Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis, is a rare disease. It is a type of vasculitis, or inflammation of the blood vessels. The inflammation limits the flow of blood to important organs, causing damage. It can affect any organ, but it mainly affects the sinuses, nose, trachea (windpipe), lungs, and kidneys.

The cause of GPA is unknown. It can affect people at any age. Men and women are equally affected. It is more common in whites. Symptoms may include joint pain, weakness, tiredness, and cold symptoms such as a runny nose that doesn't get better. Doctors use blood tests, chest X-rays, and biopsies to diagnose GPA and rule out other causes of the symptoms.

Early treatment is important. Most people improve with medicines to slow or stop the inflammation.

Granulomatosis with polyangiitis (GPA) is a condition that causes inflammation that primarily affects the respiratory tract (including the lungs and airways) and the kidneys. This disorder is formerly known as Wegener granulomatosis. A characteristic feature of GPA is inflammation of blood vessels (vasculitis), particularly the small- and medium-sized blood vessels in the lungs, nose, sinuses, windpipe, and kidneys, although vessels in any organ can be involved. Polyangiitis refers to the inflammation of multiple types of vessels, such as small arteries and veins. Vasculitis causes scarring and tissue death in the vessels and impedes blood flow to tissues and organs.

Another characteristic feature of GPA is the formation of granulomas, which are small areas of inflammation composed of immune cells that aid in the inflammatory reaction. The granulomas usually occur in the lungs or airways of people with this condition, although they can occur in the eyes or other organs. As granulomas grow, they can invade surrounding areas, causing tissue damage.

The signs and symptoms of GPA vary based on the tissues and organs affected by vasculitis. Many people with this condition experience a vague feeling of discomfort (malaise), fever, weight loss, or other general symptoms of the body's immune reaction. In most people with GPA, inflammation begins in the vessels of the respiratory tract, leading to nasal congestion, frequent nosebleeds, shortness of breath, or coughing. Severe inflammation in the nose can lead to a hole in the tissue that separates the two nostrils (nasal septum perforation) or a collapse of the septum, causing a sunken bridge of the nose (saddle nose).

The kidneys are commonly affected in people with GPA. Tissue damage caused by vasculitis in the kidneys can lead to decreased kidney function, which may cause increased blood pressure or blood in the urine, and life-threatening kidney failure. Inflammation can also occur in other regions of the body, including the eyes, middle and inner ear structures, skin, joints, nerves, heart, and brain. Depending on which systems are involved, additional symptoms can include skin rashes, inner ear pain, swollen and painful joints, and numbness or tingling in the limbs.

GPA is most common in middle-aged adults, although it can occur at any age. If untreated, the condition is usually fatal within 2 years of diagnosis. Even after treatment, vasculitis can return.

GPA is a rare disorder that affects an estimated 3 in 100,000 people in the United States.

The genetic basis of GPA is not well understood. Having a particular version of the HLA-DPB1 gene is the strongest genetic risk factor for developing this condition, although several other genes, some of which have not been identified, may be involved. It is likely that a combination of genetic and environmental factors lead to GPA.

GPA is an autoimmune disorder. Such disorders occur when the immune system malfunctions and attacks the body's own tissues and organs. Approximately 90 percent of people with GPA have an abnormal immune protein called an anti-neutrophil cytoplasmic antibody (ANCA) in their blood. Antibodies normally bind to specific foreign particles and germs, marking them for destruction, but ANCAs attack normal human proteins. Most people with GPA have an ANCA that attacks the human protein proteinase 3 (PR3). A few affected individuals have an ANCA that attacks a protein called myeloperoxidase (MPO). When these antibodies attach to the protein they recognize, they trigger inflammation, which contributes to the signs and symptoms of GPA.

The HLA-DPB1 gene belongs to 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). Each HLA gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign proteins. A particular variant of the HLA-DPB1 gene called HLA-DPB1*0401 has been found more frequently in people with GPA, especially those with ANCAs, than in people without the condition.

Because the HLA-DPB1 gene is involved in the immune system, changes in it might be related to the autoimmune response and inflammation in the respiratory tract and kidneys characteristic of GPA. However, it is unclear what specific role the HLA-DPB1*0401 gene variant plays in development of this condition.

Normal Function

The HLA-DPB1 gene provides instructions for making a protein that plays a critical role in the immune system. The HLA-DPB1 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. The HLA-DPB1 gene belongs to a group of MHC genes called 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-DPB1 gene attaches (binds) to the protein produced from another MHC class II gene, HLA-DPA1. Together, they form a functional protein complex called an antigen-binding DPαβ 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-DPB1 gene, each of which is given a particular number (such as HLA-DPB1*03:01).

