Search

The cytokines interleukin (IL)-4 and IL-13, signaling via the IL-4 receptor (IL-4R), orchestrate type 2 immunity to helminth infections and toxins. Activation of epithelial and myeloid cells, and a transient neutrophils influx initiates type 2 immune responses, which are dominated by basophils, eosinophils, mast cells, B cell immunoglobulin E production, and type 2 T helper and T follicular helper cells. Interestingly, IL-4 and IL-13 can curtail chemotaxis and several effector functions of neutrophils in mice and humans. This inhibitory role of IL-4 and IL-13 probably developed to limit tissue damage by neutrophils during type 2 immunity where a “weep and sweep” response aims at expulsion and decreased fecundity, instead of killing, of macroparasites. Here, we review when IL-4R signaling cytokines appeared during evolution relative to neutrophils and adaptive immunity. Neutrophil-like granular phagocytes were present in invertebrates throughout the bilaterian clade, but we were unable to find data on IL-4, IL-13, or their receptors in invertebrates. Conversely, vertebrates had both adaptive immunity and IL-4, IL-13, and IL-4Rs, suggesting that type 2 cytokines evolved together with adaptive immunity. Further studies are necessary to determine whether IL-4R signaling in neutrophils was established simultaneously with the appearance of adaptive immunity or later.

Background: Biological agents (also termed biologics or biologicals) play a growingly central role in the treatment of immunological diseases. However, the numerous studies published on biologics complicate the decision on the most appropriate biologic for a given disease. We aim to address this problem by publishing a series of systematic reviews evaluating the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. This article assesses the safety and efficacy of atacicept, a recombinant fusion protein consisting of the binding portion of transmembrane activator and CAML interactor (TACI; also known as tumor necrosis factor receptor superfamily member 13B), which is able to bind the cytokines B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Objective: To evaluate atacicept's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment or other biologics. Methods: The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 26 July 2018 concentrating on immune-mediated disorders. Results: The literature search identified 118 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, ten articles were finally included in a narrative synthesis. Conclusions: Atacicept failed to show an effect in multiple sclerosis, optic neuritis, rheumatoid arthritis, and systemic lupus erythematosus. In patients with systemic lupus erythematosus, atacicept led to increased infection rates, but this adverse effect was not seen in the other treated diseases.

The outbreak of the SARS‐CoV‐2‐induced coronavirus disease 2019 (COVID‐19) pandemic re‐shaped doctor‐patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant number of the patients are on treatment with biologicals, and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS‐CoV‐2 is not known. Severe COVID‐19 patients may experience a “cytokine storm” and associated organ damage characterized by an exaggerated release of pro‐inflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti‐inflammatory cytokines and type 2 responses. This expert‐based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID‐19. Studies focusing on severe allergic phenotypes are lacking. At present, noninfected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self‐application. In case of an active SARS‐CoV‐2 infection, biological treatment needs to be stopped until clinical recovery and SARS‐CoV‐2 negativity is established and treatment with biologicals should be re‐initiated. Maintenance of add‐on therapy and a constant assessment of disease control, apart from acute management, are demanded.

Regulatory T cells (Tregs) represent a major population in the control of immune homeostasis and autoimmunity. Here we show that Fos-like 2 (Fosl2), a TCR-induced AP1 transcription factor, represses Treg development and controls autoimmunity. Mice overexpressing Fosl2 (Fosl2$^{tg}$) indeed show a systemic inflammatory phenotype, with immune infiltrates in multiple organs. This phenotype is absent in Fosl2$^{tg}$ × Rag2$^{-/-}$ mice lacking T and B cells, and Fosl2 induces T cell-intrinsic reduction of Treg development that is responsible for the inflammatory phenotype. Fosl2$^{tg}$ T cells can transfer inflammation, which is suppressed by the co-delivery of Tregs, while Fosl2 deficiency in T cells reduces the severity of autoimmunity in the EAE model. We find that Fosl2 could affect expression of FoxP3 and other Treg development genes. Our data highlight the importance of AP1 transcription factors, in particular Fosl2, during T cell development to determine Treg differentiation and control autoimmunity.

Tumor-infiltrating dendritic cells (DCs) correlate with effective anticancer immunity and improved responsiveness to anti-PD-1 checkpoint immunotherapy. However, the drivers of DC expansion and intratumoral accumulation are ill-defined. We found that interleukin-2 (IL-2) stimulated DC formation through innate and adaptive lymphoid cells in mice and humans, and this increase in DCs improved anticancer immunity. Administration of IL-2 to humans within a clinical trial and of IL-2 receptor (IL-2R)-biased IL-2 to mice resulted in pronounced expansion of type 1 DCs, including migratory and cross-presenting subsets, and type 2 DCs, although neither DC precursors nor mature DCs had functional IL-2Rs. In mechanistic studies, IL-2 signals stimulated innate lymphoid cells, natural killer cells, and T cells to synthesize the cytokines FLT3L, CSF-2, and TNF. These cytokines redundantly caused DC expansion and activation, which resulted in improved antigen processing and correlated with favorable anticancer responses in mice and patients. Thus, IL-2 immunotherapy-mediated stimulation of DCs contributes to anticancer immunity by rendering tumors more immunogenic.

