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Rheumatology Advance Access originally published online on April 8, 2008
Rheumatology 2008 47(6):804-808; doi:10.1093/rheumatology/ken033
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Eotaxin-3 is involved in Churg–Strauss syndrome – a serum marker closely correlating with disease activity

K. Polzer1, T. Karonitsch2, T. Neumann3, G. Eger1, C. Haberler4, A. Soleiman5, B. Hellmich6, E. Csernok6, J. Distler1, B. Manger1, K. Redlich2, G. Schett1 and J. Zwerina1

1Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 2Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria, 3Department of Internal Medicine 3, University of Jena, Jena, Germany, 4Department of Neuropathology, 5Department of Pathology, Medical University of Vienna, Vienna, Austria and 6Deparment of Rheumatology, University of Schleswig-Holstein, Kiel, Germany.

Correspondence to: J. Zwerina, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. E-mail: jochen.zwerina{at}uk-erlangen.de


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. Churg–Strauss Syndrome (CSS) is characterized by excessive eosinophil accumulation in peripheral blood and affected tissues with development of granulomatous vasculitic organ damage. The contribution of eosinophil-chemotactic cytokines (eotaxin family) to eosinophilia and disease activity in CSS is unknown. Thus, we compared serum levels of the eotaxin family members in CSS patients with healthy and disease controls.

Methods. Forty patients with CSS diagnosed according to ACR 1990 criteria, 30 healthy controls (HC) and 57 disease controls (28 asthma, 20 small vessel vasculitis, 9 hypereosinophilic syndrome) were studied. Clinical data were collected and serum levels of eotaxin-1, -2 and -3 were determined by ELISA. Further, immunohistochemistry was applied to identify eotaxin-3 expression in tissue biopsies from patients with CSS.

Results. In contrast to eotaxin-1 and -2, eotaxin-3 was highly elevated in serum samples of active CSS patients and correlated highly significantly with eosinophil counts, total immunoglobulin E (IgE) levels and acute-phase parameters. Moreover, eotaxin-3 was not elevated in other eosinophilic and vasculitic diseases. Immunohistochemical analysis revealed strong expression of eotaxin-3 in endothelial and inflammatory cells in affected tissues of active CSS patients.

Conclusions. This study reveals the specific association of elevated eotaxin-3 expression with high disease activity and eosinophilia in CSS patients. Eotaxin-3 might thus be a pathogenic player, biomarker and potential therapeutic target in CSS.

KEY WORDS: Churg–Strauss syndrome, Vasculitis, Eosinophilia, Eotaxins


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Churg–Strauss Syndrome (CSS), first described in 1951, is a necrotizing systemic vasculitis associated with substantial morbidity and mortality [1]. Although belonging to the group of vasculitides associated with ANCA, CSS shows some specific factors distinguishing it from WG and microscopic polyangiitis: almost all patients present with a preceding history of allergic disease (‘allergic granulomatous angiitis’) and development of disease can occur after a change in asthma therapy [2, 3]. Tissue biopsies of affected organs show a dense eosinophil infiltration and vasculitis, which is accompanied by increased eosinophil counts in the peripheral blood rarely seen in other ANCA-associated vasculitides.

The pathogenesis of eosinophilia and tissue damage in CSS is yet unclear, but an unknown allergen or environmental trigger is thought to provoke fatal consequences in pre-sensitized asthma patients. On a cellular level, a strong shift towards a Th2-like response with massive T-cell activation is evident [4]. In vitro, T-cell lines from CSS patients produce significant amounts of IL-4 and -13 [5]. This is underlined by the fact that active CSS patients have usually high serum levels of IgE and IgE-containing immune complexes [6]. In tissue biopsies, granulomatous vasculitic lesions filled with eosinophils, macrophages and lymphocytes are observed [7]. Local activation with degranulation of eosinophils and subsequent release of granule proteins such as eosinophil-derived neurotoxin (EDN) and major basic protein (MBP) is thought to contribute to vasculitic damage.

