Extended report Ann Rheum Dis 2010;69:1396–1402. doi:10.1136/ard.2009.121400 1396 ABSTRACT Objectives To study the presence of interferogenic autoantibodies in systemic sclerosis (SSc) and their correlation with clinical manifestations, serum levels of interferon α (IFNα) and chemokines of importance in the disease process. Methods Peripheral blood mononuclear cells (PBMCs) or purified plasmacytoid dendritic cells (pDCs) from healthy donors were stimulated with sera from patients with SSc (n=70) or healthy individuals (n=30), together with necrotic or apoptotic cell material. The IFNα produced and serum levels of IFNα, IFN-inducible protein-10 (IP-10)/chemokine (C-X-C motif) ligand 10, monocyte chemoattractant protein-1 (MCP-1)/(C-C motif) ligand-2 (CCL-2), macrophage inflammatory protein-1α (MIP-1α)/ CCL-3 and RANTES/CCL-5 were measured and correlated with the presence of autoantibodies and clinical manifestations in the patients with SSc. Results Sera from both diffuse SSc and limited SSc contained interferogenic antibodies, which correlated with the presence of anti-ribonucleoprotein and anti-Sjögren syndrome antigen autoantibodies. The pDCs were responsible for the IFNα production which required interaction with FcγRII and endocytosis. Increased serum levels of IP-10 were associated with vascular manifestations such as cardiac involvement (p=0.027) and pulmonary arterial hypertension (p=0.036). Increased MCP-1 or IFNα serum levels were associated with lung fibrosis (p=0.019 and 0.048, respectively). Digital ulcers including digital loss were associated with increased serum levels of IFNα (p=0.029). Conclusion An activated type I IFN system previously seen in several other systemic autoimmune diseases is also present in SSc and may contribute to the vascular pathology and affect the profibrotic process. INTRODUCTION Systemic sclerosis (SSc) is a rare multisystem auto- immune disease classified either as diffuse (dcSSc) or limited cutaneous (lcSSc), of which the former is more severe with extensive skin and inter- nal organ involvement. 1 2 The aetiology of SSc is largely unknown, but gene expression profiles of peripheral blood leucocytes from patients with early SSc demonstrated an increased expression of type I interferon (IFN)-inducible genes—that is, an IFN signature, besides genes involved in targeting blood leucocytes to the endothelium. 3 4 Many dif- ferent autoimmune rheumatic diseases share this IFN signature with SSc, indicating that continuing production of type I IFN is central in autoimmune processes. 5–9 An increased expression of several chemokines has also been reported in SSc and is Type I interferon system activation and association with disease manifestations in systemic sclerosis Maija-Leena Eloranta, 1 Karin Franck-Larsson, 1,2 Tanja Lövgren, 1 Sebastian Kalamajski, 3 Anders Rönnblom, 1 Kristofer Rubin, 3 Gunnar V Alm, 4 Lars Rönnblom 1 ▶ Additional data are published online only. To view these files please visit the journal online (http://ard.bmj.com). 1 Department of Medical Sciences, Uppsala University, Uppsala, Sweden 2 Wyeth AB, Solna, Sweden 3 Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden 4 Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden Correspondence to Dr Maija-Leena Eloranta, Department of Medical Sciences, Clinical Research Department 3, Systemic Autoimmunity Group, Entrance 85, 3rd Floor, Uppsala University Hospital, Uppsala S-75185, Sweden; maija-leena.eloranta@ medsci.uu.se Accepted 26 January 2010 of importance for recruitment and activation of inflammatory cells. 10 11 We have previously shown that IFNα can be produced by plasmacytoid dendritic cells (pDCs) activated by interferogenic immune complexes (ICs) containing autoantibodies and DNA and/ or RNA. 12–15 It has been reported that SSc sera containing anti-topoisomerase (Topo)-I autoanti- bodies can form interferogenic ICs, and this abil- ity was associated with lung manifestations in patients. 16 In this study, we aimed to clarify fur- ther the role of the type I IFN system activation in SSc and to correlate this with clinical manifes- tations. In an unselected group of patients with SSc we therefore investigated the interferogenic capacity of sera and serum levels of IFNα and the interferon-inducible protein-10 (IP-10)/chemokine (C-X-C motif) ligand 10, monocyte chemoat- tractant protein-1 (MCP-1)/(C-C motif) ligand-2 (CCL-2), macrophage inflammatory protein-1α (MIP-1α)/CCL-3 and RANTES/CCL-5. PATIENTS AND METHODS Patients and controls A total of 70 patients, fulfilling the 1980 prelimi- nary American College of Rheumatology (ACR) criteria for definite SSc 17 were included in the study (table 1). Gastrointestinal involvement was defined as oesophageal dysmotility, dysphagia, heartburn, constipation, diarrhoea or fecal incontinence. Lung fibrosis was diagnosed by high-resolution CT and/ or chest x-ray examination. Cardiac involvement was defined as present or previous cardiac infarc- tion, heart failure, pleuritis or arrhythmia. Presence of digital loss (radiographic evidence of acroly- sis or surgical amputation due to necrotic ulcers), pulmonary arterial hypertension (PAH), previous scleroderma renal crisis 18 or episodes of peripheral thrombosis were recorded. Present drugs included proton pump inhibitors (44/70 patients), angiotensin-converting enzyme inhibitors (36/70), calcium channel blockers (24/70), corticosteroids (26/70), non-steroidal anti- inflammatory drugs (22/70) and immunosuppres- sive drugs (17/70). Serum samples from 30 age- and sex-matched healthy blood donors were used as controls. Autoantibody determinations Patient sera were analysed for antinuclear anti- bodies (ANA) by indirect immunofluores- cence using HEp-2 cells and by Crithidia luciliae (Immunoconsept, Sacramento, California, USA) for