Background Plasmacytosis (ie, an expansion of plasma cell populations to much greater than the homeostatic level) occurs in the context of various immune disorders and plasma cell neoplasia. This ...condition is often associated with immunodeficiency that causes increased susceptibility to severe infections. Yet a causative link between plasmacytosis and immunodeficiency has not been established. Objective Because recent studies have identified plasma cells as a relevant source of the immunosuppressive cytokine IL-10, we sought to investigate the role of IL-10 during conditions of polyclonal and neoplastic plasmacytosis for the regulation of immunity and its effect on inflammation and immunodeficiency. Methods We used flow cytometry, IL-10 reporter (Vert-X) and B cell–specific IL-10 knockout mice, migration assays, and antibody-mediated IL-10 receptor blockade to study plasmacytosis-associated IL-10 expression and its effect on inflammation and Streptococcus pneumoniae infection in mice. ELISA was used to quantify IL-10 levels in patients with myeloma. Results IL-10 production was a common feature of normal and neoplastic plasma cells in mice, and IL-10 levels increased with myeloma progression in patients. IL-10 directly inhibited neutrophil migration toward the anaphylatoxin C5a and suppressed neutrophil-dependent inflammation in a murine model of autoimmune disease. MOPC.315.BM murine myeloma leads to an increased incidence of bacterial infection in the airways, which was reversed after IL-10 receptor blockade. Conclusion We provide evidence that plasmacytosis-associated overexpression of IL-10 inhibits neutrophil migration and neutrophil-mediated inflammation but also promotes immunodeficiency.
•Reduced neutralizing antibody levels after influenza vaccination during pregnancy.•Declining protective responses with immunization initiated later during pregnancy.•Vaccine primed IgG1, IgG2, and ...IgG3 antibodies decline with pregnancy progression.
Influenza immunization is universally recommended during pregnancy to protect mothers and their offspring. However, pregnancy-induced shifts in vaccine responsiveness remain poorly defined.
Quantitative and qualitative shifts in the serological response to influenza vaccination were evaluated in healthy women throughout the course of pregnancy. Serum was obtained before and after vaccination among 71 pregnant and 67 non-pregnant women during the 2011–12 and 2012–13 influenza seasons. Serum hemagglutination inhibition (HAI) assay was used to investigate anti-influenza antibody responses by comparing pre-vaccine and post-vaccine geometric mean titers (GMTs) between groups for each antigen. IgG1, IgG2, IgG3, and IgG4 anti-influenza titers were also evaluated by enzyme-linked immunosorbent assay (ELISA). Pregnancy induced shifts in HAI titers and levels of each anti-influenza antibody isotype were evaluated using linear regression models.
Post-vaccine GMTs at day 28 were significantly reduced for women vaccinated during pregnancy for A/California (H1N1) in 2011 (p = 0.027), A/Perth (H3N2) in 2011 (p = 0.037), and B/Wisconsin in 2012 (p = 0.039). Vaccine responses progressively declined with the initiation of vaccination later in pregnancy. Anti-H1N1 IgG1, IgG2, and IgG3 titers were reduced in pregnant women compared to non-pregnant controls, and these titers declined with pregnancy progression. The most striking differences were found for anti-H1N1 IgG1, where titers decreased by approximately 7% each week throughout pregnancy.
HAI responses elicited by immunization were significantly reduced during pregnancy for three different influenza vaccine antigens. Anti-H1N1 IgG1 was significantly lower in pregnant women and decreased throughout the course of pregnancy. Waning serological responsiveness to influenza vaccination with the progression of human pregnancy has important translational implications for when immunization should be optimally administered during pregnancy.
Unfortunately, even this relatively low dose was associated with unacceptable toxicity (cardiac arrhythmias, abnormal liver function, and a flu-like syndrome, which were not evaluated in the ...published mouse studies).25 Consequently, the question of whether higher-dose IL-12 might suppress human asthma became moot.\nAHR to cholinergic stimuli g.Rapid and delayed development of increased airway resistance.5 2.Both human asthma and mouse models show memory responses.10 3.Some mouse models have chronic "remodeling" with smooth muscle hyperplasia and subepithelial fibrosis.14 4.Both human asthma and at least some mouse models are suppressed to some degree by leukotriene antagonists and leukotriene receptor antagonists, mast cell depletion, IgE antagonists, phosphodiesterase 4 antagonists, and corticosteroids.1 5.Intraspecies genetic variability influences susceptibility to allergic airway disease in both mice and human subjects.5 Table II Similarities of mouse models to human asthma 1.Asthma does not spontaneously develop in mice.9 2.Mice have 6-8 generations of branching airways with no gas-exchanging respiratory bronchioles, whereas human subjects have 20-23 (or 27-29) generations of airway branching with gas-exchanging respiratory bronchioles.1 3.Mouse airways are narrower in absolute terms but wider relative to body size than human airways.2 4.Unlike human airways, most mouse airways beyond first-generation bronchi lack smooth muscle bundles.1 5.Mouse airways, except the trachea, lack submucosal mucus glands, whereas these are abundant in human large- and medium-sized airways.1 6.Mice have a more compliant chest wall and lower functional residual capacity.3 7.The mouse lung is more fully developed than the human lung at birth.1 8.Mouse eosinophils, unlike human eosinophils, show little degranulation.5 9.Eosinophils are distributed differently in mouse models vs human asthma.6 10.Vascular and perivascular inflammation are prominent in mouse models but are missing in human asthma.1 11.Clara cells account for a greater percentage of airway epithelium in mice than in human subjects.6 12.Testing for AHR is very different in mice vs human subjects.1 13.Mice are housed under different (and generally cleaner) conditions than human subjects.2 14.Mice and human subjects respond differently to many mediators (eg, neurokinins, histamine, and leukotriene C4 can cause bronchoconstriction in human subjects but not in mice).4 15.Not all effects of TH2 cytokines are similar in mice and human subjects.1 Table III Differences between mouse models and human asthma 1.Consider known differences between mouse and human immunology, anatomy, and physiology when deciding whether studies should be performed with a mouse model. 2.Evaluate whether an agent or intervention will suppress already established allergic airway disease (therapeutic usefulness).