However, the molecules specifically contributing to eosinophilia and subsequent degranulation in CSS are enigmatic. Recently, animal and human studies have revealed the role of a chemokine family (‘eotaxins’) involved in tissue eosinophilia and eosinophil maturation in allergic asthma and eosinophilic oesophagitis (EO) [8]. To date, three members of the eotaxin family have been described: eotaxin-1 (CCL11), eotaxin-2 (CCL24) and eotaxin-3 (CCL26). All eotaxins bind to and activate chemokine receptor 3 (CCR3) but have little homology and seem to possess different physiological properties. We hypothesized that these eotaxins might play a role in eosinophilia in CSS and thus compared serum levels of eotaxin-1, -2 and -3 in active and inactive CSS patients with healthy controls (HC). Furthermore, we determined local expression of eotaxin-3 at sites of active disease in CSS.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Patient characteristics
Forty patients with CSS from three Departments of Rheumatology (University of Erlangen-Nuremberg, University of Schleswig-Holstein and Medical University of Vienna) were included in this study. All patients fulfilled the ACR 1990 criteria for CSS [9]. Thirty age- and sex-matched HC without a known history of allergic disease, 28 patients with asthma, 20 patients with small-vessel systemic vasculitis (SVV; WG and microscopic polyangiitis) and 9 patients with active hypereosinophilic syndrome (HES) served as control groups. Clinical, laboratory and pathological data were obtained from all patients and a thorough chart review was performed. The study was approved by the local ethics committee. Informed consent was obtained from patients and HC before commencing the study.

Detection of eotaxin serum levels
Serum samples were collected at routine visits and immediately stored at –80°C. Detection of eotaxin-1, -2 and -3 levels was performed by ELISA (all R&D Systems, Minneapolis, MN, USA). Briefly, polystyrene microplates coated with a mouse monoclonal antibody against eotaxin-1, -2 or -3 were incubated with serum samples for 2 h at room temperature. For detection, horseradish-peroxidase conjugated polyclonal (eotaxin-1 and -2) or monoclonal antibodies (eotaxin-3) to the respective human eotaxins were added for 1 h and colour reaction was developed using 0.4 g/l tetramethylbenzidine/0.02% hydrogen peroxide. Optical density was measured with a plate reader and absolute values calculated from the eotaxin-1, -2 and -3 standard curves.

Immunohistochemistry
Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of biopsies from six patients with CSS. For immunohistochemical detection of eotaxin-3, a polyclonal goat anti-human antibody (dilution 1: 100, AF653, R&D Systems) was used. Antigen retrieval was achieved upon pre-incubation with proteinase K (Roche, Mannheim, Germany). Non-specific binding was blocked by addition of 10% goat serum for 10 min at room temperature. Afterwards, sections were incubated for 1 h at room temperature with the primary antibody followed by incubation with a species-specific biotinylated immunoglobulin (Vector, Burlingame, CA, USA) for 30 min at room temperature. After rinsing with phosphate-buffered saline, staining was detected with streptavidin AV (Dako, Hamburg, Germany). Counterstaining with haematoxylin was performed at the end of procedure. Negative control stainings with an irrelevant goat immunoglobulin showed no signal.

Statistical analysis
Data are presented as the mean ± S.E.M. For group comparisons, we used one-way factorial analysis of variance with the Bonferroni–Dunn test or the Mann–Whitney U-test. To compare clinical and serological parameters, Pearson's correlation coefficient was used. A P-value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Clinical characteristics
Forty patients with CSS were studied. To investigate the contribution of eotaxins to eosinophilia and disease activity, patients were divided into an active (n = 16) and inactive disease group (n = 24). Active CSS was characterized by increased eosinophil counts (≥10% eosinophils or >1000 eosinophils/µl) and active vasculitis in at least one organ involved as evidenced by histological proof or surrogate parameters (radiology, clinical or laboratory data). Disease manifestations were typical for CSS and equally distributed in both groups: all patients had eosinophilia, 98% asthma, 75% sinusitis, 45% pulmonary involvement, 30% cardiac disease and 48% had vasculitic polyneuropathy. With respect to therapy, 6 of 16 patients in the active disease group received low-dose steroids for control of allergic asthma, whereas 3 patients were receiving immunsuppressive drugs (two cyclophosphamide, one methotrexate). In the inactive group, all CSS patients received corticosteroids and nine received additional immunosuppressants (azathioprine or methotrexate), when the serum samples were obtained. The active CSS disease group was characterized by higher levels of acute-phase reactants, eosinophil counts and serum IgE levels. In addition, we compared serum samples from four CSS patients before and after introduction of high-dose corticosteroid therapy.

