Progranulin antibodies in autoimmune diseases Lorenz Thurner a , Klaus-Dieter Preuss a , Natalie Fadle a , Evi Regitz a , Philipp Klemm a , Marina Zaks a , Maria Kemele a , Andrea Hasenfus b , Elena Csernok c , Wolfgang L. Gross d , Jean-Louis Pasquali d , Thierry Martin d , Rainer Maria Bohle b , Michael Pfreundschuh a, * a Saarland University Medical School, José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, 66421 Homburg/Saar, Germany b Saarland University Medical School, Institute of Pathology, Homburg/Saar, Germany c Department of Rheumatology and Clinical Immunology, Vasculitis Center, University Hospital Schleswig-Holstein, Bad Bramstedt, 24576 Bad Bramstedt, Germany d CNRS, UPR9021, IBMC, Hopitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France article info Article history: Received 21 June 2012 Received in revised form 9 October 2012 Accepted 15 October 2012 Keywords: Progranulin TNF-R1&2 Neutralizing autoantibody Systemic vasculitis Autoimmune connective tissue disorders Rheumatoid arthritis abstract Systemic vasculitides constitute a heterogeneous group of diseases. Autoimmunity mediated by B lymphocytes and their humoral effector mechanisms play a major role in ANCA-associated vasculitis (AAV) as well as in non-ANCA associated primary systemic vasculitides and in the different types of autoimmune connective tissue disorders and rheumatoid arthritis. In order to detect autoantibodies in systemic vasculitides, we screened protein macroarrays of human cDNA expression libraries with sera from patients with ANCA-associated and ANCA-negative primary systemic vasculitides. This approach led to the identification of antibodies against progranulin, a 88 kDA secreted glycoprotein with strong anti-inflammatory activity in the course of disease of giant-cell arteritis/polymyalgia rheumatica (14/65), Takayasu’s arteritis (4/13), classical panarteritis nodosa (4/10), Behcet’s disease (2/6) and in the course of disease in granulomatosis with polyangiitis (31/75), ChurgeStrauss syndrome (7/23) and in microscopic polyangiitis (7/19). In extended screenings the progranulin antibodies were also detected in other autoimmune diseases such as systemic lupus erythematosus (39/91) and rheumatoid arthritis (16/44). Progranulin antibodies were detected only in 1 of 97 healthy controls. Anti-progranulin positive patients with systemic vasculitides, systemic lupus erythematosus or rheumatoid arthritis had significant lower progranulin plasma levels, indicating a neutralizing effect. In light of the anti-inflammatory effects of progranulin, progranulin antibodies might exert pro-inflammatory effects thus contributing to the pathogenesis of the respective autoimmune diseases and might serve as a marker for disease activity. This hypothesis is supported by the fact that a positive progranulin antibody status was associated with active disease in granulomatosis with polyangiitis. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction The demonstration of anti-neutrophil cytoplasmic antibodies (ANCAs) is a diagnostic hallmark supporting the diagnosis of vasculitis. Historically, ANCAs were identified coincidentally during studies of the role of anti-nuclear antibodies (ANA) in glomerulonephritis [1]. ANCA-associated vasculitides (AAV) constitute a heterogeneous group of small-vessel vasculitides, comprising granulomatosis with polyangiitis (GPA, formerly known as Wegener granulomatosis), ChurgeStrauss syndrome (CSS) and microscopic polyangiitis (MPA). Granulomatosis with polyangiitis is a chronic inflammatory and autoimmune disease, starting with granulomatous inflammation of the upper and/or lower respiratory tract and evolving into a generalized proteinase 3 (PR3)-ANCA-associated vasculitis [2]. ChurgeStrauss syndrome can be easily distinguished from the other ANCA-associated vasculitides by the pentad of asthma or other atopic diseases, elevated IgE, eosinophilia, P-ANCA and small-vessel vasculitis. A pathogenetic role of PR3-ANCAs was demonstrated in an acute lung-injury model of TNF-alpha primed rat lungs, which were perfused with PR3-ANCA [3]. The pathogenicity of myeloperox- idase (MPO)-ANCAs was demonstrated in vivo in a passive transfer mouse model, which resulted in the development of * Corresponding author. Dept. of Internal Medicine I, University hospital Homburg/Saar, Kirrberger Str., D-66424 Homburg/Saar, Germany. Tel.: þ49 68411623003. E-mail addresses: Lorenz.Thurner@uks.eu (L. Thurner), inkdpr@uks.eu (K.-D. Preuss), e.csernok@klinikumbb.de (E. Csernok), Jean-louis.Pasquali@chru- strasbourg.fr (J.-L. Pasquali), Thierry.Martin@chru-strasbourg.fr (T. Martin), rainer.bohle@uks.eu (R.M. Bohle), michael.pfreundschuh@uks.eu (M. Pfreundschuh). Contents lists available at SciVerse ScienceDirect Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm 0896-8411/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jaut.2012.10.003 Journal of Autoimmunity xxx (2012) 1e10 Please cite this article in press as: Thurner L, et al., Progranulin antibodies in autoimmune diseases, Journal of Autoimmunity (2012), http:// dx.doi.org/10.1016/j.jaut.2012.10.003