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New Insights into the Disease Mechanism of Vasculitis. Potential Target for Specific Therapy

16.05.2007
A potential therapeutic target for autoimmune vasculitis has been identified by researchers of the Franz Volhard Clinic for Cardiovascular Diseases (FVK) of the Charité – University Medicine Berlin/HELIOS-Klinikum and the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch.

They discovered that a specific surface receptor (NB1) mediates the expression of a molecule (autoantigen) on the surface of certain white blood cells, where the immune system recognizes and binds it. This reaction starts the inflammation process. Thus, NB1 is a potential drug target for ANCA-associated vasculitis, as Dr. Sibylle von Vietinghoff (FVK), Professor Friedrich Luft (FVK, MDC) and Professor Ralph Kettritz (FVK) report in the American journal Blood (Vol. 109, No. 10, pp. 4487-4493, May 15, 2007)*.

Autoimmune vasculitis is a broad term encompassing a group of disorders characterized by blood vessel inflammation. It is triggered by antibodies formed by the immune system which are no longer able to distinguish between “self” and “non-self”. The antibodies target the most common white blood cells, the neutrophil granulocytes, or more precisely an enzyme that is normally found in the cell plasma of these blood cells, proteinase 3 (PR3).

Neutrophil granulocytes are part of the immune system, and their primary function is to attack viruses and bacteria. In the cell plasma of all neutrophil granulocytes, the enzyme proteinase 3 (PR3) is present. PR3 plays a role in one form of vasculitis because it elicits the formation of autoantibodies. These antibodies are therefore called ANCA (antineutrophil cytoplasmatic autoantibodies).

However, ANCA autoantibodies only attack the white blood cells which “display” the enzyme PR3 on their surface. The blood cells which retain the enzyme inside the cell away from the cell surface avoid the attack of the autoantibodies. The binding of the ANCA antibodies to the PR3 localized on the cell membrane activates the white blood cells, which thereupon attack the body’s own structures and trigger the inflammation processes in the blood vessels. The resulting inflammation can affect any and all organs and become life-threatening.

Receptor protein

Prior to this study it was not known how the enzyme is presented on the membrane surface of the blood cells. Dr. von Vietinghoff and her colleagues in Berlin-Buch were able to show that it has a “helper” presenting it on the surface of the blood cells: the membrane anchor protein NB1 (CD177). For their study they tested and compared blood samples obtained from 200 healthy volunteer donors and patients with ANCA vasculitis. The researchers discovered that the enzyme PR3 and the receptor NB1 were more often found on the surfaces of blood cells in patients with ANCA vasculitis. Using molecular techniques the researchers were able to prove that NB1 is necessary for PR3 membrane presentation.

Aim – Development of a specific therapy

NB1 therefore appears to be a promising therapeutic target, according to Sibylle von Vietinghoff, Ralph Kettritz and Friedrich Luft. Although today there are treatments for vasculitis and related disorders such as Wegener’s granulomatosis, a rare but serious disease which affects all body organs including the kidneys, currently used drugs suppress the entire immune system. The disadvantage is that this makes patients more vulnerable to infection.

With unspecific immune therapy and dialysis, the kidneys of the affected patients often recover their function. “It is one of the few kidney diseases in which patients are able to come off dialysis,” Ralph Kettritz said. But a risk of recurrence always remains. If NB1 could be inhibited and PR3 expression on the blood cell surfaces prevented, vasculitis could be better controlled or even cured and recurrences avoided. “That is why our findings provide hope for patients with vasculitis,” he said. “A specific therapy approach based on our study may hold the key to overcoming the disease.”

Barbara Bachtler | alfa
Further information:
http://bloodjournal.hematologylibrary.org/

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