Dividing the Janus vasculitis? Pathophysiology of eosinophilic granulomatosis with polyangitis

AUTREV-01776; No of Pages 7 Autoimmunity Reviews xxx (2015) xxx–xxx

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Article history: Received 2 October 2015 Accepted 15 October 2015 Available online xxxx

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Keywords: Eosinophilic granulomatosis with polyangitis Vasculitis Eosinophilia Th2 response ANCA-MPO

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Eosinophilic granulomatosis with polyangitis (EGPA) is a rare small- and medium-sized vessel vasculitis belonging to the group of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV). It is commonly divided into two phenotypes depending on the presence of ANCAs targeting myeloperoxidase (MPO). MPO-ANCAs are present in 31% to 38% of patients and are associated with a vasculitis phenotype of the disease, whereas patients without MPO-ANCA are at risk of cardiac involvement. Despite significant advances in understanding the overall pathogenesis of the disease, the explanation for this dichotomy is still unclear. In this review, we synthesize our knowledge of the pathogenesis of EGPA and attempt to i) distinguish EGPA from other diseases including other AAVs, asthma, allergy and hypereosinophilic-associated conditions and ii) speculate about the preponderant mechanisms, which could explain the two disease phenotypes. © 2015 Published by Elsevier B.V.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . EGPA at a crossroads of different diseases . . . . . . . . . . . . . . . . . . 2.1. EGPA and AAV . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. AAV revised classification . . . . . . . . . . . . . . . . . . 2.1.2. Genetic predisposition . . . . . . . . . . . . . . . . . . . . 2.1.3. Granuloma . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. EGPA and allergy . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. EGPA and asthma . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. EGPA and hypereosinophilic-associated conditions . . . . . . . . . . . 3. Two phenotypes should be explained by two processes . . . . . . . . . . . . 3.1. The vasculitis phenotype: MPO-ANCAs, neutrophils and B lymphocytes . . 3.1.1. MPO-ANCAs . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Neutrophils . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. B lymphocytes . . . . . . . . . . . . . . . . . . . . . . . 3.2. The non-vasculitis phenotype: an over-expression of an eosinophil defect? 4. Summary and concluding remark . . . . . . . . . . . . . . . . . . . . . . 5. Uncited references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France d Université Paris Descartes, Faculté de Médecine, Pôle de Médecine Interne, Centre de référence pour les vascularites nécrosantes et la sclérodermie systémique, hôpital Cochin, Assistance PubliqueHôpitaux de Paris, Paris, France b

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Benjamin Chaigne a,b,c,d, Benjamin Terrier a,b,c,d, Nathalie Thieblemont a,b,c, Véronique Witko-Sarsat a,b,c, Luc Mouthon a,b,c,d,⁎

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Dividing the Janus vasculitis? Pathophysiology of eosinophilic granulomatosis with polyangitis☆

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57 ☆ Financial support/conflict of interests: the authors have not received any financial support or other benefits from commercial sources for the work reported in the manuscript, or do not have any other financial interests, which could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work. ⁎ Corresponding author at: Service de Médecine Interne, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France. Tel.: +33 1 58 41 42 43; fax: +33 1 58 41 29 68. E-mail address: [email protected] (L. Mouthon).

http://dx.doi.org/10.1016/j.autrev.2015.10.006 1568-9972/© 2015 Published by Elsevier B.V.

Please cite this article as: Chaigne B, et al, Dividing the Janus vasculitis? Pathophysiology of eosinophilic granulomatosis with polyangitis, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.10.006

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2.1. EGPA and AAV

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2.1.1. AAV revised classification The revised international Chapel Hill Consensus Conference nomenclature of vasculitides classified systemic AAVs by the presence or absence of granuloma and asthma (Table 1) [2]. EGPA was classified as systemic vasculitis with granulomatosis, asthma, and blood eosinophilia, microscopic polyangiitis (MPA) as vasculitis without asthma or granuloma, and granulomatosis with polyangiitis (GPA) as evidence of granulomatosis without asthma. Such classification helps in bedside diagnosis but not in understanding the entire specificity of the disease pathogenicity of EGPA that is necessarily different from the other two AAVs.

