Systemic Sclerosis — A New Path Forward and a Link to Marfan Syndrome

Kenneth Y. Tsai, MD, PhD

Defective integrin mediation and resultant loss of restraint of transforming growth factor β signaling contribute to stiff skin syndrome.

Detailed mechanistic study of systemic sclerosis (SS) has suffered from a lack of animal models that recapitulate the key clinical findings of this disease. Finding that fibrillin 1 (FBN1) is mutated in familial stiff skin syndrome (SSS), another pathological skin fibrosis, Gerber and colleagues created a mouse model based on two mutations in the gene. Integrins are multifunctional proteins that anchor cells to the extracellular matrix (hemidesmosomes) and regulate the secretion of cytokines such as transforming growth factor β (TGFβ). When fibrillin 1 fails to interact with integrins, unrestrained TGFβ pathway activation leads to fibrosis.

To directly test the role of integrin–fibrillin-1 interactions, the investigators generated mice with a W1572C mutation found in SSS and the D1545E mutation, which causes loss of integrin binding. Surprisingly, mice heterozygous for either mutation exhibited symptoms of SSS, including increased dermal collagen, decreased fat, microfibrillar aggregates, and dilution of elastin. Modulation of β1 or β3 integrin activity or treatment of the SSS model mice with TGFβ antibodies to prevent signaling reversed these clinical features. Even the infiltration of the skin by helper T-cells, plasmacytoid dendritic cells, and plasma cells with elaboration of autoantibodies seen in SSS mice were reversed with anti-TGFβ therapy.

Citation(s):

Gerber EE et al. Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature 2013 Oct 9; [e-pub ahead of print].