Priority Research Area Asthma and Allergy
Autoimmunity of the Lung
Mission Projects Funding Techniques Publications Staff
In patients with systemic autoimmune diseases, the disease often manifests in the internal organs, especially in the lung. A good example for this is systemic sclerosis, a disease characterized by autoimmunity, pulmonary fibrosis, vasculopathy and pulmonary hypertension (PAH). Due to the essential function of the lung, manifestations in this organ are the leading cause of death in patients with SSc. The pathogenesis of autoimmunity-associated lung diseases is largely unknown. Although autoimmunity is a major factor in the development of pathology in the lungs, the involvement of other unknown factors must be assumed. Specific therapeutic approaches for the treatment of the SSc-associated lung diseases are essentially limited to the treatment of autoimmunity itself or follow the treatment regimen for idiopathic pulmonary fibrosis and PAH. In order to develop new and more specific treatment methods, it is therefore necessary to elucidate the pathomechanisms of the SSc-associated disease. Using both clinical material from SSc patients from the Rheumatology Clinic and mouse models of SSc we try to elucidate the pathological principles of autoimmune diseases in the lung using genetic, immunological and biochemical tools.
Pathological changes in lung architecture are a central problem of many chronic lung diseases, especially in asthma and chronic obstructive pulmonary disease (COPD). Similar to processes in autoimmune lung diseases, the pathogenesis of the diseases is nonlinear but characterized by periods of relative stability and exacerbating episodes. From our work, we therefore expect to contribute to the identification of similar and different mechanisms of pathogenesis in the various clinical pictures of SSc, asthma and COPD.
Currently, we are focusing on two major projects:
1. The role of autoantibodies against AT1R in SSc
According to the latest findings, the activation of the angiotensin receptor type-1 (AT1R) has an essential function in the development of pulmonary arterial hypertension (PAH). According to our hypothesis, receptor-activating autoantibodies to AT1R could play a key role in the pathogenesis of PAH. In line with this hypothesis, we were able to demonstrate that the levels of these autoantibodies were expressed significantly higher in SSc patients than in the healthy controls and patients with other systemic autoimmune diseases. Moreover, concentrations of the antibodies correlate significantly with the severity of the disease symptoms, identifying them as biomarkers for the prediction of mortality and the development of PAH in the SSc. Moreover, a number of in vitro studies have shown that autoantibodies against AT1R can induce biological functions in various cell types, such as endothelial cells or monocytes, which are sensitive to blockade by corresponding receptor antagonists.
To further investigate the role of autoantibodies against AT1R in vivo we established novel animal models based on active immunization with human AT1R. AT1R-immunized mice develop a SSc-like disease featured by fibrosis and inflammation in the skin as well as pulmonary inflammation. Therefore, this novel mouse model for SSc demonstrates a essential role of autoimmunity against AT1R in the development of SSc. In the future, we will further explore the pathogenesis of the AT1R-induced mouse model.
2. The role of autoimmunity in COPD
Over the past decade, an increasing body of evidence has been accumulated for a link between COPD and autoimmunity. Studies with clinical samples have demonstrated that autoantibodies are present in sera of COPD patients and some of these antibodies correlate with specific disease phenotypes. Furthermore, evidence from animal models of COPD has shown that autoimmunity against pulmonary antigens occur during disease development and is capable of mediating COPD-like symptoms. The idea that autoimmunity could contribute to the development of COPD provides a new angle to understand the pathogenesis of the disease.
In this project we aim to address two questions. The first is whether autoantibodies can be use as biomarkers for COPD diagnosis and prognosis. The second one is whether autoantibodies play a pathogenic role in the development of COPD.