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2.1.3. Granuloma As recalled in the new classification, an important aspect of the immune response is the formation of a granuloma, originally described as an “allergic granuloma”. A granuloma consists of a palisade of giant cells or epithelioid histiocytes surrounding necrotizing eosinophils [1]. Pathology descriptions also showed fibrinoid necrosis, eosinophil infiltration, lymphocytes, and exceptional vascular localization. Thus, EGPA granulomas are specific because they contain eosinophils, exhibit necrosis and are associated with both vasculitis and Th2-related cytokine production. Such specificity has been a matter of debate because granulomas are found in various rheumatic diseases such as systemic vasculitides or connective tissue diseases (systemic lupus erythematosus or rheumatoid arthritis), as well as lymphoproliferative diseases and common variable immunodeficiency, and even bacterial endocarditis, or chronic hepatitis [18,19]. Indeed, granulomas can be found in other rheumatic pulmonary diseases, but mainly Th1-related inflammatory conditions,

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From its first description in 1951, by Jacob Churg and Lotte Strauss, until the revision of the Chapel Hill nomenclature in 2012, allergic granulomatosis and angiitis was called Churg–Strauss syndrome [1]. Its name was recently changed to eosinophilic granulomatosis with polyangitis (EGPA) to reduce the use of eponyms [2]. EGPA is a rare small- and medium-sized vessel vasculitis belonging to the group of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs). The American College of Rheumatology diagnostic criteria are asthma, eosinophilia, mono-polyneuropathy, pulmonary infiltrates, non-fixed paranasal sinus abnormalities and extravascular eosinophils; four of six criteria are needed for a diagnosis [3]. EGPA includes features of allergy, asthma, hypereosinophilic diseases and AAVs, but we have few data for understanding its pathophysiology [4]. Specific features of the disease are needed for characterizing it. Why are ANCAs detected in only 31% of 38% of patients in a disease belonging to the group of AAVs [5–7]? How do we explain the formation of granulomas in a T-helper (Th) 2-mediated non-parasitic disease? Moreover, we have limited evidence supporting the central role of eosinophils in EGPA, so should we assume their key position in the pathogenesis of the disease? Finally, should we consider splitting the disease [8]? This review synthesizes current knowledge of the pathogenesis of EGPA. In the first part we consider EGPA at a crossroads of AAV, hypereosinophilic-associated conditions, asthma and allergy. Then, we speculate about the two disease phenotypes, which are the vasculitisphenotype, which is associated with the presence of myeloperoxidase (MPO)-ANCAs and the non-vasculitis-phenotype, which is mainly characterized by cardiac involvement.

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2.1.2. Genetic predisposition Our understanding of vasculitides has benefitted from genetic studies. A British genome-wide association study (GWAS) showed a genetic component in AAV pathogenesis with both human leukocyte antigen (HLA) and non-HLA associations. The strongest associations related to autoantigens of the vasculitis, not the clinical syndrome. PR3 ANCAs were linked to the HLA-DP subtype and the genes encoding α1antitrypsin or PR3, whereas MPO-ANCA presence was associated with HLA-DQ [9]. Although informative, this study involved only GPA and MPA patients, not EGPA patients. Still, genetic susceptibility/predisposition has been suggested for EGPA from associations between EGPA and HLA. A positive association was found for HLA DRB1*04 and HLA-DRB1*07 twice, whereas a protective effect was reported with HLA-DRB3 and HLA-DRB1*13 [10,11]. Of note, a study of the HLA-DRB1 locus in 403 patients with GPA and 103 with EGPA linked the extended interleukin 10 (IL-10)-3575/-1082/592 TAC haplotypes with ANCA-negative EGPA [12]. Even though IL-10 level was reported to be elevated in EGPA, we lack a posttranscription analysis of the haplotypes [13]. Genes related to the costimulatory molecule CD226 (DNAX accessory molecule 1), the intracellular signaling-involved molecule PTPN22 and eotaxin-3 single nucleotide polymorphisms were investigated but were not associated with EGPA [14–16]. Exome sequencing has led to significant understanding in the field of vasculitis, especially in polyarteritis nodosa in which a mutation in CERC1, the gene encoding adenosine deaminase 2, was found in multiple affected families of Georgian, Jewish or German descent [17]. Exome sequencing and GWAS studies are still needed in EGPA.

