Our group is interested primarily in the pathogenesis and therapy of systemic sclerosis (SSc), which is studied in human patients
as well as in the spontaneous avian model UCD-200/206, the only animal model that manifests the whole clinical, histopathological
and serological spectrum of human SSc. Our previous studies have clearly shown that microvascular endothelial cells are the primary
target of the autoimmune attack, subsequently undergoing apoptosis. Furthermore, in the follow-up study we could show that
endothelial cell apoptosis in SSc is induced by AECA (anti-endothelial cell antibody)-dependent cellular cytotoxicity (ADCC) via the
Fas/Fas ligand pathway. After many years studying pathomechanisms and genetic factors underlying the disease, we are now focusing
on the development of novel therapeutic approaches. There is an unmet need for an effective pro-angiogenic therapy of ischemic
lesions in patients with SSc. Vascular alterations in both, human and avian SSc, predominantly affect the microvasculature.
Intimal proliferation, occlusion of blood vessels, and capillary rarefaction lead to decreased blood flow, a state of chronic ischemia,
and to clinical manifestations such as fingertip ulcers and comb lesions. Tissue hypoxia normally induces angiogenesis, but in SSc
vascular repair and angiogenesis seem to be strongly disturbed. One of the key molecules in the induction of angiogenesis is vascular
endothelial growth factor (VEGF). In SSc chronic and uncontrolled over-expression of VEGF results in chaotic vessels, and intractable
fingertip ulcers. Vice versa, VEGF is a potent mediator of angiogenesis if its availability is temporally and spatially controlled. We have
addressed this therapeutic dilemma in SSc by a novel approach using a VEGF121 variant that covalently binds to fibrin, and gets
released on demand by cellular enzymatic activity, only as long as needed. With this approach we mimic nature, where longer VEGF
isoforms are bound to extracellular matrix components until liberated in a tightly controlled manner by local enzymatic activity of cells
invading the matrix. Using UCD-206 chickens, we could show that cell-demanded release of locally applied fibrin-bound VEGF121 leads
to the formation of morphologically normal blood vessels, and clinical improvement of early and late ischemic lesions. Currently we
study the long-term effects of this VEGF121-fibrin therapy.
Allipour Birgani S, Mailänder M, Wasle I, Dietrich H, Gruber J, Distler O, Sgonc R (2016) Efficient therapy of ischaemic lesions with VEGF121-fibrin in an animal model of systemic sclerosis. Ann Rheum Dis. 75:1399-406.
Wick G, Grundtman C, Mayerl C, Wimpissinger TF, Feichtinger J, Zelger B, Sgonc R, Wolfram D (2013) The immunology of fibrosis. Annu Rev Immunol. 31:107-135.
Wick G, Backovic A, Rabensteiner E, Plank N, Schwendtner C, Sgonc R (2010) The immunology of fibrosis: innate and adaptive
fibrosis. Trends Immunol. 31:110-119.
Sgonc R, Wick G. (2008): Pro- and anti-fibrotic effects of TGF-beta in scleroderma. Rheumatology (Oxford). 2008 Oct;47
Wick G, Andersson L, Hala K, Gershwin ME, Selmi CF, Erf GF, Lamont SJ, Sgonc R (2006): Avian models with spontaneous
autoimmune diseases. Adv. Immunol. 92:71-117.
Prelog M, Scheidegger P, Peter S, Gershwin ME, Wick G, Sgonc R (2005): Diminished TGF-beta2 production leads to increased
expression of a profibrotic procollagen alpha 2 type I mRNA variant in embryonic fibroblasts of UCD-200 chickens, a model
for systemic sclerosis. Arthritis Rheum. 52:1804-1811.
Worda M, Sgonc R, Dietrich H, Niederegger H, Sundick RS, Gershwin ME, Wick G (2003): In vivo analysis of the apoptosis-inducing
effect of anti-endothelial cell antibodies in systemic sclerosis by the chorionallantoic membrane assay.
Arthritis Rheum. 48:2605-2614.
Sgonc R, Gruschwitz MS, Boeck G, Sepp N, Gruber J, Wick G (2000): Endothelial cell apoptosis in systemic sclerosis is induced by
antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum. 43:2550-2562.
Sgonc R (1999): The vascular perspective of systemic sclerosis: of chickens, mice and men. Int. Arch. Allergy Immunol. 120:
Sgonc R, Christner PJ, Dietrich H, Sieberer C, Jimenez SA, Wick G (1999): Lack of endothelial cell apoptosis in the dermis of
tight skin 1 and tight skin 2 mice. Arthritis Rheum. 42: 581-584.
Sgonc R, Gruschwitz M, Dietrich H, Recheis H, Gerschwin ME, Wick G (1996): Endothelial cell apoptosis is a primary pathogenetic
event underlying skin lesions in avian and human scleroderma. J. Clin. Invest. 98: 785-792.
Sgonc R, Boeck G, Dietrich H, Gruber J, Recheis H, Wick G (1994): Simultaneous determination of cell surface antigens and
apoptosis. Trends in Genetics 10: 41-42.
Oliver Distler, Center of Exp. Rheumatology, University Hospital Zurich, Switzerland
Roberto Giacomelli, University of Aquila, School of Medicine, Italy
Susanne Kerje, Department of Medical Sciences, Uppsala University, Sweden