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Nephrol Dial Transplant (2014) 29: 1105–1107 doi: 10.1093/ndt/gft526 Advance Access publication 23 January 2014 In Focus Autoantibodies in anti-neutrophil cytoplasm antibody-associated vasculitis Alan D. Salama and Andrew J. Rees UCL Centre for Nephrology, Royal Free Hospital, London, UK and Clinical Department of Pathology, Medical University of Vienna, Vienna, Austria Correspondence and offprint requests to: Alan D. Salama; E-mail: [email protected] The discovery of autoantibodies to neutrophil cytoplasm antigens (ANCA) just over 30 years ago and their association with focal necrotizing glomerulonephritis (FNGN) and small vessel vasculitis created a paradigm shift: within a few years these diseases had changed from archetypal ‘immune complex diseases’ into the autoantibody mediated diseases they are considered today, justifying the term ANCA-associated vasculitis (AAV). Although most extensively studied, ANCA are not the only autoantibodies found in AAV and Suzuki et al. describe a novel autoantibody that may also contribute to pathogenesis [1]. ANCA were originally described in a small group of individuals presenting with systemic illness and FNGN whose renal biopsies were ‘indistinguishable from microscopic polyarteritis nodosa’ (now known as microscopic polyangiitis—MPA) [2]. Shortly afterwards, ANCA were described independently in two larger cohorts of patients with Wegener’s granulomatosis (now called granulomatosis with polyangiitis—GPA) firmly establishing their association with systemic vasculitis [3] and ultimately leading to the term ANCA-associated vasculitis [4]. Indirect immunofluorescence identified two distinct ANCA staining patterns: perinuclear (pANCA) usually indicative of autoantibodies to myeloperoxidase (MPO); and cytoplasmic (cANCA) that reflect autoantibodies to proteinase 3 (PR3). These in turn are strongly (but not exclusively) associated with clinical diagnoses of MPA and GPA, respectively. Other ANCA targets have been identified (including elastase, lactoferrin and bacterial permeability increasing protein), but these are not associated with vasculitic syndromes. ANCA specific for either MPO or PR3 (but rarely both) can be detected in 85–90% of patients presenting with pauciimmune FNGN and positive assays for them have a diagnostic sensitivity and specificity of around 90%. This strongly suggests their involvement in pathogenesis and there is a wealth of clinical, © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. experimental and genetic evidence to support this. Antibodies to MPO and PR3 both activate primed human neutrophils and enhance neutrophil mediated endothelial injury in vitro (reviewed in [5] and [6]); and passive immunization with antibodies to MPO and possibly PR3 induces FNGN in mice although injury is mild unless an additional stimulus such as bacterial lipopolysaccharide is administered [7, 8]. Finally, a recent genome-wide association study identified single-nucleotide polymorphisms in genes encoding PR3 and its inhibitor a1-anti-trypsin, which both increase susceptibility to develop autoantibodies to PR3 and clinical diagnosis of GPA but not to MPA or autoantibodies to MPO [9]. Despite the strength of this evidence, new data that have emerged over the past 5 years which challenge the assumption that injury in pauci-immune FNGN is uniquely caused by autoantibodies to MPO or PR3 and suggest the need for a more nuanced approach. First, results from certain randomized prospective controlled trials [10] and from meta-analyses [11] show that neither the presence, or the titre, of autoantibodies to MPO or PR3 consistently correlates with disease activity or clinical response to treatment, and does not predict clinical relapses [12]. This is in contrast to earlier cohort studies demonstrating that significant increases in ANCA can predict relapses and may be used as a basis for alteration in immune therapies [13, 14]. Second, the renal morphology of ANCA-negative patients presenting with pauci-immune FNGN is indistinguishable from ANCA-positive patients [15], raising the question of what causes injury in the absence of detectable antibodies to MPO and PR3. However, even this does not preclude an exclusive role for autoantibodies to MPO and PR3 in pathogenesis as there is evidence that antibodies specific for particular MPO [16] or PR3 [17, 18] epitopes better reflect disease activity, and 1105 IN FOCUS autoantibodies to MPO may be masked by fragments of the acute phase reactant ceruloplasmin in ANCA-negative patients [16]. Nevertheless, it seems highly likely that additional factors other than the classical ANCA are required for the full expression of AAV and this coincides with the need for a critical analysis of the role of more recently described autoantibodies, such as those specific for LAMP-2 [19], plasminogen [20, 21] and now moesin [1]. Autoantibodies to LAMP-2 have been described in 80–90% of patients presenting with pauci-immune FNGN [19, 22] although a lower frequency has been reported by others [23]. They become rapidly undetectable after the start of immunosuppressive treatment, are rare in patients during remission, but recur in those with clinical relapses. Antibodies to LAMP-2 cause FNGN in rodent models [19, 24] and can also be detected in ANCA-negative patients with FNGN and the autoantibodies from these patients bind glomerular endothelium [25]. Antiplasminogen antibodies are found in approximately a quarter of patients with AAV (both MPO- and PR3-ANCA) and interfere with fibrinolysis. They are associated with more severe glomerular pathology and with a higher incidence of thromboembolic disease [20, 26] that is increased in AAV, during both active disease and remission [21, 27]. The limited longitudinal data available show a variable response of the autoantibodies to treatment [26] but have identified a single example of fluctuations in anti-plasminogen antibody mirroring clinical thromboembolic events [20]. Clearly, much needs to be learnt about both these autoantibodies and their interactions with those specific for MPO and PR3, and the same is true for the autoantibodies to moesin described by Suzuki et al. Moesin is a member of the ezrin family of proteins that links actin to the plasma membrane. The Suzuki group originally described anti-moesin antibodies in serum from SCG/Kj mice that spontaneously develop vasculitis, FNGN with immune complexes and a range of autoantibodies including anti-MPO [28]. In a cross-sectional study of 60 patients [1], they now describe anti-moesin antibodies in the serum from around half of the Japanese patients with MPO-associated AAV. The autoantibodies bound to moesin in neutrophils and monocytes both on the cell surface and intracellularly resulting in a cytoplasmic ANCA pattern on indirect immunofluorescence. The anti-moesin antibodies were detected in both active disease and remission but were associated with more renal damage (as assessed by measures of BUN, serum creatinine and proteinuria) regardless of the titre of MPOANCA, and with higher concentrations of selected circulating pro-inflammatory cytokines. IgG containing anti-moesin antibodies bound to neutrophils and monocytes in vitro and stimulated them to release cytokines, including IL-17, IL-8, IL-6, TNF-α, MCP-1 and IFN-γ. This raises the possibility that anti-moesin autoantibodies contribute to inflammation and organ damage in some patients with AAV, although more work is needed to determine their clinical significance. In particular, the studies need to be extended to non-Japanese populations and to patients with PR3 related disease. Additionally, there is a critical need for longitudinal studies to correlate their presence with disease activity and susceptibility for relapse. 1106 Interestingly, these findings raise the possibility that antibodies to moesin might underlie some of the apparently paradoxical observations in AAV. For example, could they explain the infrequent finding of an immunofluorescent cytoplasmic ANCA pattern, in association with an anti-MPO antibody? Or why disease activity and ANCA titre can dissociate—as it appears that anti-moesin antibodies can persist during remission at similar titres to those in acute disease. There is a gathering consensus that patients with AAV should be stratified according to whether they have antibodies to MPO or PR3 [9, 12], but should prospective studies also take account of other autoantibodies, such as those specific for moesin, LAMP-2 or plasminogen to better understand what clinical phenotypes these autoantibodies may impart? For the time being at least, these antibodies need to be validated in other AAV cohorts, which include patients with PR3-ANCA, and those who are ANCA negative. The collaboration with European and North American investigators could rapidly allow the validation of this antibody using serum from clinical trial banks that would allow not only cross-sectional verification but also longitudinal analysis following standardized induction therapy. Clearly, Suzuki et al. have identified another autoantibody that could influence disease initiation or progression in Japanese AAV patients. Their observations emphasize the wider issue of the urgent need for sufficiently powered international collaborative studies to define the relations between the canonical ANCA, newly identified autoantibodies and other potential pathogenic factors. This would require gathering a global sample collection from well-phenotyped patients that would allow all of the associated autoantibodies that have been identified to be validated and allow us to better define clinical subsets. AC K N O W L E D G E M E N T S A.J.R. received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 261382 (INTRICATE). C O N F L I C T O F I N T E R E S T S TAT E M E N T The results presented in this paper have not been published previously in whole or part, except in abstract format. (See related article by Suzuki et al. A novel autoantibody against moesin in the serum of patients with MPO-ANCA-associated vasculitis. Nephrol Dial Transplant 2014; 29: 1168–1177.) REFERENCES 1. Susuki K, Nagao T, Itabashi M et al. A novel autoantibody against moesin in the serum of patients with MPO-ANCA-associated vasculitis. Nephrol Dial Transplant 2014; 29: 1168–1177 2. Davies DJ, Moran JE, Niall JF et al. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? Br Med J (Clin Res Ed) 1982; 285: 606 A.D. Salama and A. Rees Autoantibodies in ANCA-associated vasculitis 17. Selga D, Segelmark M, Gunnarsson L et al. Epitope shift of proteinase-3 anti-neutrophil cytoplasmic antibodies in patients with small vessel vasculitis. Clin Exp Immunol 2010; 160: 318–324 18. Silva F, Hummel AM, Jenne DE et al. Discrimination and variable impact of ANCA binding to different surface epitopes on proteinase 3, the Wegener’s autoantigen. J Autoimmun 2010; 35: 299–308 19. Kain R, Exner M, Brandes R et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med 2008; 14: 1088–1096 20. Bautz DJ, Preston GA, Lionaki S et al. Antibodies with dual reactivity to plasminogen and complementary PR3 in PR3-ANCA vasculitis. J Am Soc Nephrol 2008; 19: 2421–2429 21. Stassen PM, Derks RP, Kallenberg CG et al. Venous thromboembolism in ANCA-associated vasculitis—incidence and risk factors. Rheumatology (Oxford) 2008; 47: 530–534 22. Kain R, Tadema H, McKinney EF et al. High prevalence of autoantibodies to hLAMP-2 in anti-neutrophil cytoplasmic antibody-associated vasculitis. J Am Soc Nephrol 2012; 23: 556–566 23. Roth AJ, Brown MC, Smith RN et al. Anti-LAMP-2 antibodies are not prevalent in patients with antineutrophil cytoplasmic autoantibody glomerulonephritis. J Am Soc Nephrol 2012; 23: 545–555 24. Takeuchi S, Kimura S, Soma Y et al. Lysosomal-associated membrane protein-2 plays an important role in the pathogenesis of primary cutaneous vasculitis. Rheumatology (Oxford) 2013; 52: 1592–1598 25. Peschel A, Basu N, Benharkou A et al. Autoantibodies to hLAMP-2 in ANCA-Negative Pauci-Immune Focal Necrotizing GN. J Am Soc Nephrol 2013 (Epub ahead of print) 26. Berden AE, Nolan SL, Morris HL et al. Anti-plasminogen antibodies compromise fibrinolysis and associate with renal histology in ANCA-associated vasculitis. J Am Soc Nephrol 2010; 21: 2169–2179 27. Hilhorst M, Winckers K, Wilde B et al. Patients with antineutrophil cytoplasmic antibodies associated vasculitis in remission are hypercoagulable. J Rheumatol 2013; 40: 2042–2046 28. Nagao T, Suzuki K, Utsunomiya K et al. Direct activation of glomerular endothelial cells by anti-moesin activity of anti-myeloperoxidase antibody. Nephrol Dial Transplant 2011; 26: 2752–2760 Received for publication: 13.11.2013; Accepted in revised form: 18.12.2013 1107 IN FOCUS 3. van der Woude FJ, Rasmussen N, Lobatto S et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet 1985; 1: 425–429 4. Jennette JC, Falk RJ, Bacon PA et al. 2012 revised international chapel hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013; 65: 1–11 5. Pankhurst T, Savage CO, Little MA. Review article: leukocyte-endothelial dysregulation in systemic small vessel vasculitis. Nephrology (Carlton) 2009; 14: 3–10 6. Flint J, Morgan MD, Savage CO. Pathogenesis of ANCA-associated vasculitis. Rheum Dis Clin North Am 2010; 36: 463–477 7. Little MA, Al-Ani B, Ren S et al. Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system. PLoS One 2012; 7: e28626 8. Xiao H, Heeringa P, Hu P et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002; 110: 955–963 9. Lyons PA, Rayner TF, Trivedi S et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med 2012; 367: 214–223 10. Miloslavsky EM, Specks U, Merkel PA et al. Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2013; 65: 2441–2449 11. Tomasson G, Grayson PC, Mahr AD et al. Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis—a meta-analysis. Rheumatology (Oxford) 2012; 51: 100–109 12. Specks U, Merkel PA, Seo P et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med 2013; 369: 417–427 13. Tervaert JW, Huitema MG, Hene RJ et al. Prevention of relapses in Wegener’s granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre. Lancet 1990; 336: 709–711 14. Sanders JS, Huitma MG, Kallenberg CG et al. Prediction of relapses in PR3-ANCA-associated vasculitis by assessing responses of ANCA titres to treatment. Rheumatology (Oxford) 2006; 45: 724–729. 15. Chen M, Kallenberg CG, Zhao MH. ANCA-negative pauci-immune crescentic glomerulonephritis. Nat Rev Nephrol 2009; 5: 313–318 16. Roth AJ, Ooi JD, Hess JJ et al. Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis. J Clin Invest 2013; 123: 1773–1783