Allergen-Specific Antibodies Regulate Secondary Allergen-Specific Immune Responses

Immunoglobulin E (IgE)-associated allergy is the most common immunologically-mediated hypersensensitivity disease. It is based on the production of IgE antibodies and T cell responses against per se innocuous antigens (i.e., allergens) and subsequent allergen-induced inflammation in genetically pre-disposed individuals. While allergen exposure in sensitized subjects mainly boosts IgE production and T cell activation, successful allergen-specific immunotherapy (AIT) induces the production of allergen-specific IgG antibodies and reduces T cell activity. Under both circumstances, the resulting allergen-antibody complexes play a major role in modulating secondary allergen-specific immune responses: Allergen-IgE complexes induce mast cell and basophil activation and perpetuate allergen-specific T cell responses via presentation of allergen by allergen presenting cells to T cells, a process called IgE-facilitated antigen presentation (FAP). In addition, they may induce activation of IgE memory B cells. Allergen-induced production of specific IgGs usually exerts ameliorating effects but under certain circumstances may also contribute to exacerbation. Allergen-specific IgG antibodies induced by AIT which compete with IgE for allergen binding (i.e., blocking IgG) inhibit formation of IgE-allergen complexes and reduce activation of effector cells, B cells and indirectly T cells as FAP is prevented. Experimental data provide evidence that by binding of allergen-specific IgG to epitopes different from those recognized by IgE, allergen-specific IgG may enhance IgE-mediated activation of mast cells, basophils and allergen-specific IgE+ B cells. In this review we provide an overview about the role of allergen-specific antibodies in regulating secondary allergen-specific immune responses

Characterisation of factors controlling CD23-mediated IgE facilitated allergen presentation

CD23, der niedrigaffine IgE Rezeptor, wird hauptsächlich an der Oberfläche von B Zellen exprimiert. Die Hauptfunktion dieses Rezeptors ist die Vermittlung der IgE-erleichterten Allergenpräsentation (IgE-FAP). Dabei binden IgE-Antigen-Komplexe an CD23 und werden von der Zelle aufgenommen. Diese Komplexe werden in den Endosomen prozessiert und mit Allergen-Peptiden beladene MHC II Moleküle werden an die Zelloberfläche gebracht. Diese können von spezifischen T Zellen erkannt werden. In weiterer Folge induziert IgE-FAP die Aktivierung von spezifischen T Zellen, die zur Sekretion von entzündungsfördernden Zytokinen führt und zur Aufrechterhaltung einer anhaltenden Immunantwort beiträgt. CD23-vermittelte FAP ist sehr empfindlich: 100-1000-fach geringere Allergenkonzentrationen komplexiert mit spezifischem IgE sind im Vergleich zur Flüssigphasen-Endozytose ausreichend, um eine spezifische T Zell-Aktivierung zu induzieren. In Gegenwart von blockierenden Antikörpern, die durch Immuntherapie induziert werden können, kann IgE-FAP blockiert werden. Dies unterstreicht die Relevanz von CD23-vermitteltem IgE-FAP in allergischen Reaktionen in vivo. Über die Regulation von IgE-FAP ist jedoch wenig bekannt. Auf der einen Seite wird die CD23-Dichte auf der Oberfläche von Antigen-präsentierenden Zellen mit dem Ausmaß der Allergenaufnahme und mit der nachfolgenden spezifischen T Zell-Aktivierung assoziiert. Auf der anderen Seite beeinflusst die Diversität des IgE-Repertoires auch die Bildung von IgE-Allergen-Komplexen und die anschließende Induktion der spezifischen T Zell-Aktivierung über CD23-vermittelte IgE-FAP. In dieser Dissertation wurde durch Messung der spezifischen T Zell-Aktivierung untersucht, wie unterschiedlich zusammengesetzte IgE-Allergen-Komplexe CD23-vermittelte IgE-FAP beeinflussen. Wir verwendeten ein sehr genau definiertes zelluläres und molekulares Modell, um zu verstehen, wie nicht kreuzvernetzende (spezifisches Bet v 1 IgE und Bet v 1 Monomer) und kreuzvernetzende (spezifisches Bet v 1 IgE und Bet v 1 Oligomer) Komplexe die CD23-vermittelte IgE-FAP beeinflussen. Darüber hinaus untersuchten wir auch die Rolle der CD23-Kreuzvernetzung in der Induktion der spezifischen T Zell-Proliferation in mononukleären Zellen des peripheren Bluts (PBMCs), die von Patienten mit Birkenpollenallergie stammten. Wir beobachteten, dass die Kreuzvernetzung von CD23 mit IgE-Allergen-Komplexen das Ausmaß der durch IgE-FAP vermittelten spezifischen T Zell-Aktivierung in unserem Zellmodell bestimmte. Die CD23-Kreuzvernetzung bestimmte auch die spezifische T Zell-Proliferation in PBMCs von Personen mit Birkenpollenallergie, solange B Zellen vorhanden waren. Trotzdem trat eine spezifische T Zell-Aktivierung auch in Abwesenheit einer CD23-Kreuzvernetzung auf. Dank der Verwendung eines sehr gut definierten zellulären und molekularen Modells konnten wir außerdem feststellen, dass IgE der limitierende Faktor für CD23-vermittelte IgE-FAP ist. Zusammenfassend tragen die Ergebnisse dieser Arbeit zum Verständnis des Mechanismus der CD23-vermittelten IgE-FAP hinsichtlich der Rolle der CD23-Kreuzvernetzung bei.CD23, the low affinity for IgE, is mainly expressed on the surface of B cells. The main function of this receptor is to mediate IgE-facilitated allergen presentation (IgE-FAP). In this process, IgE-allergen complexes bind to CD23 and are endocytosed. The complexes are then processed and allergen-derived peptides are displayed on MHC II, which can be recognised by specific T cells. IgE-FAP ultimately induces specific T cell activation, which triggers the secretion of pro-inflammatory cytokines, contributing to the maintenance of an ongoing immune response. CD23-mediated FAP is very effective as 100-1000 fold lower amounts of allergen complexed with specific IgE are enough to induce specific T cell activation in comparison to fluid phase endocytosis. IgE-FAP can be blocked in the presence of blocking IgG antibodies produced after immunotherapy treatment. This highlights the relevance of CD23-mediated IgE-FAP in allergic responses in vivo. However, little is known about the regulation of IgE-FAP. Regarding CD23 expression, CD23 density on the surface of antigen presenting cells determines the extent of allergen uptake and subsequent specific T cell activation. On the other hand, the diversity of the IgE repertoire also influences the formation of IgE-allergen complexes and subsequent induction of specific T cell activation via CD23-mediated IgE-FAP. The aim of this thesis was to study how differently composed IgE-allergen complexes shape CD23-mediated IgE-FAP by measuring specific T cell activation. We used a well-defined cellular and molecular model in order to understand how non-crosslinking (IgE specific for Bet v 1 and Bet v 1 monomer) and crosslinking (IgE specific for Bet v 1 and Bet v 1 oligomer) complexes influence CD23-mediated IgE-FAP. Moreover, we also assessed the role of CD23-crosslinking in inducing specific T cell proliferation in PBMCs derived from birch pollen allergic patients. We observed that CD23-crosslinking with IgE-allergen complexes determined the extent of specific T cell activation mediated by IgE-FAP in our cellular model. CD23-crosslinking also determined specific T cell proliferation in PBMCs from birch pollen allergic individuals, only when B cells were present. Nonetheless, specific T cell activation also occurred in the absence of CD23-crosslinking. Moreover, thanks to the use of a well-defined molecular and cellular model, we established that IgE was the limiting factor governing CD23-mediated IgE-FAP. In summary, the results of this thesis contribute to the understanding of the mechanism of CD23-mediated IgE-FAP with regard to the role of CD23-crosslinking.Abweichender Titel laut Übersetzung der Verfasserin/des VerfassersArbeit an der Bibliothek noch nicht eingelangt - Daten nicht geprüftMedizinische Universität Wien, Diss., 2019(VLID)493700

