Search

Plasmacytoid dendritic cells (pDC) is a unique cell population that produces large amounts of type I interferon upon recognition of nucleic acids placing them at the crossroad of both innate and adaptive immunity. Their ability to produce interferon makes them central to anti-viral responses. They are also responsive to circulating autoantibodies bound to nuclear antigens and in that scenario the release of interferons initiate self-directed immune responses. There are now a growing number of autoimmune disorders where unabated activation of pDC is suspected to be pathogenic. Here, we discuss the different mechanisms responsible for breaking tolerance to self-nucleic acids by pDC, including the novel role of IgE autoantibodies in systemic lupus erythematosus. We also summarized the recent progress on therapies undergoing clinical testing that target either pDC or type I interferons. [ABSTRACT FROM AUTHOR]

There is accumulating evidence to suggest that IgE plays a significant role in autoimmunity. The presence of circulating self-reactive IgE in patients with autoimmune disorders has been long known but, at the same time, largely understudied. However, studies have shown that the increased IgE concentration is not associated with higher prevalence for atopy and allergy in patients with autoimmune diseases, such as systemic lupus erythematosus. IgE-mediated mechanisms are conventionally known to facilitate degranulation of mast cells and basophils and promote T H 2 immunity, mechanisms that are not only central to mounting an appropriate defense against parasitic worms, noxious substances, toxins, venoms, and environmental irritants but that also trigger exuberant allergic reactions in patients with allergies. More recently, IgE autoantibodies have been recognized to participate in the self-inflicted damaging immune responses that characterize autoimmunity. Such autoimmune responses include direct damage on tissue-containing autoantigens, activation and migration of basophils to lymph nodes, and, as observed most recently, induction of type 1 interferon responses from plasmacytoid dendritic cells. The importance of IgE as a central pathogenic mechanism in autoimmunity has now been clinically validated by the approval of omalizumab, an anti-IgE mAb, for patients with chronic spontaneous urticaria and for the clinical benefit of patients with bullous pemphigoid. In this review we summarize recent reports describing the prevalence of self-reactive IgE and discuss novel findings that incriminate IgE as central in the pathogenesis of inflammatory autoimmune disorders. [ABSTRACT FROM AUTHOR]

Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders. [Copyright &y& Elsevier]

Background: Many asthmatic patients exhibit sputum eosinophilia associated with exacerbations. Benralizumab targets eosinophils by binding IL-5 receptor ?, inducing apoptosis through antibody-dependent cell-mediated cytotoxicity. Objectives: We sought to evaluate the safety of benralizumab in adults with eosinophilic asthma and its effects on eosinophil counts in airway mucosal/submucosal biopsy specimens, sputum, bone marrow, and peripheral blood. Methods: In this multicenter, double-blind, placebo-controlled phase I study, 13 subjects were randomized to single-dose intravenous placebo or 1 mg/kg benralizumab (day 0; cohort 1), and 14 subjects were randomized to 3 monthly subcutaneous doses of placebo or 100 or 200 mg of benralizumab (days 0, 28, and 56; cohort 2). Cohorts 1 and 2 were consecutive. Results: The incidence of adverse events was similar between groups. No serious adverse events related to benralizumab occurred. In cohort 1 intravenous benralizumab produced a median decrease from baseline of 61.9% in airway mucosal eosinophil counts (day 28; placebo: +19.6%; P = .28), as well as an 18.7% decrease (day 21) in sputum and a 100% decrease (day 28) in blood counts. Eosinophils were not detectable in bone marrow of benralizumab-treated subjects (day 28, n = 4). In cohort 2 subcutaneous benralizumab demonstrated a combined (100 + 200 mg) median reduction of 95.8% in airway eosinophil counts (day 84; placebo, 46.7%; P = .06), as well as an 89.9% decrease (day 28) in sputum and a 100% decrease (day 84) in blood counts. Conclusion: Single-dose intravenous and multiple-dose subcutaneous benralizumab reduced eosinophil counts in airway mucosa/submucosa and sputum and suppressed eosinophil counts in bone marrow and peripheral blood. The safety profile supports further development. Additional studies are needed to assess the clinical benefit in asthmatic patients. [Copyright &y& Elsevier]

