Alopecia areata

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Autoimmune Addison disease

Certain versions of 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 own tissues and organs.

Normally, the immune system responds only to proteins made by foreign invaders, not to the body's own proteins. In people with autoimmune Addison disease, however, an immune response is triggered by a protein made by the adrenal glands, which are small, hormone-producing glands that are located on top of each kidney. In about 85 percent of people with autoimmune Addison disease, the trigger protein is 21-hydroxylase. 21-hydroxylase 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 outer layer of the adrenal glands, 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. These include 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 version of the HLA-DRB1 gene called HLA-DRB1*04:04 is the most well-known risk factor for developing autoimmune Addison disease; however, it is not clear how HLA-DRB1*04:04 and other versions of the HLA-DRB1 gene are involved in the inappropriate immune response that causes autoimmune Addison disease.

Crohn's disease

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Graves' disease

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Hashimoto's disease

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Idiopathic inflammatory myopathy

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Idiopathic pulmonary fibrosis

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Juvenile idiopathic arthritis

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Lyme disease

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Multiple sclerosis

Versions of 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 version of the HLA-DRB1 gene, called HLA-DRB1*15:01, is strongly linked to a high risk of developing multiple sclerosis.

Because the HLA-DRB1 gene is involved in the immune response, changes in the gene might lead to the autoimmune response and inflammation that damage the nerves and cause the signs and symptoms of multiple sclerosis. However, it is unclear exactly what role different versions of the HLA-DRB1 gene play in the development of multiple sclerosis. A combination of genetic and environmental factors is likely involved in this condition.

Narcolepsy

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Psoriatic arthritis

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Rheumatoid arthritis

Several versions of the HLA-DRB1 gene are associated with a person's risk of developing rheumatoid arthritis. This disease causes chronic 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 developing this disease.

The versions of the HLA-DRB1 gene, HLA-DRB1*04 and HLA-DRB1*01, are strongly linked to a high risk of developing rheumatoid arthritis. These versions of the gene lead to the production of beta chains that often contain a specific sequence of protein building blocks (amino acids) known as the shared epitope. These variants alter the part of the protein that binds to viral or bacterial peptides. This binding normally triggers the immune response that attacks foreign invaders. Changes in the beta chain caused by the shared epitope make the protein more likely to bind to the body's own proteins, resulting in an abnormal immune system response.

While changes in the HLA-DRB1 gene can influence the development of rheumatoid arthritis, many other genetic and environmental factors also contribute to a person's overall risk of developing this condition.

A few versions of the HLA-DRB1 gene appear to decrease the risk of developing rheumatoid arthritis. It is unclear why these particular changes may prevent the development of this condition.

Rosacea

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Type 1 diabetes

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

The risk of developing type 1 diabetes is highly influenced by two specific combinations 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. The people who have the 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 mildly increase the risk of type 1 diabetes, while some haplotypes seem to protect people from developing this condition. Variations in other genes and environmental factors are also thought to affect the risk of developing type 1 diabetes.

Autoimmune disorders

Certain versions of the HLA-DRB1 gene have been associated with many other autoimmune disorders, including pemphigus and sarcoidosis. 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 the different versions of the HLA-DRB1 gene influence the risk of developing these autoimmune disorders. These disorders typically result from a combination of multiple environmental and genetic factors. Changes in other HLA and non-HLA genes also likely contribute to the risk of developing these complex conditions.