Please cite this article in press as: Van de Velde NC, et al. Transgenic mice expressing human FcRIIa have enhanced sensitivity to induced autoimmune arthritis as well as elevated Th17 cells. Immunol Lett (2010), doi:10.1016/j.imlet.2009.12.005 ARTICLE IN PRESS G Model IMLET-4887; No. of Pages 7 Immunology Letters xxx (2010) xxx–xxx Contents lists available at ScienceDirect Immunology Letters journal homepage: www.elsevier.com/locate/ Transgenic mice expressing human FcRIIa have enhanced sensitivity to induced autoimmune arthritis as well as elevated Th17 cells Nicholas C. Van de Velde a , Patricia L. Mottram a , Maree S. Powell a , Bock Lim a , Rikard Holmdahl b , P. Mark Hogarth a,∗ a Helen Macpherson Smith Laboratory, Burnet Institute, 85 Commercial Rd, Melbourne, VIC 3004, Australia b Division of Medical Inflammation Research, Department of Medical, Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden article info Article history: Received 17 November 2009 Received in revised form 30 November 2009 Accepted 2 December 2009 Available online xxx Keywords: Inflammation Arthritis Autoimmune disease Th17 FcRIIa abstract The major human Fc receptor, huFcRIIa, is implicated in the development of autoimmune arthritis in humans but until recently has not been studied in mouse models. We evaluated potential roles of FcRIIa by using transgenic mice expressing the receptor. We examined two models of induced autoimmune arthritis pristane-induced arthritis (PIA) and collagen-induced arthritis (CIA) as well as the anti-collagen- II antibody-induced arthritis (CAIA) model. In the induced arthritis models PIA and CIA, the transgenic mice developed a more severe arthritis than the other arthritis-prone SJL or DBA1 mice. Interestingly, anti-collagen-II antibodies were elevated in PIA in the susceptible mice. In the CIA model, the highly susceptible transgenic mouse had IgG subclass levels equivalent to the unaffected and disease resistant C57BL/6 mouse strain implying that the FcRIIa lowers the threshold of IgG dependent leukocyte activation. This is consistent with the greatly enhanced sensitivity of the FcRIIa transgenic mice to CAIA which clearly indicates a role for the receptor at least at the inflammatory effector cell level. Other roles for huFcRIIa or other gene products in the development of autoimmunity cannot be ruled out however, especially as the mice exhibited elevated Th1 or Th17 CD4 T cells in the draining lymph nodes. Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved. 1. Introduction Many of the mechanisms believed to occur in development of human autoimmune disease are often based on studies largely con- ducted in animal models, usually in rodent species. This is certainly true of many analyses of the immunoglobulin Fc receptors (FcR) and their role in autoimmunity and antibody related tissue destruc- tion. Previous studies of mouse models of autoimmune arthritis have demonstrated that receptors for immunoglobulin G (FcR) are important in the pathogenesis of some autoimmune dis- eases as well as the subsequent antibody-induced tissue damage. Investigations using recombinant FcR-specific small chemical enti- Abbreviations: CIA, collagen-induced arthritis; PIA, pristane-induced arthritis; CAIA, collagen antibody-induced arthritis; ITAM, intracellular tyrosine activatory motif; ITIM, intracellular tyrosine inhibitory motif; FcR, fraction crystallisable recep- tor; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; HAGG, heat aggregated gamma globulin. ∗ Corresponding author. Tel.: +61 3 85321915; fax: +61 3 92822100. E-mail address: pmhogarth@burnet.edu.au (P.M. Hogarth). ties or FcR deficient mice show that the regulation of immune complex induced inflammatory cell activation results in differ- ences in pathology, as well as severity and incidence of disease [1–8]. These animal studies have focused on the activating recep- tors FcRI, FcRIII and the inhibitory FcRIIb. However, the most widely expressed human FcR, FcRIIa, has no orthologue in rodents, which until recently has limited the analysis of this important receptor in IgG driven inflammatory responses [1,9–12]. We have characterised a transgenic mouse expressing human FcRIIa [13–15]. In this strain, the FcRIIa is expressed at physio- logical levels and sites under the control of its own promoter and uses endogenous signalling pathways. The transgenic strain was found to be highly susceptible to collagen-induced arthritis (CIA), despite a genetic background that is antipathetic to the develop- ment of this disease [14,16,17]. Most interestingly, these mice also spontaneously develop multi-system autoimmunity after 25 weeks of age [14]. We have extended our analysis of the role of human FcRIIa in autoimmune inflammation in three well-characterized models of arthritis, involving active induction of autoimmunity by type-II collagen (CII) (CIA) [16] or pristane (PIA) [18,19] or passive transfer of antibodies recognizing CII (CAIA) [20,21]. 0165-2478/$ – see front matter. Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.imlet.2009.12.005