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Background: The soluble isoform of FcɛRI, the high‐affinity IgE receptor (sFcεRI), is a protein of the IgE network with poorly defined functions. Objective: To define cellular sources and signals that result in the production of human sFcεRI and study its in vivo functions. Methods: FcεRI‐transfected human cell lines (MelJuso), human monocyte‐derived dendritic cells (moDCs), and murine bone marrow‐derived mast cells (MC) were stimulated by FcεRI cross‐linking and release of sFcεRI was analyzed (ELISA, Western Blot). Lysosomal‐associated membrane protein 1 degranulation assays and human basophil activation tests (BATs) were used to study IgE‐dependent activation. Recombinant sFcεRI (rsFcεRI) was used to assess its role in murine models of anaphylaxis with WT (wild‐type) and IgE−/− (IgE‐deficient) mice. Results: Antigen‐specific cross‐linking of IgE‐loaded FcɛRI on MelJuso cells that express the trimeric or tetrameric receptor isoform induced the production of sFcεRI. Using MCs and moDCs, we confirmed that IgE/FcɛRI activation induces sFcɛRI release. We demonstrated that generation of sFcɛRI requires Src phosphorylation and endo/lysosomal acidification. In experimental mouse models, sFcɛRI diminishes the severity of IgE‐mediated anaphylaxis. BATs confirmed that, comparable to the anti‐IgE monoclonal antibody omalizumab, sFcɛRI is an inhibitor of the human innate IgE effector axis, implying that sFcɛRI and omalizumab potentially inhibit each other in vivo. Conclusion: sFcɛRI is produced after antigen‐specific IgE/FcɛRI‐mediated activation signals and functions as an endogenous inhibitor of IgE loading to FcɛRI and IgE‐mediated activation. Our results imply, therefore, that sFcɛRI contributes to a negative regulatory feedback loop that aims at preventing overshooting responses after IgE‐mediated immune activation. The soluble isoform of FcεRI, sFcεRI is released after antigen‐specific cross‐linking on monocyte‐derived dendritic cells and murine bone marrow‐derived mast cells, where Src phosphorylation and endo/lysosomal acidification are key events. Comparable to omalizumab, sFcεRI prevents IgE binding and activation on human basophils in vitro. In experimental mouse models, sFcεRI diminishes severity of IgE‐mediated anaphylaxis and decreases surface IgE on basophils. [ABSTRACT FROM AUTHOR]

Background Food allergies are a growing health problem, and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome ( WAS) and defined whether spontaneous disease in Was −/− mice recapitulates the pathology of a conventional disease model and/or human food allergy. Methods Comparative Immuno CAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was −/− mice was compared to an adjuvant-based model in wild-type mice ( WT- OVA/alum). Intestinal and systemic anaphylaxis was assessed, and the role of the high-affinity IgE Fc receptor (Fcε RI) in allergic sensitization was evaluated using Was −/− Fcer1a −/− mice. Results Polysensitization to food was detected in both WAS and food-allergic patients which was recapitulated in the Was −/− model. Oral administration of ovalbumin (OVA) in Was −/− mice induced low titers of OVA-specific IgE compared to the WT- OVA/alum model. Irrespectively, 79% of Was −/− mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was −/− mice (95%) with a mortality rate >50%. Spontaneous sensitization and intestinal allergy occurred independent of Fcε RI expression on mast cells (MCs) and basophils. Conclusions Was −/− mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/Fcε RI activation cascade will not affect sensitization to food. [ABSTRACT FROM AUTHOR]

