Wegener’s granulomatosis, now more commonly called granulomatosis with polyangiitis (GPA), is a complex autoimmune disease that primarily affects small to medium-sized blood vessels, causing inflammation and damage in various organs, especially the respiratory tract and kidneys. The exact cause of GPA is not fully understood, but it arises from a combination of genetic, environmental, and immune system factors that together trigger an abnormal immune response.
At the core of GPA’s development is an autoimmune process where the body’s immune system mistakenly attacks its own blood vessels. This attack is largely driven by the presence of specific autoantibodies called antineutrophil cytoplasmic antibodies (ANCA), particularly those targeting a protein called proteinase 3 (PR3) found in neutrophils, a type of white blood cell. These ANCA-PR3 antibodies activate neutrophils abnormally, causing them to adhere to and damage the walls of blood vessels, leading to inflammation and the formation of granulomas—organized clusters of immune cells that form in response to persistent inflammation or infection.
Genetic predisposition plays a significant role in GPA. Certain gene variants, especially those related to the immune system such as HLA-DPB1*04 and SEMA6A, have been linked to a higher risk of developing the disease. These genetic factors likely influence how the immune system recognizes self and non-self, making some individuals more susceptible to autoimmune reactions.
Environmental factors also contribute to the onset of GPA. Exposure to infectious agents, particularly bacteria like Staphylococcus aureus, is thought to trigger or exacerbate the disease in genetically predisposed individuals. These infections may stimulate the immune system excessively or alter immune regulation, leading to the production of ANCA and subsequent vascular inflammation. Some studies suggest that infections can mimic or induce ANCA positivity, complicating diagnosis and understanding of the disease’s triggers.
The immune dysregulation in GPA involves not only autoantibodies but also T-cell abnormalities. T-helper cells, which normally help regulate immune responses, become dysregulated, promoting inflammation and tissue damage. This immune imbalance results in the characteristic necrotizing granulomatous inflammation seen in affected tissues.
In summary, Wegener’s granulomatosis (GPA) is caused by a multifaceted interplay of genetic susceptibility, environmental exposures (notably infections), and immune system dysfunction. The hallmark of the disease is the production of ANCA autoantibodies that target neutrophils, leading to blood vessel inflammation and granuloma formation. This complex immune attack damages organs and causes the wide range of symptoms associated with GPA.