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Hypereosinophilic associated-conditions [72]

ANCA-associated vasculitides [2]

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- Infections, particularly tissue-invasive parasites - Allergy/atopy and hypersensitivity conditions - Drug reaction - Collagen-vascular diseases - Pulmonary eosinophilic diseases - Allergic gastroenteritis - Metabolic conditions - Non-myeloid malignancies - Rare conditionsa

Eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels, and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present.

Necrotizing vasculitis, with few or no immune deposits, affecting small vessels. Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent.

Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels. Necrotizing glomerulonephritis is common.

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ANCA: anti-neutrophil cytoplasm antibody, EGPA: eosinophilic granulomatosis with polyangitis, MPA: microscopic polyangiitis, GPA: granulomatosis with polyangiitis, PDGFRα: plateletderived growth factor receptor alpha, PDGFRβ: platelet-derived growth factor receptor beta, FGFR1: fibroblast growth factor receptor 1, IgE: immunoglobulin E. a Rare conditions include familial eosinophilia, hyper IgE syndrome, Omenn syndrome, Gleich's syndrome, and eosinophilia-myalgia syndrome.

Please cite this article as: Chaigne B, et al, Dividing the Janus vasculitis? Pathophysiology of eosinophilic granulomatosis with polyangitis, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.10.006

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2.3. EGPA and asthma

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Asthma is more predominant than allergy in EGPA. Although still unproven, it is very likely that both diseases share a number of common pathogenic aspects. In asthma and in EGPA environmental factors or other stimuli are considered to trigger innate immunity via airway epithelial cell secretion of cytokines such as thymic stromal lymphopoietin, IL-25, and IL-33, which act on subepithelial dendritic cells, mast cells, and innate lymphoid cells to initiate and enhance an adaptive immune response [39]. Among chemokines known to be responsible for the recruitment of inflammatory cells in tissues in asthma, (C–C motif) ligand-17 (CCL-17, also called TARC) and eotaxin-3 levels have indeed been reported to be elevated in EGPA [16,40]. Some elements of the T-cell response are also common between asthma and EGPA. A Th2-cytokine environment with increased production of interleukins such as IL-4 and IL-13 is a major characteristic of both diseases. In EGPA, Th2 cells produced these cytokines in blood samples, respiratory tissue lesions of paranasal sinus biopsies, and bronchoalveolar lavage fluid [27,28]. Released cytokines act on eosinophils, epithelial cells and smooth muscle cells [39], which leads to mucus hypersecretion, airway hyperresponsiveness and eosinophil activation [42] for both asthma symptoms and blood eosinophilia. This response also affects the nasal epithelium and causes concurrent nasal polyposis or other ear, nose and throat involvement [43]. Although the T-cell response is mainly skewed toward a Th2 phenotype, Th1 and Th17 cells are also involved in the EGPA pathogenesis. For

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Based on the 2012 World Health Organization-defined eosinophilic disorders update, EGPA can be also classified as a hypereosinophilicassociated condition (Table 1). Indeed, eosinophils represent the cornerstone of the diagnosis and possibly the pathogenesis of EGPA, which justified the name change from Churg–Strauss syndrome to EGPA. As for other hypereosinophilic-associated conditions, tissue damage results from eosinophil proliferation and activation, which leads to organ deposition and granule protein release. Any organs can be affected, including respiratory, gastrointestinal, cutaneous, kidney, peripheral nerve and cardiac organs [48]. Eosinophil proliferation is important in EGPA. Indeed eosinophils N 1500/mm3 were considered a Lanham diagnostic criterion of the disease [49]. Furthermore, a series of 383 patients showed a mean eosinophil count of 7569 ± 6428/mm3 at the time of diagnosis [6]. Following activation, eosinophils release their granules containing stored cytotoxic proteins and toxins such as eosinophil-derived neurotoxin, major basic protein (MBP), eosinophil peroxidase and eosinophil cationic protein (ECP) leading to tissue damages [50]. ECP was found in granulomas, sera, sputum, bronchoalveolar lavage fluid and tissue biopsy from patients with active disease [51–54]. More recently, Soragni et al. described MPB toxicity to epithelial cells as a result of its aggregation [55]. Still we do not know what specifically drives eosinophil activation and accumulation in EGPA. On one hand, a major specific defect such as a genetic mutation seen in hypereosinophilic syndrome is lacking, but on the other hand a reactive cause for eosinophilia has not been reported yet.

