Collagen XIII in Lung Physiology and Fibrosis, and Thyroid-Associated Ophthalmopathy

Collagen XIII is a transmembrane collagen encoded by the COL13A1 gene. Mutations in the gene cause congenital myasthenic syndrome 19 in which the development of neuromuscular junctions is severely impaired. In addition to severe muscle weakness, the patients present with breathing difficulties and impaired lung function. Thus, one of the aims of this thesis was to investigate the role of collagen XIII in pulmonary physiology and also in the development of restrictive lung disease i.e., pulmonary fibrosis. Collagen XIII expression was found in basement membranes surrounding alveolar fibroblasts, yet the lungs of collagen XIII knockout mice were found normal in structure. However, lung function tests uncovered distinct abnormalities in lung volume and extendibility of the chest cage, suggesting a manifestation of the myasthenic phenotype of the mice. In human pulmonary fibrosis patients, collagen XIII was highly expressed in specific disease-associated structures, including hyperplastic epithelial cells. Similarly, immunostainings showed an increase in expression in the bleomycin mouse model of pulmonary fibrosis, but the extent of fibrosis was unchanged in the Col13a1-modified mice. In addition, insufficient information was found about the normalisation of real-time quantitative PCR in the bleomycin model and therefore the most suitable reference genes were determined experimentally.

Another goal of this doctoral study was to investigate the role of collagen XIII in thyroid-associated ophthalmopathy (TAO), most commonly associated with Graves’ disease. Graves’ disease is one of the most common autoimmune diseases and up to 50% of the patients have eye symptoms. Previously, autoantibodies against collagen XIII were discovered in TAO and their presence was found to correlate with disease activity. Thus, the expression of collagen XIII was evaluated in tissues of the orbit and the thyroid. In the orbit, collagen XIII expression was found in extraocular muscles and blood vessels of orbital connective tissue and fat. In the thyroid, the expression of collagen XIII varied between samples and correlated with TGFB1. In a subsequent experiment, TGF-β1 appeared to induce collagen XIII expression in thyroid epithelial cells.