Background Cysteinyl leukotrienes contribute to Th2-type inflammatory immune responses. Their levels in oesophageal tissue, however, do not distinguish patients with eosinophilic oesophagitis (EoE) from controls. Objective We asked whether mRNA levels of leukotriene C4 synthase (LTC4S), a key regulator of leukotriene production, could serve as a marker for EoE. Methods Digital mRNA expression profiling (nCounter® Technology) was performed on proximal and distal oesophageal biopsies of 30 paediatric EoE patients and 40 non-EoE controls. Expression data were confirmed with RT- qPCR. LTC4S mRNA levels were quantified in whole blood samples. Leukotriene E4 was measured in urine. Results LTC4S mRNA levels were elevated in proximal (2.6-fold, P < 0.001) and distal (2.9-fold, P < 0.001) oesophageal biopsies from EoE patients. Importantly, increased LTC4S mRNA transcripts identified a subpopulation of EoE patients (28%). This patient subgroup had higher serum IgE levels (669 U/mL vs. 106 U/mL, P = 0.01), higher mRNA transcript numbers of thymic stromal lymphopoietin (TSLP) (1.6-fold, P = 0.009) and CD4 (1.4-fold, P = 0.04) but lower IL-23 mRNA levels (0.5-fold, P = 0.04). In contrast, elevated levels of IL-23 mRNA were found in oesophageal biopsies of patients with reflux oesophagitis. LTC4S mRNA transcripts in whole blood and urinary excretion of leukotriene E4 were similar in EoE patient subgroups and non-EoE patients. Conclusion & Clinical Relevance Elevated oesophageal expression of LTC4S mRNA is found in a subgroup of EoE patients, concomitant with higher serum IgE levels and an oesophageal transcriptome indicative of a more-pronounced allergic phenotype. Together with TSLP and IL-23 mRNA levels, oesophageal LTC4S mRNA may facilitate diagnosis of an EoE subpopulation for personalized therapy. [ABSTRACT FROM AUTHOR]

Background: In recent years, a histamine-releasing anti-FcεRIα autoantibody has been demonstrated in about one-third of patients with chronic urticaria. However, its clinical significance is still unclear. The objective was to detect a possible correlation between the occurrence of the anti-FcεRIα autoantibody and the clinical type or cause of urticaria. Methods: Sera from 66 consecutively seen in- and outpatients with various types of urticaria and five healthy controls were examined for the presence of anti-FcεRIα autoantibodies with a sandwich ELISA technique. In addition, basophil histamine release was studied in 13 autoantibody-positive sera. Results: Anti-FcεRIα autoantibodies were found in 17/48 patients with chronic urticaria, in 2/4 with angioedema, in 1/2 with urticarial vasculitis, and in 2/11 with dermographic urticaria. However, no anti-FcεRIα autoantibodies were detected in acute, cold, or delayed-pressure urticaria; in urticaria pigmentosa; or in normal controls. Of all chronic urticaria patients, 22 were classified as idiopathic since no underlying cause could be found. Of this group, seven were seropositive for anti-FcεRIα. However, anti-FcεRIα was also found in patients who went into remission after treatment of identified causes; namely, in one with type I allergy, one with drug intolerance, one with Helicobacter infection, and six with food intolerance. The autoantibody was also detected in 2/4 patients with associated autoimmune diseases. Functional activity was shown in basophil histamine release in 3/4 autoantibody-positive sera of patients with chronic idiopathic urticaria and in 4/6 autoantibody-positive sera of patients who went into remission after the treatment of underlying causes. Conclusions: These data confirm that anti-FcεRIα autoantibodies in urticaria are mostly... [ABSTRACT FROM AUTHOR]

SummaryWhereas dendritic cells (DC) and Langerhans cells (LC) isolated from organs of adult individuals express surface major histocompatibility complex (MHC) class II antigens, DC lines generated from fetal murine skin, while capable of activating naive, allogeneic CD8+ T cells in a MHC class I-restricted fashion, do not exhibit anti-MHC class II surface reactivity and fail to stimulate the proliferation of naive, allogeneic CD4+ T cells. To test whether the CD45+ MHC class I+ CD80+ DC line 80/1 expresses incompetent, or fails to transcribe, MHC class II molecules, we performed biochemical and molecular studies using Western blot and polymerase chain reaction analysis. We found that 80/1 DC express MHC class II molecules neither at the protein nor at the transcriptional level. Ultrastructural examination of these cells revealed the presence of a LC-like morphology with indented nuclei, active cytoplasm, intermediate filaments and dendritic processes. In contrast to adult LC, no LC-specific cytoplasmic organelles (Birbeck granules) were present. Functionally, 80/1 DC in the presence, but not in the absence, of concanavalin A and anti-T-cell receptor monoclonal antibodies stimulated a vigorous proliferative response of naive CD4+ and CD8+ T cells. Furthermore, we found that the anti-CD3-induced stimulation of naive CD4+ and CD8+ T cells was critically dependent on the expression of FcγR on 80/1 DC and that the requirement for co-stimulation depends on the intensity of T-cell receptor signalling. [ABSTRACT FROM AUTHOR]