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In 2005, two independent teams have identified two distinct phenotypes of the disease [5,6]. Sinico et al. reported that in 93 patients with EGPA, patients with ANCAs had statistically significantly more purpura, more pulmonary hemorrhage, more mononeuritis multiplex and more renal rapidly progressive glomerulonephritis but less heart involvement than patients without ANCA [5,6]. In the works by Sablé-Fourtassou et al. and Comarmond et al., the French Vasculitis Study Group confirmed that among patients with EGPA, the patients with ANCAs had a predominant vasculitis-phenotype with more neurologic symptoms, more purpura, more gastrointestinal manifestations, more renal manifestations and less cardiac manifestations (including pericarditis and cardiomyopathy) [5,7]. Specific evidence lacks to explain this dichotomy and we do not have enough data to split the disease in two subsets or two diseases. Still any discussion of pathophysiology has to account for both phenotypes. Therefore we present data regarding disease pathophysiology based

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EGPA is related to allergy, mainly because some patients with EGPA have a history of allergy. EGPA undeniably shares intrinsic mechanisms with allergy. Patients have increased serum IgE level, the disease evolution is characterized by flares, and in some patients, the vasculitis developed after high exposure to grain, flour, pigeon or cereal dust, which suggests a hypersensitivity mechanism [24]. However, EGPA also clearly lacks the extrinsic mechanisms of allergy. First, there is no seasonal disease evolution, and to the best of our knowledge, the disease does not show an exposure–reexposure process. Second, the specific causative agent remains unknown. A few environmental factors reported to be associated with manifestation onset include infectious agents [25]; drugs such as macrolides [26], carbamazepine [27], and quinine [28]; and allergic hyposensitization and vaccinations, although this last aspect remains controversial [29]. The use of anti-asthmatic drugs has been debated. Suspected drugs were the leukotriene-receptor antagonists montelukast, zafirlukast [30–33], and omalizumab [34–36]. The causative role of these drugs is still unproven because their use allows for steroid tapering, which can reveal latent EGPA [37]. Finally, in studying common allergens in EGPA, Bottero et al. did not find a higher prevalence of atopy in EGPA patients than controls [38].

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instance, Th1 cells were found in biopsies of EGPA skin lesions [44]. Interestingly, the presences of Th17 and regulatory T-cell (Treg) have been compared between asthma and EGPA. In a different manner than in asthma, Th17 cells could be predominant in active disease. Indeed, Saito et al. detected Th17 cells characterized by the production of IL17A and IL-22 more frequently in the peripheral blood of patients with active EGPA than in healthy controls or patients with chronic eosinophilic pneumonia, or inactive EGPA, and asthma [45]. This increase in Th17 cell number is associated with a decrease in Treg number in EGPA. EGPA patients with frequent disease relapse (once every 2 years after a period of remission) showed decreased number of Tregs in the peripheral blood, which suggests a role for these cells in preventing the disease [46]. Furthermore, the number of whole blood FOXP3+ cells among CD4+ T cells and the proportion of CD4+CD25+ T cells positive for IL-10, transforming growth factor β, and IL-2 were found lower in patients than controls including patients with chronic eosinophilic pneumonia and asthma [47].

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such as sarcoidosis and hypersensitivity pneumonitis. Poorly formed non-necrotizing granulomas are a debated hallmark of the acute and chronic form of hypersensitivity pneumonitis, and the absence of necrosis is a well-known characteristic of sarcoidosis granulomas [20]. Other causes of granulomas developed in a Th2-environment are not rheumatologic conditions and comprise parasitic infections such as chronic paracoccidioidomycosis [21] and schistosomiasis [22]. Yet, we have little information about the role of the formation of a granuloma in the pathogenesis of EGPA. The formation could be an interface for cell cooperation whereby immune cells would be activated and/or stimulated, thereby creating a vicious circle for inflammation. In that sense, the description of T cell subsets involved and/or present in the granuloma would be of interest and has not been reported yet. Alternatively, in both EGPA and GPA, the formation of a granuloma is considered a response to wall off the zone of necrosis generated by neutrophil activation [23].

