

Techniques

HLA typing techniques range from serological methods, which use antibodies to detect HLA antigens on the cell surface, to molecular methods, which use PCR to amplify HLA genes for analysis. PCR-based methods are increasingly preferred for their higher resolution and ability to detect rare alleles.

Limitations

Despite its importance, HLA typing has limitations. The HLA system is highly polymorphic — many alleles exist for each HLA gene — making perfect matching for transplantation challenging. HLA typing can also be expensive and time-consuming, and the interpretation of results can be difficult for rare or novel alleles.

New developments

Recent developments make HLA typing easier to perform and interpret. Next-generation sequencing (NGS) can sequence large amounts of DNA in a single run, allowing more complete and accurate HLA typing — the technology underlying Cytion's high-resolution typing on every line in this database. Improved software for HLA typing analysis has also helped overcome challenges associated with rare alleles.