Intestinal worm infections characteristically induce T‐helper 2 cell (Th2) cytokine production. We reviewed studies performed with mice infected with either of two intestinal nematode parasites, ...Nippostrongylus brasiliensis or Trichinella spiralis, that evaluate the importance of the Th2 cytokine interleukin‐4 (IL‐4) and IL‐13 in protection against these parasites. These studies demonstrate that while IL‐4/IL‐13 protect against both parasites by activating signal transducer and activator of transcription 6 (Stat6) through IL‐4 receptor α (IL‐4Rα) ligation, Stat6 activation protects against these parasites through different mechanisms. Stat6‐dependent gene transcription promotes expulsion of N. brasiliensis solely through effects on non‐bone marrow‐derived cells that may include enhancement of intestinal smooth muscle contractility, changes in intestinal epithelial cell function, and increased intestinal mucus secretion. In contrast, Stat6 signaling promotes immunity to T. spiralis both through effects on bone marrow‐derived cells that can be reproduced by treating mice with IL‐4 or IL‐13 and through effects on non‐bone marrow‐derived cells. The former effects appear to include T‐cell‐dependent induction of intestinal mastocytosis, while the latter sensitize non‐bone marrow‐derived cells to mast cell‐produced mediators. We argue that a limited ability of the host immune system to distinguish among different nematode parasites has led to the evolution of a stereotyped Th2 response that activates a set of effector mechanisms that protects against most intestinal nematode parasites.
Previous mouse and clinical studies demonstrate a link between Th2 intestinal inflammation and induction of the effector phase of food allergy. However, the mechanism by which sensitization and mast ...cell responses occurs is largely unknown. We demonstrate that interleukin (IL)-9 has an important role in this process. IL-9-deficient mice fail to develop experimental oral antigen-induced intestinal anaphylaxis, and intestinal IL-9 overexpression induces an intestinal anaphylaxis phenotype (intestinal mastocytosis, intestinal permeability, and intravascular leakage). In addition, intestinal IL-9 overexpression predisposes to oral antigen sensitization, which requires mast cells and increased intestinal permeability. These observations demonstrate a central role for IL-9 and mast cells in experimental intestinal permeability in oral antigen sensitization and suggest that IL-9-mediated mast cell responses have an important role in food allergy.
ABSTRACT
Asparaginase (ASNase) is an important drug for the treatment of leukemias. However, hypersensitivity to ASNase can increase the risk of leukemia relapse. Two mechanisms of ASNase ...hypersensitivity have been identified in mice. The existence of a pathway involving anti‐ASNase IgG and Fc‐γ receptor III (FC‐γRIII) implies that IgG and ASNase immune complexes (ICs) could directly induce hypersensitivity. The aim of this study was to detect ASNase ICs in mice after hypersensitivity reactions and determine their role in hypersensitivity. Protein G beads were used to detect plasma ASNase ICs by flow cytometry. Anti‐ASNase IgG was purified from the plasma of sensitized mice, and ASNase ICs were prepared ex vivo at various ratios of ASNase to anti‐ASNase IgG. The levels of ASNase ICs detected after hypersensitivity reactions correlated with reaction severity (R2 = 0.796; P = 0.0005). ASNase ICs prepared ex vivo required high levels of anti‐ASNase IgG for formation, and binding to naive and sensitized immune cells depended on soluble anti‐ASNase IgG, antigen:antibody ratio, and FC‐γRIII. Similarly, basophil activation by ASNase ICs depended on the antigen:antibody ratio and FC‐γRIII. Consistent with the ex vivo results, naive mice receiving ASNase ICs developed hypersensitivity reactions. Our data demonstrate that ASNase ICs can directly contribute to the onset and severity of ASNase hypersensitivity.—Rathod, S., Ramsey, M., DiGiorgio, D., Berrios, R., Finkelman, F. D., Fernandez, C. A. Asparaginase immune complexes induce Fc‐γRIII‐dependent hypersensitivity in naive mice. FASEB J. 33, 10996–11005 (2019). www.fasebj.org
Allergic reactions to drugs are a serious public health concern. In 2013, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases ...sponsored a workshop on drug allergy. International experts in the field of drug allergy with backgrounds in allergy, immunology, infectious diseases, dermatology, clinical pharmacology, and pharmacogenomics discussed the current state of drug allergy research. These experts were joined by representatives from several National Institutes of Health institutes and the US Food and Drug Administration. The participants identified important advances that make new research directions feasible and made suggestions for research priorities and for development of infrastructure to advance our knowledge of the mechanisms, diagnosis, management, and prevention of drug allergy. The workshop summary and recommendations are presented herein.
