HLA-DQB1

The HLA-DQB1 gene provides instructions for making a protein that plays a critical role in the immune system. The HLA-DQB1 gene is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria.

The HLA complex is the human version of the major histocompatibility complex (MHC), a gene family that occurs in many species. Genes in this complex are categorized into three basic groups: class I, class II, and class III. The HLA-DQB1 gene is classified as part of MHC class II.

MHC class II genes provide instructions for making proteins that are present on the surface of certain immune system cells. These proteins attach to protein fragments (peptides) outside the cell. MHC class II proteins display these peptides to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it triggers a response to attack the invading viruses or bacteria.

The protein produced from the HLA-DQB1 gene attaches (binds) to the protein produced from another MHC class II gene, HLA-DQA1. Together, they form a functional protein complex called an antigen-binding DQαβ heterodimer. This complex displays foreign peptides to the immune system to trigger the body's immune response.

Each MHC class II gene has many possible variations, allowing the immune system to react to a wide range of foreign invaders. Researchers have identified hundreds of different versions (alleles) of the HLA-DQB1 gene, each of which is given a particular number (such as HLA-DQB1*06:02).

celiac disease - increased risk from variations of the HLA-DQB1 gene

At least two specific versions of the antigen-binding DQαβ heterodimer have been found to increase the risk of developing celiac disease. One of these heterodimer versions, known as DQ2, is composed of the protein produced from HLA-DQB1 gene variants known as HLA-DQB1*02:01 or HLA-DQB1*02:02 bound to the protein produced from HLA-DQA1 gene variants known as HLA-DQA1*05:01 or HLA-DQA1*05:05. The other heterodimer version, known as DQ8, is composed of the protein produced from the HLA-DQB1 gene variant known as HLA-DQB1*03:02 bound to the protein produced from HLA-DQA1 gene variants known as HLA-DQA1*03:01 or HLA-DQA1*03:02.

The DQ2 and DQ8 heterodimers, which may occur separately or together, seem to increase the risk of an inappropriate immune response to the protein gluten, which is found in wheat, rye, and barley. This immune system malfunction results in the damage to the body's organs and tissues that occurs in celiac disease. However, the DQ2 and DQ8 variants are also found in 30 percent of the general population, and only 3 percent of individuals with the gene variants develop celiac disease.

narcolepsy - increased risk from variations of the HLA-DQB1 gene

A version of the HLA-DQB1 gene called HLA-DQB1*06:02 increases the risk of developing the sleep disorder narcolepsy, particularly in people who also have cataplexy. (Cataplexy is a sudden loss of muscle tone in response to strong emotion, such as laughing, surprise, or anger.) It is unclear how HLA-DQB1*06:02 causes this increased risk. However, there is increasing evidence that narcolepsy is related to a malfunction of the immune system.

The sleep abnormalities associated with narcolepsy likely result from a loss of particular brain cells (neurons) in a part of the brain called the hypothalamus. These cells normally produce chemicals called hypocretins (also known as orexins), which have many important functions in the body. In particular, hypocretins regulate the daily sleep-wake cycle. Researchers speculate that an abnormality of the immune system may trigger the loss of hypocretin-producing neurons in people with narcolepsy. However, there is no direct evidence to show that immune system factors are responsible for this loss.

Most people who have narcolepsy with cataplexy have the HLA-DQB1*06:02 variation, and many also have specific versions of other, closely related HLA genes (including HLA-DQA1). However, these variations are very common in the general population, and only a small percentage of people with particular variations in HLA genes develop narcolepsy. Other genetic and environmental factors, for example certain bacterial and viral infections, also affect the chances of developing this disorder.

autoimmune disorders - associated with the HLA-DQB1 gene

Normal variations of the HLA-DQB1 gene have been associated with several additional disorders. Most of these disorders have an autoimmune basis, which means they occur when the immune system malfunctions and attacks the body's own tissues and organs. Autoimmune disorders that have been associated with HLA-DQB1 include multiple sclerosis, type I diabetes mellitus, and pemphigus.

Multiple sclerosis is a chronic disorder of the brain and spinal cord (central nervous system) that causes muscle weakness, poor coordination, numbness, and a variety of other health problems. Several variations of HLA-DQB1 appear to increase the risk of developing this disorder. One of these variations, HLA-DQB1*06:02, is the same version of the gene that increases the risk of narcolepsy.

Type 1 diabetes mellitus is characterized by high blood sugar levels resulting from a shortage of the hormone insulin. Several variations of HLA-DQB1 increase the risk of developing this form of diabetes. However, the HLA-DQB1*06:02 variation (described above) appears to decrease the risk of developing this disease. It is unknown why this version of the gene appears to increase the risk of developing certain autoimmune diseases and reduce the risk of others.

Some evidence suggests that the HLA-DQB1 gene may also play a role in several forms of pemphigus, a condition that causes severe blistering of the skin and mucous membranes (such as the moist lining of the mouth).

It is unclear how different versions of the HLA-DQB1 gene influence the risk of developing autoimmune disorders. These disorders typically result from a combination of multiple environmental and genetic factors. Changes in other HLA and non-HLA genes, some of which remain unknown, also likely contribute to the risk of developing these complex conditions.

Genetics Home Reference provides information about juvenile idiopathic arthritis, which is also associated with changes in the HLA-DQB1 gene.