Producción de nuevas variedades de Saintpaulia ionantha mediante variación somaclonal

En este artículo se presenta un proyecto que describe el proceso productivo completo para generar y comercializar nuevas variedades de violeta africana (Saintpaulia ionantha ), sin utilizar transgénesis. Para ello, se utilizan distintas técnicas biotecnológicas, basadas generalmente en el cultiv

Defective LAT signalosome pathology in mice mimics human IgG4-related disease at single-cell level

Mice with a loss-of-function mutation in the LAT adaptor (LatY136F) develop an autoimmune and type 2 inflammatory disorder called defective LAT signalosome pathology (DLSP). We analyzed via single-cell omics the trajectory leading to LatY136F DLSP and the underlying CD4+ T cell diversification. T follicular helper cells, CD4+ cytotoxic T cells, activated B cells, and plasma cells were found in LatY136F spleen and lung. Such cell constellation entailed all the cell types causative of human IgG4-related disease (IgG4-RD), an autoimmune and inflammatory condition with LatY136F DLSP-like histopathological manifestations. Most previously described T cell–mediated autoimmune manifestations require persistent TCR input. In contrast, following their first engagement by self-antigens, the autoreactive TCR expressed by LatY136F CD4+ T cells hand over their central role in T cell activation to CD28 costimulatory molecules. As a result, all subsequent LatY136F DLSP manifestations, including the production of autoantibodies, solely rely on CD28 engagement. Our findings elucidate the etiology of the LatY136F DLSP and qualify it as a model of IgG4-RD

Antibody Conjugates Bispecific for Pollen Allergens and ICAM-1 with Potential to Prevent Epithelial Allergen Transmigration and Rhinovirus Infection

Allergy and rhinovirus (RV) infections are major triggers for rhinitis and asthma, causing a socioeconomic burden. As RVs and allergens may act synergistically to promote airway inflammation, simultaneous treatment strategies for both causative agents would be innovative. We have previously identified the transmembrane glycoprotein intercellular adhesion molecule 1 (ICAM-1) as an anchor for antibody conjugates bispecific for ICAM-1 and Phleum pratense (Phl p) 2, a major grass pollen allergen, to block allergen transmigration through the epithelial barrier. Since ICAM-1 is a receptor for the major group RVs, we speculated that our bispecific antibody conjugates may protect against RV infection. Therefore, we created antibody conjugates bispecific for ICAM-1 and the major grass pollen allergen Phl p 5 and analyzed their capacity to affect allergen penetration and RV infection. Bispecific antibody conjugates significantly reduced the trans-epithelial migration of Phl p 5 and thus the basolateral Phl p 5 concentration and allergenic activity as determined by humanized rat basophilic leukemia cells and inhibited RV infection of cultured epithelial cells. A reduction in allergenic activity was obtained only through the prevention of allergen transmigration because the Phl p 5-specific IgG antibody did not block the allergen–IgE interaction. Our results indicate the potential of allergen/ICAM-1-specific antibody conjugates as a topical treatment strategy for allergy and RV infections

Viral infection engenders bona fide and bystander subsets of lung-resident memory B cells through a permissive mechanism

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