To evaluate the specificity of eotaxin serum levels, we also included other sex- and age-matched disease groups: patients with asthma, small vessel vasculitis (SVV) other than CSS and hypereosinophilic syndrome (HES) patients. SVV patients were classified according to ACR criteria, HES was diagnosed upon clinical and laboratory studies after exclusion of other causes of persistent eosinophilia. The clinical characteristics are given in Table 1.


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  		TABLE 1. Clinical characteristics of CSS patients and controls

 
Serum levels of eotaxins in CSS patients
Systemic levels of eotaxin-1, -2 and -3 were measured in sera of CSS patients as well as disease and HC by ELISA (Fig. 1A–C). Eotaxin-1 levels tended to be elevated in inactive CSS, HES and SSV patients (197.4 ± 39.6, 230.1 ± 141.1 and 194.5 ± 17.5 pg/ml, respectively) as compared with HC (mean ± S.E.M. levels: 137.2 ± 8.4 pg/ml), whereas active CSS patients and asthma patients had similar eotaxin-1 levels as HC. The median eotaxin-2 levels were similar in HC (1613 ± 189.2 pg/ml) and CSS patients irrespective of disease activity, but were significantly diminished in SVV patients (491.4 ± 88 pg/ml, P = 0.001 vs HC).


Figure 1
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  		FIG. 1. Serum levels of eotaxin-1, -2 and -3 in CSS patients and controls. (A) Active and inactive CSS patients did not significantly differ with respect to eotaxin-1 serum levels of HC and patients with asthma, HES and SVV. (B) Eotaxin-2 serum levels were significantly diminished in SVV patients, but not CSS, HES and asthma patients as compared with HC. (C) Eotaxin-3 levels were highly elevated (P < 0.0001) in active CSS patients, whereas no difference was observed between inactive CSS patients and HC. Also, asthma, HES and SVV patients had low eotaxin-3 serum levels. Values are given as mean ± S.E.M.

 
Most interestingly, we found no significant difference regarding eotaxin-3 serum levels between HC (14.8 ± 2.3 pg/ml) and inactive CSS patients (16.7 ± 3.4 pg/ml, P = NS), whereas active CSS patients had highly significantly elevated serum levels (168.2 ± 37.5 pg/ml, P < 0.0001 vs HC). Moreover, patients with HES (47.6 ± 32.1 pg/ml), asthma (8.9 ± 5.6 pg/ml) and SSV (10.9 ± 8.2 pg/ml) had levels comparable with HC. Thus, eotaxin-3 seems to be a specific marker for active CSS patients (all P < 0.05 vs active CSS).

In addition, when we compared four untreated active CSS patients before and after initiation of high-dose corticosteroid treatment, we found a significant drop in eotaxin-3 levels paralleling clinical improvement (before: 215.5 ± 71.6 pg/ml vs after: 94.1 ± 76.1 pg/ml, P < 0.05). Thus, high eotaxin-3 levels are clearly associated with active states of CSS.

Correlation of eotaxin serum levels with eosinophilia and other laboratory data
To determine possible correlations of eotaxin levels with serum IgE levels, eosinophil count and acute-phase parameters, we used Pearson's correlation. Eotaxin-1 levels did not correlate with any of the four clinical parameters (eosinophil count, total IgE levels, ESR and CRP) investigated. In contrast, we found a significant correlation of eotaxin-2 levels with eosinophil counts (r = 0.47, P = 0.003) and IgE levels (r = 0.39, P = 0.01), whereas no correlation could be observed with acute-phase parameters. Most interestingly, eotaxin-3 levels correlated highly significantly with all investigated clinical parameters: eosinophil counts (r = 0.54, P = 0.0004), IgE levels (r = 0.42, P = 0.007), ESR (0.38, P = 0.01) and CRP values (r = 0.42, P = 0.007). These findings are depicted in Table 2.