Discusses abstracts of research articles on urticaria angioedema and related disorders, published as of April 1999. History of urticaria and angioedema; Quality of life of patients with urticaria; Contact urticaria; Urticaria without rash; Solar urticaria; Exercise-induced urticaria and anaphylaxis; Histamine-releasing fators in chronic urticaria.

Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFβ. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and in situ hybridization. However, the vital role of IL11 as a driver for fibrosis was not recapitulated. While induction of IL11 secretion was observed downstream of TGFβ signaling in human lung fibroblasts and epithelial cells, the cellular responses induced by IL11 was quantitatively and qualitatively inferior to that of TGFβ at the transcriptional and translational levels. IL11 blocking antibodies inhibited IL11Rα-proximal STAT3 activation but failed to block TGFβ-induced profibrotic signals. In summary, our results challenge the concept of IL11 blockade as a strategy for providing transformative treatment for fibrosis., Competing Interests: Authors YT, KM, QZ, SO’B, MC, SP, SWi, SC, JW, MA, HA-S, DB, AC, KO, BD, BH, JM, CN, DW, CT, AB, FD, VM-T, XL, GS, MW, SA, HK, SWe, LP, TC, LR-B, RSi, KW, LR, BS, YH, LH, AM, WS, IC, SG, GV, CH, TR, RSa, and EF are employees of the company AbbVie. JX, JK, and ML were employees of AbbVie at the time of the study. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tan, Mosallanejad, Zhang, O’Brien, Clements, Perper, Wilson, Chaulagain, Wang, Abdalla, Al-Saidi, Butt, Clabbers, Ofori, Dillon, Harvey, Memmott, Negron, Winarta, Tan, Biswas, Dong, Morales-Tirado, Lu, Singh, White, Ashley, Knight, Westmoreland, Phillips, Carr, Reinke-Breen, Singh, Xu, Wu, Rinaldi, Stoll, He, Hazelwood, Karman, McCluskey, Stine, Correia, Gauld, Levesque, Veldman, Hubeau, Radstake, Sadhukhan and Fiebiger.)

The immune system interacts with many nominal 'danger' signals, endogenous danger-associated (DAMP), exogenous pathogen (PAMP) and allergen (AAMP)-associated molecular patterns. The immune context under which these are received can promote or prevent immune activating or inflammatory mechanisms and may orchestrate diverse immune responses in allergy and cancer. Each can act either by favouring a respective pathology or by supporting the immune response to confer protective effects, depending on acuity or chronicity. In this Position Paper under the collective term danger signals or DAMPs, PAMPs and AAMPs, we consider their diverse roles in allergy and cancer and the connection between these in AllergoOncology. We focus on their interactions with different immune cells of the innate and adaptive immune system and how these promote immune responses with juxtaposing clinical outcomes in allergy and cancer. While danger signals present potential targets to overcome inflammatory responses in allergy, these may be reconsidered in relation to a history of allergy, chronic inflammation and autoimmunity linked to the risk of developing cancer, and with regard to clinical responses to anti-cancer immune and targeted therapies. Cross-disciplinary insights in AllergoOncology derived from dissecting clinical phenotypes of common danger signal pathways may improve allergy and cancer clinical outcomes., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background & Aims: Diligent side-by-side comparisons of how different methodologies affect growth efficiency and quality of intestinal colonoids have not been performed leaving a gap in our current knowledge. Here, we summarize our efforts to optimize culture conditions for improved growth and functional differentiation of mouse and human colon organoids., Methods: Mouse and human colon organoids were grown in four different media. Media-dependent long-term growth was measured by quantifying surviving organoids via imaging and a cell viability readout over five passages. The impact of diverse media on differentiation was assessed by quantifying the number of epithelial cell types using markers for enterocytes, stem cells, Goblet cells, and enteroendocrine cells by qPCR and histology upon removal of growth factors., Results: In contrast to Wnt3a-conditioned media, media supplemented with recombinant Wnt3a alone did not support long-term survival of human or mouse colon organoids. Mechanistically, this observation can be attributed to the fact that recombinant Wnt3a did not support stem cell survival or proliferation as demonstrated by decreased LGR5 and Ki67 expression. When monitoring expression of markers for epithelial cell types, the highest level of organoid differentiation was observed after combined removal of Wnt3a, Noggin, and R-spondin from Wnta3a-conditioned media cultures., Conclusion: Our study defined Wnt3a-containing conditioned media as optimal for growth and survival of human and mouse organoids. Furthermore, we established that the combined removal of Wnt3a, Noggin, and R-spondin results in optimal differentiation. This study provides a step forward in optimizing conditions for intestinal organoid growth to improve standardization and reproducibility of this model platform., Competing Interests: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication., (Copyright © 2021 Wilson, Mayo, Melim, Knight, Patnaude, Wu, Phillips, Westmoreland, Dunstan, Fiebiger and Terrillon.)

