Scleroderma: at San Raffaele identified key molecule in the development of the disease

Systemic sclerosis is a disabling autoimmune disease, difficult to diagnose and orphan for an effective treatment; also called Scleroderma, it is characterized by inflammation and by an unrelenting damage of small blood vessels and by the progressive thickening of the skin and internal connective tissues. Until now the mechanism that triggers and maintains the activation of the immune system has remained poorly understood, which has not helped the development of effective therapies; however, a study by the researchers of Vita- Salute San Raffaele University and San Raffaele Hospital could open new perspectives.

The research published today in Science Translational Medicine identifies for the first time the key role of HMGB1 as a single molecule responsible for the initiation and coordination of some of the key mechanisms of the pathology.

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In patients with scleroderma, inflammation of small blood vessels causes platelet activation, which release HMGB1-coated microparticles in the bloodstream. These interact with neutrophils, a type of white blood cells: as a result, neutrophils release outside the contents of their nucleus – including DNA – with inflammatory effects on the surrounding tissues.

As we have shown both in vitro and in an animal model of the disease, it is sufficient the presence of microparticles expressing this protein, collected from patients’ blood samples, to activate the immune system, in particular neutrophils, in a pathological way”, explains Dr. Norma Maugeri, first name of the research, researcher at the Autoimmunity and Vascular Inflammation Unit.

Dr. Maugeri
Dr. Maugeri

HMGB1 plays a dual role – inflammatory and regenerative (already identified by Prof. Bianchi group, among the authors of the study): in addition to damaging the tissues, the protein promotes regeneration which, if not properly controlled, can give rise to the phenomenon of fibrosis, a thickening of the tissues (especially pulmonary tissues) that could give rise to serious complications.

Once this process starts, the neutrophils activated by HMGB1 fail to perceive the inhibitory signals that normally control their action, thus triggering a continuous aggression to the vessels and the surrounding tissues, which because of the scarring become progressively  dysfunctional.

Future research will have to confirm and expand these results, but we believe that the presence of excessive amounts of HMGB1 outside the cells may be the first responsible for damaging the vessels and fibrosis of connective tissues, and therefore the triggering of the disease”, says Prof. Angelo Manfredi, Associate of Rheumatology UniSR, Head of the Autoimmunity and Vascular Inflamamtion  Unit and coordinator of this research.

If other studies will validate this discovery, HMGB1 could become a therapeutic target for scleroderma in the future: by interfering with its release in the bloodstream by platelets or by removing it from patients’ blood, we may perhaps hope to interfere with the evolution of the disease.

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