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  		TABLE 2. Correlation coefficients and P-values of eotaxin-1, -2 and -3 serum levels with clinical activity parameters in CSS patients

 
Expression of eotaxin-3 in tissue biopsies from CSS patients
To investigate the origin of elevated serum eotaxin-3 levels, we stained tissue biopsies of affected organs from six CSS patients with an antibody against eotaxin-3. Biopsies were taken at first disease manifestation for diagnostic purposes from nasal conchae, gall bladder, sural nerve and tongue, respectively. Eotaxin-3 was highly expressed in all biopsies investigated as shown in representative pictures (Fig. 2). In all biopsies except one, endothelial cells of small-sized vessels stained positive for eotaxin-3. Expression could be found in arterioles, venules as well as lymphatic vessels. Eotaxin-3 was also found to be expressed in smooth muscle cells of small arterioles. Further, we could observe eotaxin-3 expression in the perineurium of the sural nerve and a marked expression in respiratory epithelium (nasal biopsies) and dense eosinophilic infiltrates (Table 3). Hence, eotaxin-3 is expressed at active sites of disease in tissues of CSS patients.


Figure 2
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  		FIG. 2. Eotaxin-3 expression in tissue biopsies of active CSS patients. Immunohistochemistry of eotaxin-3 in biopsies from gall bladder (A), nasal conchae (B), sural nerve (C) and skeletal muscle (D) of active CSS patients (original magnification 40x). Paraffin-embedded sections were stained with a polyclonal antibody against eotaxin-3. Strong staining is found in arterial and venous endothelial cells (E and H), infiltrating eosinophils (F) and perineural structures (G). Brown colour indicates positive staining, original magnification 100x.

 

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  		TABLE 3. Expression of eotaxin-3 in CSS tissue biopsies

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
Eosinophilia and tissue eosinophilic infiltration with the formation of granulomatous vasculitis are key pathologies of CSS. The pathogenesis of increased eosinophil production and infiltration into organs, however, is yet unclear. In this study, we show that: (i) eotaxin-3 is highly elevated in serum of active CSS patients but not disease controls, (ii) eotaxin-3 levels correlate with markers of disease activity and (iii) eotaxin-3 is expressed at active sites of disease in tissue biopsies from CSS patients.

Accumulation and activation of eosinophils in target tissues is regarded as a crucial step for the development of organ damage in CSS patients. The pathophysiological pathways resulting in the increased production, trafficking and activation of eosinophils in CSS remain to be elucidated. CSS is regarded as a ‘classical’ Th-2-mediated disease with increased antibody production, mainly IgE immunoglobulins and the formation of IgE-containing immune complexes [6]. A strong cellular shift towards an increase of Th-2 cells that produce IL-4, -13 and -5 has been observed [5, 10]. Current understanding of CSS implies that T-cell-dependent activated eosinophils further activate T-cells to produce Th2-associated cytokines (IL-4 and -13) and also secrete themselves a variety of harmful mediators such as MBP, eosinophil cationic protein and EDN. The latter might directly mediate cardiac and nerve toxicity in addition to damage caused by granulomatous vasculitis [11, 12].

IL-5 is one of the candidate molecules as pathological mediators for eosinophilia in CSS as increased levels are found in serum and broncho-alveolar fluid of highly active CSS patients [13, 14]. The relevance of IL-5 is further underlined by the characterization of IL-5 transgenic mice, which show profound eosinophilia, whereas deletion of the IL-5 gene markedly reduces eosinophilia after allergen challenge in mice [15, 16]. The clinical relevance of IL-5 in humans was demonstrated by clinical trials utilizing a neutralizing anti-IL-5 antibody (mepolizumab), which causes dramatic reduction in peripheral blood eosinophilia in human bronchial asthma and EO [17, 18]. Currently, first clinical trials with mepolizumab in refractory CSS are conducted and will reveal the potential role of IL-5 in CSS. However, antigen-induced eosinophilia in inflamed lungs can occur independently of IL-5 suggesting that distinct mechanisms are responsible for peripheral blood and tissue eosinophilia, the latter also being dependent on the specific organ targeted [19]. As organ damage in CSS is thought to be at least partly mediated by direct invasion and degranulation of eosinophils in tissues, other mediators than IL-5 might be important for the pathogenesis of CSS.

