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• W2892913291 abstract "Intravenous immunoglobuin (IVIG) exerts protective effects in experimental allergic bronchopulmonary aspergillosis (ABPA) via a sialylation-dependent mechanism. The protection was associated with reduced recruitment of eosinophils, diminished goblet cell hyperplasia, suppressed Th2 and Th17 responses and reciprocally enhanced regulatory T cells and IL-10, and decreased IgE levels in the circulation. Aspergillus fumigatus has been implicated in causing life-threatening infections as well as severe asthma and allergic diseases. Allergic affliction like allergic bronchopulmonary aspergillosis (ABPA) is a disabling lung disease seen in atopic individuals and particularly in asthma and cystic fibrosis patients. ABPA is characterized by markedly elevated Aspergillus-specific IgE and total IgE levels, and eosinophilia. Both Th2 and Th17 cells are implicated in the pathogenesis of ABPA 1. Corticosteroids are most commonly used to control ABPA but are associated with immunosuppression and resistance. Therefore, alternative immunotherapies that target inflammatory process without causing immunosuppression and toxicity are preferred. Immunoglobulins from the pooled plasma of healthy donors are available in liquid formulations, suitable for i.v. or s.c. application (IVIG/SCIG) for the immunotherapy of diverse autoimmune and inflammatory diseases 2. Experimental use of IVIG/SCIG in allergy and asthma has been described and protective effects have been shown in experimental OVA-induced allergic airway inflammation (AAI) 3, 4. However, IgG immunotherapy has never been explored in fungi-mediated allergic conditions. Based on several reports including ours showing that intravenous immunoglobulin (IVIG) reciprocally regulates Th17 cells that are one of the pathogenic cells in fungal allergic diseases, and Tregs that are immunoprotective 1, 5, 6, we hypothesized that IVIG therapy protects from experimental ABPA. ABPA was induced in C57BL6 (H-2b) mice (Fig. 1A) 7 (See Supporting Information). Experiments were performed according to the Italian Approved Animal Welfare Assurance A-3143-01. Mice were sensitized by concomitant intraperitoneal (i.p.) and subcutaneous administration of A. fumigatus culture filtrate extract dissolved in incomplete Freund's adjuvant. Twice at weekly interval, the extract was instilled to these mice by intranasal route. At third week, bronchial colonization of A. fumigatus was induced (Fig. 1A). For the infection model, naïve mice were infected at third week for two consecutive days with resting conidia by intranasal route to induce bronchial colonization of A. fumigatus (Fig. 1B). The protective role of IVIG (1g/kg, i.p route) was evaluated both during the induction (prophylaxis) and the elicitation (therapy) phase of ABPA. For the prophylaxis, IgG was administered on day 0, 7 and 14 of induction of allergy. For the therapy, IgG was administered on day 21. The protective role of both native and desialylated IVIG was investigated. Desialylation of IVIG was confirmed by reverse phase HPLC (Fig. 1C). At day 28, mice were assessed for the various parameters of allergic airway inflammation. IVIG-treated mice either under prophylaxis or therapeutic regime have shown minimal fungal burden in the lungs as assessed by CFU (Fig. 1D). In addition, eosinophils, one of the major players of allergic response to A. fumigatus, were mostly absent in the BAL fluid of IVIG-treated mice (Fig. 1E). Histopathology analysis of lungs confirmed the induction of extensive goblet cell hyperplasia in untreated allergic mice but not in IVIG group (Fig. 1F). Equimolar dose of human serum albumin, used as an irrelevant protein control for IVIG had no effect on allergic responses (Fig. 1D–F). The fungal growth and the occurrence of allergy were inversely related. Studies in experimental model of autoimmune diseases have shown that α2,6-sialic acid linkages at Asn297 of Fc-domain of IgG plays an important role in mediating the anti-inflammatory action of IVIG 8. Sialylation of IgG was also reported to be critical for the protection against OVA-induced airway hyperresponsiveness (AHR) 4. Therefore, we investigated if sialylation of IgG is key for the IVIG-mediated inhibition of hypersensitivity to A. fumigatus. We found that desialylated IVIG failed to inhibit inflammatory responses in the lungs and these mice had elevated fungal burden (Fig. 1D–F), thus confirming that sialylation of IgG is indispensable for rendering the protection against allergic response