Health Conditions Related to Genetic Changes

Granulomatosis with polyangiitis

At least one variant of the HLA-DPB1 gene has been associated with granulomatosis with polyangiitis (GPA). This condition occurs when the immune system malfunctions and attacks the body's own tissues and organs (autoimmunity), causing inflammation that affects the lungs, airways, and kidneys. The associated variant, called HLA-DPB1*0401, has been found more frequently in people with GPA than in those who do not have the condition; this variant is thought to increase the risk of developing GPA.

Because the HLA-DPB1 gene is involved in the immune system, changes in it might be related to the autoimmune response and inflammation that damage the lungs, kidneys, and other organs. However, it is unclear what specific role the HLA-DPB1 gene variant plays in development of this condition. It is likely that environmental factors trigger the condition in people who are genetically predisposed to it. Other genetic factors are also likely to be involved in GPA.

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Other disorders

Variants of the HLA-DPB1 gene are associated with immune reactions to beryllium, a metallic element that can be toxic. Beryllium exposure can occur in manufacturing plants and the nuclear and aerospace industries. About 2 to 10 percent of people exposed to beryllium develop beryllium sensitization or chronic beryllium disease. Sensitization is an immune reaction that occurs in response to beryllium exposure; sensitization can cause an increase in the number of certain immune system cells in the blood, but it may not lead to any symptoms. In some people, sensitization leads to chronic beryllium disease, which is a lung disease characterized by the formation of small masses of inflammatory cells (granulomas). The lungs can become scarred and stiff and lose their ability to function. Having variants of the HLA-DPB1 gene that contain the protein building block (amino acid) glutamic acid at position 69 (written as E69) increases the risk of developing beryllium sensitization or chronic beryllium disease.

Other Names for This Gene

• beta1 domain MHC class II HLA DPB
• class II HLA beta chain
• DPB1
• DPB1_HUMAN
• HLA class II histocompatibility antigen, DP beta 1 chain
• HLA class II histocompatibility antigen, DP(W4) beta chain
• HLA DP14-beta chain
• HLA-DP
• HLA-DP histocompatibility type, beta-1 subunit
• HLA-DP1B
• HLA-DPB
• major histocompatibility complex class II antigen beta chain
• MHC class II antigen beta chain
• MHC class II antigen DP beta 1 chain
• MHC class II antigen DPB1
• MHC class II antigen DPbeta1
• MHC class II HLA-DP-beta-1
• MHC class II HLA-DRB1
• MHC HLA DPB1

Genomic Location

Changes (also known as pathogenic variants or mutations) in a particular gene are not known to be associated with granulomatosis with polyangiitis (GPA). In most cases, a person who has GPA is the only person in his or her family who has the disease. Therefore, it is not thought that GPA is passed directly from parent to child.

In some cases, instances of multiple people within the same family having GPA have been reported. It is thought that these cases may be caused by family members having normal variants in certain genes, such as the HLA-DPB1 gene, that increase the risk to develop GPA. However, having these normal variants does not guarantee that a person will develop GPA. It is thought that genetic changes in combination with environmental factors cause most cases of the disease.

Granulomatosis with polyangiitis (GPA) is suspected when a doctor observes signs and symptoms that are consistent with the disease. These signs and symptoms often include a recurrent respiratory infection, tiredness (fatigue), weight loss, and unexplained fevers. Laboratory tests may then be ordered to confirm the diagnosis and rule out other causes of the symptoms. These tests may include:

• Blood test to determine if there are signs of swelling (inflammation) in the body
• Blood test for the presence of antineutrophil cytoplasmic antibodies (ANCA)
• Chest x-ray or CT scan of the lungs to determine if there is inflammation

Although none of these tests can be used by themselves to determine if a person has GPA, the tests can be used together to support a diagnosis of the disease. If GPA is suspected, a biopsy (removing a small piece of tissue) can be done to determine if the tissue shows granulomatosis (inflammation involving the immune cells) and vasculitis (swelling of the blood vessels). The part of the body from which a biopsy is taken is most commonly the lungs, sinuses, or kidneys.

Once a diagnosis of GPA has been confirmed, further tests may be necessary to determine if other parts of the body are affected. Tests of kidney or lung function may be completed, and an eye exam may be recommended.

The treatment for granulomatosis with polyangiitis (GPA) usually includes a combination of multiple medications. These medications typically include:

• Glucocorticoids such as prednisone
• Immunosuppressive drugs such as rituximab

If there are skin lesions present, they may be treated with a topical steroid that is applied to the affected area. Surgery may be recommended if swelling of the airway or lungs is preventing normal breathing.

Other medications may be recommended to help treat GPA. These medications are often used to treat the side-effects that may be associated with glucocorticoids and immunosuppressive drugs and may include:

• Bisphosphonate to prevent bone weakening that can be caused by prednisone
• Antibiotics to prevent lung infections