IgG Subclass-Dependent Pulmonary Antigen Retention during Acute IgG-Dependent Systemic Anaphylaxis in Mice.

Mouse models of active systemic anaphylaxis rely predominantly on IgG Abs forming IgG-allergen immune complexes that induce IgG receptor-expressing neutrophils and monocytes/macrophages to release potent mediators, leading to systemic effects. Whether anaphylaxis initiates locally or systemically remains unknown. In this study, we aimed at identifying the anatomical location of IgG-allergen immune complexes during anaphylaxis. Active systemic anaphylaxis was induced following immunization with BSA and i.v. challenge with fluorescently labeled BSA. Ag retention across different organs was examined using whole-body fluorescence imaging, comparing immunized and naive animals. Various mouse models and in vivo deletion strategies were employed to determine the contribution of IgG receptors, complement component C1q, myeloid cell types, and anaphylaxis mediators. We found that following challenge, Ag diffused systemically, but specifically accumulated in the lungs of mice sensitized to that Ag, where it formed large Ab-dependent aggregates in the vasculature. Ag retention in the lungs did not rely on IgG receptors, C1q, neutrophils, or macrophages. IgG2a-mediated, but neither IgG1- nor IgG2b-mediated, passive systemic anaphylaxis led to Ag retention in the lung. Neutrophils and monocytes significantly accumulated in the lungs after challenge and captured high amounts of Ag, which led to downmodulation of surface IgG receptors and triggered their activation. Thus, within minutes of systemic injection in sensitized mice, Ag formed aggregates in the lung and liver vasculature, but accumulated specifically and dose-dependently in the lung. Neutrophils and monocytes recruited to the lung captured Ag and became activated. However, Ag aggregation in the lung vasculature was not necessary for anaphylaxis induction.

Pharmacological approaches to target type 2 cytokines in asthma.

Asthma is the most common chronic lung disease, affecting more than 250 million people worldwide. The heterogeneity of asthma phenotypes represents a challenge for adequate assessment and treatment of the disease. However, approximately 50% of asthma patients present with chronic type 2 inflammation initiated by alarmins, such as IL-33 and thymic stromal lymphopoietin (TSLP), and driven by the TH2 interleukins IL-4, IL-5 and IL-13. These cytokines have therefore become important therapeutic targets in asthma. Here, we discuss current knowledge on the structure and functions of these cytokines in asthma. We review preclinical and clinical data obtained with monoclonal antibodies (mAbs) targeting these cytokines or their receptors, as well as novel strategies under development, including bispecific mAbs, designed ankyrin repeat proteins (DARPins), small molecule inhibitors and vaccines targeting type 2 cytokines.

Comment on "Tumor-initiating cells establish an IL-33-TGF-ß niche signaling loop to promote cancer progression".

Taniguchi et al (Research Articles, 17 July 2020, p. 269) claim that the cytokine interleukin-33 induces accumulation of tumor-associated macrophages expressing the immunoglobulin E receptor FcεRI. Although these findings hold great therapeutic promise, we provide evidence that the anti-FcεRI antibody used in this study is not specific for FcεRI on macrophages, which raises concerns about the validity of some of the conclusions.

Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome.

Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as "cryopyrin-associated periodic syndromes" (CAPS). Treatment of CAPS patients with IL-1-targeted therapies is effective, confirming a central pathogenic role for IL-1ß. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1ß production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1ß. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology.

Dual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice.

Allergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus hypersecretion and eosinophilia. Approved therapeutic monoclonal antibodies targeting IgE or IL-4/IL-13 reduce asthma symptoms but require costly lifelong administrations. Here, we develop conjugate vaccines against mouse IL-4 and IL-13, and demonstrate their prophylactic and therapeutic efficacy in reducing IgE levels, AHR, eosinophilia and mucus production in mouse models of asthma analyzed up to 15 weeks after initial vaccination. More importantly, we also test similar vaccines specific for human IL-4/IL-13 in mice expressing human IL-4/IL-13 and the related receptor, IL-4Rα, to find efficient neutralization of both cytokines and reduced IgE levels for at least 11 weeks post-vaccination. Our results imply that dual IL-4/IL-13 vaccination may represent a cost-effective, long-term therapeutic strategy for the treatment of allergic asthma as demonstrated in mouse models, although additional studies are warranted to assess its safety and feasibility.

Approaches to target IgE antibodies in allergic diseases.

IgE is the antibody isotype found at the lowest concentration in the circulation. However IgE can undeniably play an important role in mediating allergic reactions; best exemplified by the clinical benefits of anti-IgE monoclonal antibody (omalizumab) therapy for some allergic diseases. This review will describe our current understanding of the interactions between IgE and its main receptors FcεRI and CD23 (FcεRII). We will review the known and potential functions of IgE in health and disease: in particular, its detrimental roles in allergic diseases and chronic spontaneous urticaria, and its protective functions in host defense against parasites and venoms. Finally, we will present an overview of the drugs that are in clinical development or have therapeutic potential for IgE-mediated allergic diseases.