to A. fumigatus. ABPA is characterized by a protracted Th2 and Th17 responses in the lungs, and experimental models have demonstrated that Tregs have a pivotal role in the protection 1, 7. Analysis of CD4+ T-cell response in the thoracic lymph nodes by using isolated CD4+ T cells or in the lungs by quantitative RT-PCR assessment of either lineage-specific transcription factors (Tbet, Rorc, Gata3, Foxp3) or cytokines (ifng, il17a, il17f, il4, il5, il13, il10) revealed that hypersensitive response to A. fumigatus is characterized by predominant Th2-signature cytokines and il17f (Fig. 2A). However, Th1 and Treg responses were not altered in ABPA mice as compared to infected or control mice. IVIG significantly attenuated Th2-transcription factor Gata3 and cytokines il4, il5, and il13 gene expression. In addition, Th17 response, and il17f in particular, was also diminished in IVIG-treated mice (Fig. 2A). Interestingly, attenuation of Th2 and Th17 response by IVIG was associated with reciprocal enhancement of Treg response and significantly increased il10 (Fig. 2A). The inhibitory effect of IVIG on Th2 allergic response was also reflected in significantly decreased IgE levels in these mice (Fig. 2B). Again, desialylated IVIG lacked the ability to suppress Th2, Th17, and IgE responses (Fig. 2A, B). Further work is necessary to corroborate these data with intra cellular staining of T-cell subsets and cytokine analysis in the lungs at protein level. It was reported that IVIG exerts anti-inflammatory actions through interaction of α(2,6) sialylated linkages at Asp-297 of Fc fragment with type II Fc receptors, such as DC-SIGN (or SIGN-R1) or CD23 expressed on splenic myeloid regulatory cells 8. This interaction induces IL-33 that acts on basophils for the production of IL-4. The action of IL-4 on effector macrophages enhances inhibitory FcγRIIB and renders them tolerogenic for the activation by immune complexes. However, this concept has met with controversies as other reports have demonstrated sialylation- and FcγRIIB-independent protective effects of IVIG (discussed in 5). F(ab’)2 fragments of IVIG exerted protection similar to intact IVIG and reciprocally regulated Tregs and Th17 cells in EAE 6. IVIG could protect from AAI by FcγRIIIA-dependent inhibitory effect on iNKT cells 3. Also, FcγRIIB on dendritic cells was dispensable for mediating protection against OVA-induced AHR 4, thus pointing out that IVIG might protect from experimental ABPA and modulate inflammatory responses independent of FcγRIIB. Further exploration is essential to dissect the role of FcγRs and the contribution of F(ab’)2 versus Fc-fragments in IVIG-mediated protection against experimental ABPA. Although sialylation of IgG is critical for the protection against ABPA, it is not clear whether sialylation of Fc- or Fab-domain mediates this effect. Fab region is glycosylated in 15–20% of IgG and α(2,6) sialylated linkages are represented in nearly 70% of those IgG 9. SIGN-R1 was initially reported as a receptor for sialylated Fc-domain, but subsequent report later confirms that SIGNR-1 has a partial role in mediating anti-inflammatory effects of IVIG 10. Hence other lectin receptors could also mediate protective effects of IVIG. In fact, in OVA-induced AHR model, interaction of sialylated IgG with dendritic cell immunoreceptor (DCIR) on pulmonary CD11c+ dendritic cells but not with SIGN-R1+ macrophages mediates protection 4. Thus, the target receptors for sialic acid residues of IgG might diverge depending on the pathology and/or target organ. Future investigations should aim at exploring the mode of action of sialylated IgG in ABPA, in particular the requirement of DCIR and DC-SIGN receptors and the cell types that are targeted by IVIG. To conclude, our data show that IVIG protects from experimental ABPA by sialylation-dependent mechanism. As safer therapy for ABPA is not yet available, IVIG immunotherapy could be explored in ABPA patients. This work was supported by the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement 260338 ALLFUN (Luigina Romani and Jagadeesh Bayry) and the Specific Targeted Research Project FunMeta (ERC-2011-AdG-293714) to Luigina Romani). Fabian Käsermann is an employee of CSL Behring, Switzerland. Other authors have no conflicts of interests to declare. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2892913291 title "Intravenous immunoglobulin protects from experimental allergic bronchopulmonary aspergillosis via a sialylation‐dependent mechanism" @default.
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