The discovery of a chemokine family, the eotaxins, has contributed substantially to the knowledge on eosinophil trafficking to inflammatory sites [20]. To date, eotaxin-1 (CCL11), eotaxin-2 (CCL24) and eotaxin-3 (CCL26) are grouped together in the eotaxin family due to their eosinotactic activity both in vitro and in vivo. Interestingly, though all eotaxins are CC chemokines and signal through the same receptor (CCR3), they show little homology (only ~40%) and the eotaxin genes are located on different chromosomes. Consistent with the association of Th2-type responses in allergic and eosinophilic diseases such as CSS, IL-4 and -13 are potent and synergistic inducers of the eotaxins in epithelial and endothelial cells [21, 22]. Consequently, increased local expression of the eotaxins has been described in various eosinophilic diseases.

We could not find alterations in eotaxin-1 serum levels in active CSS patients as compared with HC. However, even inactive CSS patients tended to have increased eotaxin-1 levels. Whether this could be a regulatory up-regulation remains unclear, but cross-regulation or cross-inhibition between eotaxin-1 and other eotaxins has not been described. Eotaxin-1 levels are thus not altered in active CSS patients, well-fitting to previous reports in long-lasting asthma patients with persistent eosinophilia [23]. In line with these clinical observations, eotaxin-1 deficiency in mice delays but cannot alter tissue eosinophil infiltration upon allergen challenge [24]. Thus, eotaxin-1 does not seem to be the major mediator of the sustained and severe eosinophilia seen in CSS.

In contrast, experimental evidence suggests crucial involvement of eotaxin-2 and -3 in the perpetuation of tissue eosinophilia. Expression of eotaxin-2 and -3 is significantly increased in late stages after allergen challenge in bronchial asthma and associated with the late-phase asthmatic response [23]. Consequently, eotaxin 1/2 double-knockout mice are protected from experimental allergic tissue eosinophilia in the lung [25]. Interestingly, eotaxin-3 has recently been linked to the pathogenesis of EO rather than eotaxin-1 and -2 [26]. In our study, serum eotaxin-3 levels were strongly elevated in active CSS patients whereas eotaxin-2 expression was not elevated. In contrast to eotaxin-1 and -2, eotaxin-3 also strongly correlated with peripheral blood eosinophilia, serum IgE levels and acute-phase reactants as surrogate markers of disease activity in CSS and immunsuppressive treatment led to a rapid reduction of circulating eotaxin-3 levels. Moreover, we also determined serum eotaxin levels in other vasculitic and eosinophilic disorders including asthma, idiopathic HES and other forms of SVV and could not find significant elevations of eotaxin-3. Thus, eotaxin-3, rather than the other eotaxins, seems to play a major and specific role in the sustained severe eosinophil infiltration in CSS.

To further elucidate the origin of the highly increased eotaxin-3 expression in active CSS, we performed immunhistochemical analyses of tissue biopsies of CSS. First described in 1999, eotaxin-3 was found to be expressed primarily in heart and ovaries [27]. We now show strong expression of eotaxin-3 in affected tissues of CSS patients. Well-fitting to previous in situ data, we found eotaxin-3 most confined to endothelial cells of microvascular vessels. This is consistent with the notion of small vessels being the primary target for vasculitis and eosinophil transmigration in CSS. However, we also found strong expression of eotaxin-3 in eosinophils in biopsies. As eosinophils are not known to express eotaxin-3, secreted eotaxin-3 might bind on the surface of eosinophils and thereby attract more eosinophils as part of a vicious circle. Certainly, further studies are needed to focus on the expression pattern and activation pathways of eotaxin-producing cells in CSS.

In conclusion, we found a significant and specific alteration of the eotaxins in active CSS patients. Eotaxin-3 might constitute (i) a pathogenic player in tissue eosinophilia and subsequent organ damage, (ii) a biomarker for disease activity and (iii) an interesting therapeutic target in CSS.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
We thank Isabell Schmidt and Birgit Tuerk for excellent technical assistance.

Funding: This study was supported by the START prize of the Austrian Science Fund (G.S.) and the Carmela and Dennis Banfield Honor Grant of the Vasculitis Foundation (J.Z.).

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 5 July 2007; revised version accepted 14 January 2008.
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