Tumour immunotherapy, and particularly immue checkpoint inhibitors, have resulted in considerable response rates in patients with metastatic cancer. However, most of these approaches are limited to immunogenic tumours. Based on its ability to stimulate cytotoxic T cells, interleukin-2 (IL-2) has been used to treat patients with metastatic melanoma and metastatic kidney cancer. Clinical efficacy achieved through high doses is countered by severe adverse effects on vascular endothelial cells and various organs, a short in vivo half-life, and the stimulation of regulatory T cells that counteract antitumour immune responses. Accumulating evidence suggests that IL-2 receptor β (CD122)-biased IL-2 formulations address the shortcomings of IL-2 cancer immunotherapy. This knowledge stems from studies using CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2 complexes), which preferentially stimulate CD8+ T cells, while interaction with regulatory T cells and vascular endothelial cells is disfavoured by the anti-IL-2 antibody used. CD122-biased IL-2 complexes, when assessed in different mouse cancer models, cause stronger antitumour effects and significantly less adverse effects than high-dose IL-2. A recently developed and characterised anti-human IL-2 antibody, termed NARA1, forms human CD122-biased IL-2 complexes. Alternative strategies based on this concept, such as site-directed pegylation and mutation of IL-2, have also been pursued. Moreover, recent data have shown that a combination of CD122-biased IL-2 formulations with immune checkpoint inhibitors, antigen-specific immunotherapy and epigenetic modifying drugs results in synergistic anti-cancer effects in various tumour models. Thus, CD122-biased IL-2 approaches constitute a novel class of immunotherapy for metastatic cancer that has the potential to complement and increase the efficacy of other antitumour strategies.

Interleukin-4 (IL-4) receptor (IL-4R) signaling plays a pivotal role in type 2 immune responses. Type 2 immunity ensures several host-protective processes such as defense against helminth parasites and wound repair, however, type 2 immune responses also drive the pathogenesis of allergic diseases. Neutrophil granulocytes (neutrophils) have not traditionally been considered a part of type 2 immunity. While neutrophils might be beneficial in initiating a type 2 immune response, their involvement and activation is rather unwanted at later stages. This is evidenced by examples of type 2 immune responses where increased neutrophil responses are able to enhance immunity, however, at the cost of increased tissue damage. Recent studies have linked the type 2 cytokines IL-4 and IL-13 and their signaling via type I and type II IL-4Rs on neutrophils to inhibition of several neutrophil effector functions. This mechanism directly curtails neutrophil chemotaxis toward potent intermediary chemoattractants, inhibits the formation of neutrophil extracellular traps, and antagonizes the effects of granulocyte colony-stimulating factor on neutrophils. These effects are observed in both mouse and human neutrophils. Thus, we propose for type 2 immune responses that neutrophils are, as in other immune responses, the first non-resident cells to arrive at a site of inflammation or infection, thereby guiding and attracting other innate and adaptive immune cells; however, as soon as the type 2 cytokines IL-4 and IL-13 predominate, neutrophil recruitment, chemotaxis, and effector functions are rapidly shut off by IL-4/IL-13-mediated IL-4R signaling in neutrophils to prevent them from damaging healthy tissues. Insight into this neutrophil checkpoint pathway will help understand regulation of neutrophilic type 2 inflammation and guide the design of targeted therapeutic approaches for modulating neutrophils during inflammation and neutropenia.

Background: During the past years biologic agents (also termed biologicals or biologics) have become a crucial treatment option in immunological diseases. Numerous articles have been published on biologicals, which complicates the decision making process on the use of the most appropriate biologic for a given immune-mediated disease. This systematic review is the first of a series of articles assessing the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. Objective: To evaluate rituximab's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment, or other biologics. Methods: The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 26 July 2018 concentrating on immune-mediated disorders. Results: The literature search identified 19,665 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 105 articles were finally included in a narrative synthesis. Conclusions: Rituximab is both safe and effective for the treatment of acquired angioedema with C1-inhibitor deficiency, ANCA-associated vasculitis, autoimmune hemolytic anemia, Behçet's disease, bullous pemphigoid, Castleman's disease, cryoglobulinemia, Goodpasture's disease, IgG4-related disease, immune thrombocytopenia, juvenile idiopathic arthritis, relapsing-remitting multiple sclerosis, myasthenia gravis, nephrotic syndrome, neuromyelitis optica, pemphigus, rheumatoid arthritis, spondyloarthropathy, and systemic sclerosis. Conversely, rituximab failed to show an effect for antiphospholipid syndrome, autoimmune hepatitis, IgA nephropathy, inflammatory myositis, primary-progressive multiple sclerosis, systemic lupus erythematosus, and ulcerative colitis. Finally, mixed results were reported for membranous nephropathy, primary Sjögren's syndrome and Graves' disease, therefore warranting better quality