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State of the Art. Mechanisms of Scleroderma-induced Lung Disease

¹ Clinical Genomics Group, Royal Brompton Hospital, London, United Kingdom

Correspondence and requests for reprints should be addressed to R. M. du Bois, M.A., M.D., F.R.C.P., Clinical Genomics Group, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: r.dubois{at}rbht.nhs.uk

ABSTRACT

Scleroderma (systemic sclerosis) is characterized by dermal thickening and is subclassified, on the basis of the pattern of skin involvement, as diffuse or limited cutaneous disease. The lung fibrosis associated with systemic sclerosis is histopathologically nonspecific interstitial pneumonia and occurs to various extents. A key determinant of the development of lung fibrosis is the carriage of the anti–DNA topoisomerase II autoantibody, which is driven by genotype, particularly major histocompatibility complex class II alleles. Epithelial and endothelial cell injury initiates lung pathology and the local milieu expresses all the expected components of an immune/inflammatory chronic process that has fibrosis as an associated feature. However, novel concepts of the pathogenesis include the role of epithelial mesenchymal transition as a source of myofibroblasts following epithelial cell triggering and the concept of fibroblast heterogeneity in terms of both origin and function. Focus on the poles of the pathogenetic process, than on the redundancy of multiple mediator pathways, may provide more translational ideas in terms of elucidating how epithelial triggering initiates the downstream events and how fibroblast proliferation and connective matrix deposition is controlled, together with establishing how the process of autoantibody formation relates to the pathophysiologic events. Although much remains to be learned about the mechanisms of scleroderma-induced lung disease the clarity of the questions is improving.

Key Words: systemic sclerosis • genetics • autoantibody • epithelial mesenchymal transition