Eosinophils, Mast Cells and Basophils in Allergic Disease
Hartmann, K., et al.
"Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology."
J Allergy Clin Immunol 137(1): 35-45. 2016.
WAO Committee’s reasons for recommending: In this paper it is shown that the monomorphic variant of mastocytosis cutaneous manifestatioins, if it develops in children, often persists into adulthood. This finding might have important prognosis implications.
Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma.
Picard, M., et al.
"Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions."
J Allergy Clin Immunol 137(4): 1154-1164 e1112. 2016.
WAO Committee’s reasons for recommending: The paper shows that based on the severity of HSRs and skin testing it is safe to reintroduce taxane in many patients.
BACKGROUND: The optimal approach to patients with hypersensitivity reactions (HSRs) to taxanes has not been established.
OBJECTIVE: We sought to assess the safety and efficacy of risk stratification based on the severity of the initial HSR and skin testing for guiding taxane reintroduction in patients with an HSR to these agents.
METHODS: Data on 164 patients treated for a taxane-related HSR from April 2011 to August 2014 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital were collected retrospectively. Patients were re-exposed to taxanes either through desensitization, challenge, or regular infusion based on the severity of the initial HSR and skin test response. Depending on the initial risk stratification and tolerance to re-exposure, patients were then treated with shorter desensitization protocols, challenge, or both with the aim of resuming regular infusions, except in patients with a severe immediate initial HSR.
RESULTS: Of 138 patients desensitized, 29 (21%) had an immediate and 20 (14%) had a delayed HSR with the procedure. Of 49 patients challenged, 2 (4%) had a mild immediate and 1 (2%) had a delayed HSR with the procedure. No patients had a severe immediate HSR with desensitization or challenge. Thirty-six (22%) patients eventually resumed regular infusions. These patients were more likely to have negative skin test responses and to have experienced a delayed or mild immediate initial HSR.
CONCLUSIONS: Risk stratification based on the severity of the initial HSR and skin testing to guide taxane reintroduction is safe and allows a significant number of patients to resume regular infusion.
Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung.
de Kleer IM, Kool M, de Bruijn MJ, Willart M, van Moorleghem J, Schuijs MJ, Plantinga M, Beyaert R, Hams E, Fallon PG, Hammad H, Hendriks RW, Lambrecht BN. Immunity.
2016 Dec 20;45(6):1285-1298. doi: 10.1016/j.immuni.2016.10.031. Epub 2016 Dec 6.
WAO Committee’s reasons for recommending:
It is known that young children exposed to allergens are prone to develop asthma later in life, but the underling mechanism is unknown. The authors identify IL-33 as a key player in the developing lung for sensitization to environmental allergens and airway hyperreactivity.
Allergic disease originates in early life and polymorphisms in interleukin-33 gene (IL33) and IL1RL1, coding for IL-33R and decoy receptor sST2, confer allergy risk. Early life T helper 2 (Th2) cell skewing and allergy susceptibility are often seen as remnants of feto-maternal symbiosis. Here we report that shortly after birth, innate lymphoid type 2 cells (ILC2s), eosinophils, basophils, and mast cells spontaneously accumulated in developing lungs in an IL-33-dependent manner. During the phase of postnatal lung alveolarization, house dust mite exposure further increased IL-33, which boosted cytokine production in ILC2s and activated CD11b+ dendritic cells (DCs). IL-33 suppressed IL-12p35 and induced OX40L in neonatal DCs, thus promoting Th2 cell skewing. Decoy sST2 had a strong preventive effect on asthma in the neonatal period, less so in adulthood. Thus, enhanced neonatal Th2 cell skewing to inhaled allergens results from postnatal hyperactivity of the IL-33 axis during a period of maximal lung remodeling.
Acidic chitinase primes the protective immune response to gastrointestinal nematodes.