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Please cite this article as: Chaigne B, et al, Dividing the Janus vasculitis? Pathophysiology of eosinophilic granulomatosis with polyangitis, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.10.006

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3.1.2. Neutrophils Neutrophils are instrumental cells in the pathogenesis of AAVs, being both targets of autoimmunity and effector cells in endothelial damage. On priming with TNFα or IL-1β secreted by macrophages under the inflammatory condition, neutrophils express MPO and adhere to vessels. Then, the binding of anti-MPO-ANCAs on neutrophils completes their activation and leads to local production of reactive oxygen species and release of granule contents that damage the endothelium of vessels. Furthermore, neutrophils can transfer MPO to endothelial cells via β2 integrin-mediated close contact. This mechanism could increase both MPO antigenic presentation and vessel damage [60]. The formation of neutrophil extracellular traps (NETs) consisting of the disruption of neutrophils with DNA extrusion combined with granular enzyme release, also called “netosis,” has been described in AAV pathogenesis. In vitro, ANCA-stimulated neutrophils can lead to the release of DNA along with granular proteins. Moreover, circulating DNA associated with granular proteins was found in sera of patients and in kidney biopsies. Although specific data on neutrophils and NETs are lacking in EGPA, netosis was recently linked to the development of MPO-ANCAs in animal models. Nakazawa et al. treated rats with propylthiouracil and phorbol myristate acetate: rats that generated NETs also showed MPO-ANCAs and pulmonary capillaritis [61]. Sangaletti et al. proposed that NETs could transfer MPO to antigenpresenting cells [62]. The same team also described that sera from patients with MPO-ANCA-associated MPA induced netosis and impaired NET degradation, which could increase MPO presentation.

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3.1.3. B lymphocytes B cells have been recently studied and are of interest in EGPA because of the reported success of B-cell-depleting therapy in both inducing and maintaining disease remission in AAV [63]. Tsurikisawa et al. demonstrated a significant increase in proportion of B cells positive for CD80, CD27 and CD95 in the blood of EGPA patients with frequent

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3.2. The non-vasculitis phenotype: an over-expression of an eosinophil 339 defect? 340 The non-vasculitis phenotype is mainly characterized by the predominant development of myocarditis or pericarditis in patients. Although eosinophilia is present in the two diseases phenotypes [5,6], we speculate that the non-vasculitis phenotype is associated with a yet unknown specific defect or activation of the eosinophil in EGPA, which enhances its ability to cause cardiac lesions. There is evidence that EGPA cardiac involvement could be linked to eosinophil. First, cardiac toxicity of eosinophils is well established and explained by eosinophil-mediated toxicity to endothelial cells [65]. Second, eosinophilic infiltration is also cardiotoxic, and eosinophilic degranulation of ECP can damage endomyocardial tissue and contribute to eosinophilic myocarditis [66]. Last, in a study of 42 patients with EGPA who underwent a magnetic resonance imaging, the patients with a cardiomyopathy had a higher eosinophil count than the patients without cardiomyopathy (7960/mm3 vs 4720/mm3, p b 0.05) [67]. Moreover, the non-vasculitis phenotype is also associated with an increased number of patients with pleural effusions [7]. Eosinophil can also be linked to pleural effusions. Indeed, it has been suggested that granulocyte/macrophage colony-stimulating factor, Il-5, Il-3 and eotaxin-3 are associated with pleural fluid eosinophilia [68,69]. Both Il-5 and eotaxin-3 levels are elevated in serum of patients with active disease and eotaxin-3 correlated with eosinophilia in EGPA [70,71]. Among the few specific characteristics of eosinophils already described in EGPA, eosinophils are activated more in patients with active disease than in remission. Surface-cell analysis revealed that levels of activating factors (CD69, CD25) are increased in peripheral-blood eosinophils with active disease [72,73]. As well, eosinophils seem to be protected against apoptosis, which explains their massive accumulation [73,74]. Although not differing in rate of spontaneous apoptosis, blood eosinophils from nine patients with active disease showed a low expression of proapoptotic genes [73]. Furthermore, eosinophils from one patient showed high mRNA levels of soluble CD95 in vitro, which could interfere with Fas-mediated apoptosis [74]. This protection against apoptosis and the Th2 cytokines in the environment contribute to enhancing eosinophil proliferation. Eosinophil phagocytosis by macrophages may be impaired in EGPA and enhanced eosinophilia [75]. Moreover, eosinophils are well known to secrete immunoregulating factors such as cytokines, chemokines and growth factors. Eosinophils secrete IL-25, which induces their own proliferation in a Th2dependent manner in EGPA [76]. IL-5 level is elevated in serum of patients with active disease [70]. As a result of this secretion, eosinophils enhance their CCR-3-dependent transendothelial migration from the vasculature [70]. Such adhesion to the inner surface of vessels could also participate in the anti-apoptotic process by interacting with integrins such as α4β1 or α4β7 on eosinophils as well as vascular cell adhesion molecule 1, which is expressed on endothelial cells [77,78]. Altogether it seems that eosinophils have the capacity to drive the non-vasculitis phenotype but the few specific data about the cell in the disease pathophysiology are not sufficient to verify this hypothesis yet.

