HLA-DRB1

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Certain variations in the HLA-DRB1 gene have been linked to an increased risk of developing an autoimmune disorder called autoimmune Addison disease. Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs. In autoimmune Addison disease, the immune system attacks the adrenal glands, which are small hormone-producing glands located on top of each kidney. Loss of hormones produced by the adrenal glands leads to the features of the condition, which include extreme tiredness (fatigue), nausea, low blood pressure (hypotension), and abnormally dark areas of skin (hyperpigmentation), especially in regions that experience a lot of friction such as the armpits, elbows, and knuckles. A particular HLA-DRB1 gene variant called HLA-DRB1*04:04 is the most well-known risk factor for autoimmune Addison disease.

Normally, the immune system responds only to proteins made by foreign invaders, not to the body's own proteins. In autoimmune Addison disease, however, an immune response is triggered by a normal adrenal gland protein; in about 85 percent of people with autoimmune Addison disease, the protein is 21-hydroxylase. 21-hydroxylase is found in the adrenal glands where it plays a key role in producing a variety of hormones that regulate many essential functions in the body. The prolonged immune attack triggered by 21-hydroxylase damages the adrenal glands (specifically the outer layers of the glands known, collectively, as the adrenal cortex), preventing hormone production. A shortage of adrenal hormones (adrenal insufficiency) disrupts several normal functions in the body, leading to the diverse features of autoimmune Addison disease. It is not clear how HLA-DRB1*04:04 and other HLA-DRB1 variations are involved in the inappropriate immune response that causes autoimmune Addison disease.

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Variations in the HLA-DRB1 gene have been associated with an increased risk of developing multiple sclerosis. This condition affects the brain and spinal cord (central nervous system), causing muscle weakness, poor coordination, numbness, and a variety of other health problems. One variant of this gene, called HLA-DRB1*15:01, is the most strongly linked genetic factor for the risk of multiple sclerosis.

Because the HLA-DRB1 gene is involved in the immune system, changes in it might be related to the autoimmune response and inflammation that damage nerves and the protective coating surrounding them (the myelin sheath), leading to the signs and symptoms of multiple sclerosis. However, it is unclear exactly what role HLA-DRB1 gene variants play in development of multiple sclerosis. A combination of genetic and environmental factors is likely involved in this condition.

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Several common variations of the HLA-DRB1 gene are associated with a person's risk of developing rheumatoid arthritis. This disease causes chronic abnormal inflammation that primarily affects the joints. HLA-DRB1 is one of several genes in the HLA complex that have been associated with rheumatoid arthritis; variations of this gene are the most significant known genetic risk factor for the disease.

The HLA-DRB1 gene variations associated with an increased risk of rheumatoid arthritis affect single protein building blocks (amino acids) in the beta chain. These changes occur near the antigen-recognizing binding groove, which is the part of the protein that attaches (binds) to viral or bacterial peptides. This binding triggers the immune response that attacks foreign invaders. Although the mechanism by which HLA-DRB1 gene variations increase the risk of rheumatoid arthritis is unclear, researchers suspect it is related to changes in peptide binding that stimulate an abnormal immune response. However, many other genetic and environmental factors also contribute to a person's overall risk of developing rheumatoid arthritis.

A few variations of the HLA-DRB1 gene appear to decrease the risk of developing rheumatoid arthritis. It is unclear why these particular changes may be protective.

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Combinations of variations in the HLA-DRB1 gene and other HLA genes affect the risk of type 1 diabetes. Type 1 diabetes is characterized by high levels of blood glucose, also called blood sugar, resulting from a shortage of the hormone insulin and is caused by autoimmune damage to insulin-producing cells in the pancreas.

Type 1 diabetes risk is most increased by two specific combinations of variations of the HLA-DRB1 gene and other HLA genes called HLA-DQA1 and HLA-DQB1. Combinations of HLA gene variants are called HLA haplotypes. One haplotype, written as DRB1*03:01-DQA1*05:01-DQB1*02, is called DR3. The other haplotype, written as DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*02, is called DR4. People at highest risk of developing type 1 diabetes have one copy of the DR3 haplotype and one copy of the DR4 haplotype in each cell. Other HLA haplotypes only mildly increase the risk of type 1 diabetes, while some haplotypes seem to protect against developing this condition. Variations in other genes and environmental factors are also thought to affect the risk of this complex disorder.

Normal variations of the HLA-DRB1 gene have been associated with many other autoimmune disorders, including pemphigus, sarcoidosis, and others listed on this page. Pemphigus is a condition that causes severe blistering of the skin and mucous membranes (such as the moist lining of the mouth). Sarcoidosis is a disorder in which inflammation occurs in many organs and tissues of the body.

It is unclear how different versions of the HLA-DRB1 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.