Background: Allergen exposure at lung and gut mucosae can lead to aberrant TH2 immunity and allergic disease. The epithelium-associated cytokines thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 are suggested to be important for the initiation of these responses. Objective: We sought to investigate the contributions of TSLP, IL-25, and IL-33 in the development of allergic disease to the common allergens house dust mite (HDM) or peanut. Methods: Neutralizing antibodies or mice deficient in TSLP, IL-25, or IL-33 signaling were exposed to HDM intranasally or peanut intragastrically, and immune inflammatory and physiologic responses were evaluated. In vitro assays were performed to examine specific dendritic cell (DC) functions. Results: We showed that experimental HDM-induced allergic asthma and food allergy and anaphylaxis to peanut were associated with TSLP production but developed independently of TSLP, likely because these allergens functionally mimicked TSLP inhibition of IL-12 production and induction of OX40 ligand (OX40L) on DCs. Blockade of OX40L significantly lessened allergic responses to HDM or peanut. Although IL-25 and IL-33 induced OX40L on DCs in vitro, only IL-33 signaling was necessary for intact allergic immunity, likely because of its superior ability to induce DC OX40L and expand innate lymphoid cells in vivo. Conclusion: These data identify a nonredundant, IL-33–driven mechanism initiating TH2 responses to the clinically relevant allergens HDM and peanut. Our findings, along with those in infectious and transgenic/surrogate allergen systems, favor a paradigm whereby multiple molecular pathways can initiate TH2 immunity, which has implications for the conceptualization and manipulation of these responses in health and disease. [ABSTRACT FROM AUTHOR]

Background: IL-5 plays a central role in the development and maintenance of eosinophilia (EO) and eosinophil activation in a wide variety of eosinophilic disorders. Although IL-5, IL-3, and GM-CSF can modulate the expression of IL-5 receptor α (IL-5Rα) on eosinophils in vitro, little is known about soluble and surface IL-5Rα levels in vivo. Objective: To assess soluble and surface IL-5Rα levels in patients with EO and/or mastocytosis. Methods: Surface IL-5Rα expression was assessed by flow cytometry in blood and/or bone marrow from subjects with EO (n = 39) and systemic mastocytosis (n = 8) and from normal volunteers (n = 28). Soluble IL-5Rα (sIL-5Rα) level was measured in a cohort of 177 untreated subjects and correlated with EO, eosinophil activation, and serum tryptase and cytokine levels. Results: IL-5Rα expression on eosinophils inversely correlated with EO (r = −0.48; P < .0001), whereas serum levels of sIL-5Rα increased with the eosinophil count (r = 0.56; P < .0001) and serum IL-5 (r = 0.40; P < .0001) and IL-13 (r = 0.29; P = .004) levels. Of interest, sIL-5Rα level was significantly elevated in patients with systemic mastocytosis without EO. Although sIL-5Rα levels correlated with serum tryptase levels in these patients, eosinophil activation, assessed by CD69 expression on eosinophils and serum eosinophil-derived neurotoxin levels, was increased compared with that in normal subjects. Conclusions: These data are consistent with an in vivo IL-5Rα regulatory pathway in human eosinophils similar to that described in vitro and involving a balance between soluble and surface receptor levels. This may have implications with respect to the use of novel therapeutic agents targeting IL-5 and its receptor in patients with EO and/or mastocytosis. [ABSTRACT FROM AUTHOR]

Background: Peripheral blood eosinophilia and lung mucosal eosinophil infiltration are hallmarks of bronchial asthma. IL-5 is a critical cytokine for eosinophil maturation, survival, and mobilization. Attempts to target eosinophils for the treatment of asthma by means of IL-5 neutralization have only resulted in partial removal of airway eosinophils, and this warrants the development of more effective interventions to further explore the role of eosinophils in the clinical expression of asthma. Objective: We sought to develop a novel humanized anti–IL-5 receptor α (IL-5Rα) mAb with enhanced effector function (MEDI-563) that potently depletes circulating and tissue-resident eosinophils and basophils for the treatment of asthma. Methods: We used surface plasmon resonance to determine the binding affinity of MEDI-563 to FcγRIIIa. Primary human eosinophils and basophils were used to demonstrate antibody-dependent cell-mediated cytotoxicity. The binding epitope of MEDI-563 on IL-5Rα was determined by using site-directed mutagenesis. The consequences of MEDI-563 administration on peripheral blood and bone marrow eosinophil depletion was investigated in nonhuman primates. Results: MEDI-563 binds to an epitope on IL-5Rα that is in close proximity to the IL-5 binding site, and it inhibits IL-5–mediated cell proliferation. MEDI-563 potently induces antibody-dependent cell-mediated cytotoxicity of both eosinophils (half-maximal effective concentration = 0.9 pmol/L) and basophils (half-maximal effective concentration = 0.5 pmol/L) in vitro. In nonhuman primates MEDI-563 depletes blood eosinophils and eosinophil precursors in the bone marrow. Conclusions: MEDI-563 might provide a novel approach for the treatment of asthma through active antibody-dependent cell-mediated depletion of eosinophils and basophils rather than through passive removal of IL-5. [Copyright &y& Elsevier]