Vannella KM, Ramalingam TR, Hart KM, de Queiroz Prado R, Sciurba J, Barron L, Borthwick LA, Smith AD, Mentink-Kane M, White S, Thompson RW, Cheever AW, Bock K, Moore I, Fitz LJ, Urban JF Jr, Wynn TA. Nat Immunol.
2016 May;17(5):538-44. doi: 10.1038/ni.3417. Epub 2016 Apr 4
WAO Committee’s reasons for recommending:
The physiological function of the mammalian chitinase AMCase is unclear. The authors show that it is dispensable for allergic lung inflammation but is necessary for clearance of intestinal helminths.
Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103(+) dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.
Metal nanoparticles in the presence of lipopolysaccharides trigger the onset of metal allergy in mice.
Hirai T, Yoshioka Y, Izumi N, Ichihashi K, Handa T, Nishijima N, Uemura E, Sagami K, Takahashi H, Yamaguchi M, Nagano K, Mukai Y, Kamada H, Tsunoda S, Ishii KJ, Higashisaka K, Tsutsumi Y. Nat Nanotechnol.
2016 Sep;11(9):808-16. doi: 10.1038/nnano.2016.88. Epub 2016
WAO Committee’s reasons for recommending:
The authors find a potential new trigger for metal allergy. The show that that metal nanoparticles served as ion carriers enabelling metal sensitization. Hence demonstrate a potentially new trigger for metalallergy.
Many people suffer from metal allergy, and the recently demonstrated presence of naturally occurring metal nanoparticles in our environment could present a new candidate for inducing metal allergy. Here, we show that mice pretreated with silver nanoparticles (nAg) and lipopolysaccharides, but not with the silver ions that are thought to cause allergies, developed allergic inflammation in response to the silver. nAg-induced acquired immune responses depended on CD4(+) T cells and elicited IL-17A-mediated inflammation, similar to that observed in human metal allergy. Nickel nanoparticles also caused sensitization in the mice, whereas gold and silica nanoparticles, which are minimally ionizable, did not. Quantitative analysis of the silver distribution suggested that small nAg (≤10 nm) transferred to the draining lymph node and released ions more readily than large nAg (>10 nm). These results suggest that metal nanoparticles served as ion carriers to enable metal sensitization. Our data demonstrate a potentially new trigger for metal allergy.
Regulatory T Cell Specificity Directs Tolerance versus Allergy against Aeroantigens in Humans.
Bacher P, Heinrich F, Stervbo U, Nienen M, Vahldieck M, Iwert C, Vogt K, Kollet J, Babel N, Sawitzki B, Schwarz C, Bereswill S, Heimesaat MM, Heine G, Gadermaier G, Asam C, Assenmacher M, Kniemeyer O, Brakhage AA, Ferreira F, Wallner M, Worm M, Scheffold A. Cell.
2016 Nov 3;167(4):1067-1078.e16. doi: 10.1016/j.cell.2016.09.050. Epub 2016 Oct 20.
WAO Committee’s reasons for recommending:
The authors performed a comprehensive characterization of antigen-specific human Treg responses, demonstrating that aeroantigens are major tolerogenic Treg targets. Thus, discovering maybe the first allergy-related ligands for Treg. They further show that allergic patients have intact Treg responses against aeroantigens and that Th2 responses escape Treg control due to divergent antigen specificities.
FOXP3+ regulatory T cells (Tregs) maintain tolerance against self-antigens and innocuous environmental antigens. However, it is still unknown whether Treg-mediated tolerance is antigen specific and how Treg specificity contributes to the selective loss of tolerance, as observed in human immunopathologies such as allergies. Here, we used antigen-reactive T cell enrichment to identify antigen-specific human Tregs. We demonstrate dominant Treg-mediated tolerance against particulate aeroallergens, such as pollen, house dust mites, and fungal spores. Surprisingly, we found no evidence of functional impairment of Treg responses in allergic donors. Rather, major allergenic proteins, known to rapidly dissociate from inhaled allergenic particles, have a generally reduced capability to generate Treg responses. Most strikingly, in individual allergic donors, Th2 cells and Tregs always target disparate proteins. Thus, our data highlight the importance of Treg antigen-specificity for tolerance in humans and identify antigen-specific escape from Treg control as an important mechanism enabling antigen-specific loss of tolerance in human allergy.
