Afsaneh Mehrprouyan

Controlling autoimmune-mediated disease manifestations in the lung by targeting Th2 cytokines in a novel mouse model of systemic sclerosis

Systemic sclerosis(SSc) is a connective tissue disease characterized by autoimmunity, fibrosis, and vasculopathy. As a severe systemic autoimmune disorder, SSc affects the lifespan of patients considerably, with a 10-year survival of 60-70%. Among various disease manifestations, vasculopathy and fibrosis in the lungs are the leading causes of SSc-related death (Ann Rheum Dis. 66: 940). Angiotensin II receptor type 1 (AT1R) has been identified as a candidate autoantigen in SSc (Ann Rheum Dis. 70:530). We recently confirmed the relevance of autoimmunity towards AT1R. As in a recently developed mouse model, where immunization of mice with human AT1R induces multiple SSc-like symptoms, including lung and skin inflammation and skin fibrosis. However, vasculopathy and fibrosis of the inner organs are lacking in our model, indicating that beside autoimmunity a second pathogenic signal is required to develop these symptoms. First analysis revealed that a dysregulation of the Th2- responses, a feature of human SSc, was not observed in our mouse model. Therefore, we hypothesize that dysregulation of Th2 cytokines is the second hit required for the development of lung fibrosis and vasculopathy in the AT1R-immunized mice. This hypothesis is supported by our very recent findings showing that AT1R immunization in mice overexpressing IL-13 results in severe occlusive vasculopathy in the lung. Therefore, our novel mouse model provides an excellent tool for investigating the role of the Th2 immune response in the transition from autoimmunity to autoimmune disease.

  1. Investigate the role of Th2 cytokines in the pathogenesis of fibrosis and vasculopathy in the lung of the mouse model for SSc. 
  2. Evaluate the therapeutic efficacy of targeting essential Th2 cytokines and Th2-signaling pathways in the mouse model for SSc.

In the first part of the project, we will determine the role of Th2 cytokines, including IL-13, IL-4 and IL-5 in the disease manifestation in the lung of mice. Using the AT1R-induced mouse model for SSc, we will investigate the development of lung fibrosis and vasculopathy in mice with genetically modified (knockout out or transgenic) a Th2 cytokine gene. Moreover, the molecular mechanisms behind this regulation will be analyzed on signaling and gene expression level. In the second part, vasculopathy and/or fibrosis will be Autoimmune Pre-Disease 22 targeted in our mouse-model directly by anti-Th2 cytokine antibodies and indirectly by modulation of effector pathways identified in the first part.