Background: Increased eosinophil levels have been linked to airway inflammation and asthma exacerbations. IL-5 is responsible for eosinophil differentiation, proliferation, and activation; IL-5 receptors are expressed on eosinophils and their progenitors, and targeting such receptors induces eosinophil apoptosis. Objective: To evaluate the safety profile, pharmacokinetics, and pharmacodynamics of MEDI-563, a humanized mAb targeting the IL-5 receptor α chain. Methods: Single, escalating, intravenous doses (0.0003-3 mg/kg) of MEDI-563 were administered to subjects with mild atopic asthma (n = 44) over ∼3 to 30 minutes in this open-label study. Pulmonary function, symptom scores, adverse events, MEDI-563 pharmacokinetics, and levels of C-reactive protein (CRP), IL-6, eosinophil cationic protein (ECP), and eosinophils were evaluated. Results: Mean peripheral blood (PB) eosinophil levels decreased in a dose-dependent fashion (baseline ± SD, 0.27 ± 0.2 × 103/μL; 24 hours postdose, 0.01 ± 0.0 × 103/μL); 94.0% of subjects receiving ≥0.03 mg/kg exhibited levels between 0.00 × 103/μL and 0.01 × 103/μL. Eosinopenia lasted at least 8 or 12 weeks with doses of 0.03 to 0.1 and 0.3 to 3 mg/kg, respectively. ECP levels were reduced from 21.4 ± 17.2 μg/L (baseline) to 10.3 ± 7.0 μg/L (24 hours postdose). The most frequently reported adverse events were reduced white blood cell counts (34.1%), nasopharyngitis (27.3%), and increased blood creatine phosphokinase (25.0%). Mean C-reactive protein levels increased ∼5.5-fold at 24 hours postdose but returned to baseline by study end; mean IL-6 levels increased ∼3.9-fold to 4.7-fold at 6 to 12 hours postdose, respectively. Pharmacokinetic activity was dose proportional at doses of 0.03 to 3 mg/kg. Conclusion: Single escalating doses of MEDI-563 had an acceptable safety profile and resulted in marked reduction of PB eosinophil counts within 24 hours after dosing. [Copyright &y& Elsevier]

Highlights: [•] Phagocytes fight pathogens using canonical and noncanonical autophagy pathways. [•] PRRs and FcγR trigger LAP, a noncanonical autophagy pathway. [•] LAP modulates phagosome functions such as pathogen killing and cytokine responses. [•] LAP bridges innate and adaptive immunity by promoting antigen presentation. [•] Autophagy pathways may offer new therapeutic targets for treating disease. [Copyright &y& Elsevier]

CD40 is a TNF receptor superfamily member expressed on both immune and non-immune cells. Interactions between B cell-expressed CD40 and its binding partner, CD40L, predominantly expressed on activated CD4+ T cells, play a critical role in promoting germinal center formation and the production of class-switched antibodies. Non-hematopoietic cells expressing CD40 can also engage CD40L and trigger a pro-inflammatory response. This article will highlight what is known about the biology of the CD40-CD40L axis in humans and describe the potential contribution of CD40 signaling on both hematopoietic and non-hematopoietic cells to autoimmune disease pathogenesis. Additionally, novel therapeutic approaches to target this pathway, currently being evaluated in clinical trials, are discussed. [ABSTRACT FROM AUTHOR]

Eosinophils have been linked with asthma for more than a century, but their role has been unclear. This review discusses the roles of eosinophils in asthma and chronic obstructive pulmonary disease (COPD) and describes therapeutic antibodies that affect eosinophilia. The aims of pharmacologic treatments for pulmonary conditions are to reduce symptoms, slow decline or improve lung function, and reduce the frequency and severity of exacerbations. Inhaled corticosteroids (ICS) are important in managing symptoms and exacerbations in asthma and COPD. However, control with these agents is often suboptimal, especially for patients with severe disease. Recently, new biologics that target eosinophilic inflammation, used as adjunctive therapy to corticosteroids, have proven beneficial and support a pivotal role for eosinophils in the pathology of asthma. Nucala® (mepolizumab; anti -interleukin [IL]-5) and Cinquair® (reslizumab; anti-IL-5), the second and third biologics approved, respectively, for the treatment of asthma, exemplifies these new treatment options. Emerging evidence suggests that eosinophils may contribute to exacerbations and possibly to lung function decline for a subset of patients with COPD. Here we describe the pharmacology of therapeutic antibodies inhibiting IL-5 or targeting the IL-5 receptor, as well as other cytokines contributing to eosinophilic inflammation. We discuss their roles as adjuncts to conventional therapeutic approaches, especially ICS therapy, when disease is suboptimally controlled. These agents have achieved a place in the therapeutic armamentarium for asthma and COPD and will deepen our understanding of the pathogenic role of eosinophils. [ABSTRACT FROM AUTHOR]