Background IgE-allergen complexes induce mast cell and basophil activation and thus immediate allergic inflammation. They are also important for IgE-facilitated allergen presentation to T cells by ...antigen-presenting cells. Objective To investigate whether the proximity of IgE binding sites on an allergen affects immune complex shape and subsequent effector cell activation in vitro and in vivo. Methods We constructed artificial allergens by grafting IgE epitopes in different numbers and proximity onto a scaffold protein. The shape of immune complexes formed between artificial allergens and the corresponding IgE was studied by negative-stain electron microscopy. Allergenic activity was determined using basophil activation assays. Mice were primed with IgE, followed by injection of artificial allergens to evaluate their in vivo allergenic activity. Severity of systemic anaphylaxis was measured by changes in body temperature. Results We could demonstrate simultaneous binding of 4 IgE antibodies in close vicinity to each other. The proximity of IgE binding sites on allergens influenced the shape of the resulting immune complexes and the magnitude of effector cell activation and in vivo inflammation. Conclusions Our results demonstrate that the proximity of IgE epitopes on an allergen affects its allergenic activity. We thus identified a novel mechanism by which IgE-allergen complexes regulate allergic inflammation. This mechanism should be important for allergy and other immune complex–mediated diseases.
Transfusion-related acute lung injury (TRALI), a form of noncardiogenic pulmonary edema that develops during or within 6 h after a blood transfusion, is the most frequent cause of ...transfusion-associated death in the United States. Because development of TRALI is associated with donor antibodies (Abs) reactive with recipient major histocompatibility complex (MHC), a mouse model has been studied in which TRALI-like disease is caused by injecting mice with anti-MHC class I monoclonal Ab (mAb). Previous publications with this model have concluded that disease is caused by FcR-dependent activation of neutrophils and platelets, with production of reactive oxygen species that damage pulmonary vascular endothelium. In this study, we confirm the role of reactive oxygen species in the pathogenesis of this mouse model of TRALI and show ultrastructural evidence of pulmonary vascular injury within 5 min of anti-MHC class I mAb injection. However, we demonstrate that disease induction in this model involves macrophages rather than neutrophils or platelets, activation of complement and production of C5a rather than activation of FcγRI, FcγRIII, or FcγRIV, and binding of anti-MHC class I mAb to non-BM-derived cells such as pulmonary vascular endothelium. These observations have important implications for the prevention and treatment of TRALI.
Immunoglobulins protect against disease to a considerable extent by activating complement and stimulatory immunoglobulin crystallizable fragment receptors (Ig FcRs), and aggregating microbial ...pathogens. Yet IgG1, the predominant murine serum Ig isotype, cannot activate complement by the classical pathway, binds more avidly to an inhibitory than to stimulatory FcRs, and has limited ability to aggregate pathogens. In these regards, it resembles human IgG4 (ref. 4). We hypothesized that limited ability to activate effector mechanisms might protect against immune complex immunopathology. Here we show that IgG1-deficient (γ1(-)) mice, immunized with a potent antigen, develop lethal renal disease soon after they begin to produce antigen-specific antibody, whereas similarly immunized wild-type mice remain healthy. Surprisingly, renal disease in this model is complement and FcR independent and results from immune complex precipitation in glomerular capillaries, as in some cryoglobulinaemic humans. IgG3, which self-associates to form large immune complexes, accounts for more than 97% of the mouse Ig in this cryoglobulin; furthermore, glomerular disease develops when mice are injected with IgG3 anti-trinitrophenyl (TNP) monoclonal antibody followed by a TNP-labelled protein. Renal disease is prevented in both active and passive immunization models by antigen-specific IgG1; other isotypes are less potent at preventing disease. These observations demonstrate the adaptive significance of Ig isotypes that poorly activate effector mechanisms, reveal an immune-complex-dependent, complement- and FcR-independent nephrotoxic mechanism, and suggest that isotypes that poorly activate effector mechanisms may be useful for inhibiting immune complex immunopathology.
PDF