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4. Summary and concluding remark

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3.1.1. MPO-ANCAs MPO is a heme-containing peroxidase in the azurophilic granules of neutrophils and a microbicidal protein able to generate hypochlorous acid [56]. Although the development of a humoral immunity against MPO is the hallmark of the vasculitis-associated phenotype, the reason for this specific response is unclear. The response could be a molecular mimicry of another peroxidase or a functional dysregulation of the peroxidase leading to an immune tolerance rupture. MPO-ANCAs are present in only 31% to 38% of patients, so all these questions remain to be elucidated. Even though experiments documenting the pathogenic role of MPOANCAs were predominantly performed in MPA, their association with vasculitis is clear. A major breakthrough was the development of a mouse model showing that the transfer of splenocytes from MPOdeficient mice immunized with murine MPO led to the development of glomerulonephritis and pulmonary capillaritis similar to human MPA [57]. Furthermore, the case of a mother with MPO-ANCAs who gave birth to a child in whom neonatal vasculitis developed emphasized that the auto-antibody was pathogenic in humans [58]. More recently, Roth et al. differentiated natural from pathogenic MPO-ANCAs based on epitope differences identified by mass spectrometry. MPO-ANCAs reactive with the epitope amino acids 447–459 were exclusively associated with active disease [59]. For EGPA, a different targeted epitope, a change to this specific epitope conformation, or even a failure in the masking process of this epitope by the ceruloplasmin fragment could explain the presence of MPO-ANCAs.

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relapses [46]. In the same study, patients with seldom-relapsing EGPA and controls had higher CD19-positive B-cell counts and higher serum IgG level than patients with frequent relapses [46]. The authors concluded that frequently relapsing EGPA could be associated with induced B-cell apoptosis [46]. Also arguing for different mechanisms in EGPA, therapy targeting B cells were recently reported to be more efficient in ANCA-positive EGPA patients [64].

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on the speculation that a shift toward neutrophils and B lymphocytes characterize the MPO-ANCA phenotype whereas the non-vasculitis phenotype is due to a functional defect of the eosinophils.

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Significant advances have been made in understanding EGPA. De- 391 spite these significant progresses in understanding the whole disease, 392

Please cite this article as: Chaigne B, et al, Dividing the Janus vasculitis? Pathophysiology of eosinophilic granulomatosis with polyangitis, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.10.006

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Fig. 1. Two processes from an indivisible whole: hypothetical pathogenesis of EGPA to explain two clinical phenotypes: a vasculitis-phenotype characterized by an activation of B cells and neutrophils and a non-vasculitis phenotype driven by eosinophils. EGPA, eosinophilic granulomatosis with polyangitis.

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strong efforts are still needed to dissect the mechanisms of the EGPA pathophysiology and dichotomy. Based on our current knowledge we speculated that it includes two processes, the first one characterized by an enhanced activation of B cells and neutrophils and the second one characterized by eosinophils being responsible for cardiomyopathy and pleural effusions (Fig. 1). Further studies are needed to clarify these divided mechanisms in order to fully explain the clinical observation of two distinct phenotypes of the diseases.

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