IgG immune complexes (ICs) promote autoimmunity through binding fragment crystallizable (Fc) γ-receptors (FcγRs). Of these, the highly prevalent FcγRIIa (CD32a) histidine (H)-131 variant (CD32aH) is strongly linked to human autoimmune diseases through unclear mechanisms. We show that, relative to the CD32a arginine (R)-131 (CD32aR) variant, CD32aH more avidly bound human (h) IgG1 IC and formed a ternary complex with the neonatal Fc receptor (FcRn) under acidic conditions. In primary human and mouse cells, both CD32a variants required FcRn to induce innate and adaptive immune responses to hIgG1 ICs, which were augmented in the setting of CD32aH. Conversely, FcRn induced responses to IgG IC independently of classical FcγR, but optimal responses required FcRn and FcγR. Finally, FcRn blockade decreased inflammation in a rheumatoid arthritis model without reducing circulating autoantibody levels, providing support for FcRn's direct role in IgG IC-associated inflammation. Thus, CD32a and FcRn coregulate IgG IC-mediated immunity in a manner favoring the CD32aH variant, providing a novel mechanism for its disease association., Competing Interests: Disclosures: J.J. Hubbard reported a patent to US2019/017880 pending. M. Pyzik reported a patent to PCT/US2019/017880 pending, "Brigham and Women's Hospital." T. Rath reported a patent to 61/984,652 licensed and a patent to 61/909,229 licensed. A.K. Gandhi reported a patent for therapeutic FcRn-based bispecific monoclonal antibodies pending (PCT/US2019/107880). D.C. Roopenian reported a patent to US20190135915A1 licensed, "Alexion Pharmaceuticals"; and served as consultant with equity interests in Syntimmune Inc., a company developing therapeutic agents to target FcRn. Syntimmune is now a wholly owned subsidiary of Alexion Pharmaceuticals, Inc., following its acquisition by Alexion in November 2018. I. Sandlie has served as a consultant with equity interests in Syntimmune Inc., a company developing therapeutic agents to target FcRn. Syntimmune is now a wholly owned subsidiary of Alexion Pharmaceuticals, Inc., following its acquisition by Alexion in November 2018. K. Baker reported a patent to 61/984,652 issued and a patent to 61/909,229 issued. R.S. Blumberg served as consultant with equity interests in Syntimmune Inc., a company developing therapeutic agents to target FcRn. Syntimmune is now a wholly owned subsidiary of Alexion Pharmaceuticals, Inc., following its acquisition by Alexion in November 2018. In addition, R.S. Blumberg has a pending patent PCT/US2019/017880 to “BWH" and two patents licensed to "Alexion" (US2017/002073 and US2017/0045528). No other disclosures were reported., (© 2020 Hubbard et al.)