The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan.
Kotzin JJ, Spencer SP, McCright SJ, Kumar DB, Collet MA, Mowel WK, Elliott EN, Uyar A, Makiya MA, Dunagin MC, Harman CC, Virtue AT, Zhu S, Bailis W, Stein J, Hughes C, Raj A, Wherry EJ, Goff LA, Klion AD, Rinn JL, Williams A, Flavell RA, Henao-Mejia J.
Nature. 2016 Sep 8;537(7619):239-243.
Committee's reason for recommendation: Eosinophils are among the shortest-lived cells in the body. How the lifespan of these cells is strictly controlled remains largely unknown. Here the authors identify a long non-coding RNA termed Morrbid, which controls the survival of eosinophils and other immune cells in response to pro-survival cytokines. MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome. Therefore, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan/
Neutrophils, eosinophils and 'classical' monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice. To control the lifespan of these cells, Morrbid regulates the transcription of the neighbouring pro-apoptotic gene, Bcl2l11 (also known as Bim), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis, enabling allele-specific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.
Dwyer DF, Barrett NA, Austen KF; Immunological Genome Project Consortium
Expression profiling of constitutive mast cells reveals a unique identity within the immune system.
Nat Immunol. 2016 Jul;17(7):878-87.
Committee's reason for recommendation: Here the authors assessed the transcriptional profiles of mast cells isolated from peripheral connective tissues and basophils isolated from spleen and blood. They found that mast cells were transcriptionally distinct, and that mast cells demonstrated considerably greater heterogeneity across tissues than previously appreciated.
Mast cells are evolutionarily ancient sentinel cells. Like basophils, mast cells express the high-affinity receptor for immunoglobulin E (IgE) and have been linked to host defense and diverse immune-system-mediated diseases. To better characterize the function of these cells, we assessed the transcriptional profiles of mast cells isolated from peripheral connective tissues and basophils isolated from spleen and blood. We found that mast cells were transcriptionally distinct, clustering independently from all other profiled cells, and that mast cells demonstrated considerably greater heterogeneity across tissues than previously appreciated. We observed minimal homology between mast cells and basophils, which shared more overlap with other circulating granulocytes than with mast cells. The derivation of mast-cell and basophil transcriptional signatures underscores their differential capacities to detect environmental signals and influence the inflammatory milieu.
Ballesteros-Tato A, Randall TD, Lund FE, Spolski R, Leonard WJ, León B.
T Follicular Helper Cell Plasticity Shapes Pathogenic T Helper 2 Cell-Mediated Immunity to Inhaled House Dust Mite.
Immunity. 2016 Feb 16;44(2):259-73.
Committee's reason for recommendation: Exposure to environmental antigens, such as house dust mite (HDM), often leads to T helper 2 (Th2) cell-driven allergic responses. However, the mechanisms underlying the development of these responses are incompletely understood. The authors found that the initial exposure to HDM did not lead to Th2 cell development but instead promoted the formation of interleukin-4 (IL-4)-committed T follicular helper (Tfh) cells. The authors demonstrate that Tfh cells are precursors of HDM-specific Th2 cells and reveal an unexpected role of B cells and Tfh cells in the pathogenesis of allergic asthma.
Exposure to environmental antigens, such as house dust mite (HDM), often leads to T helper 2 (Th2) cell-driven allergic responses. However, the mechanisms underlying the development of these responses are incompletely understood. We found that the initial exposure to HDM did not lead to Th2 cell development but instead promoted the formation of interleukin-4 (IL-4)-committed T follicular helper (Tfh) cells. Following challenge exposure to HDM, Tfh cells differentiated into IL-4 and IL-13 double-producing Th2 cells that accumulated in the lung and recruited eosinophils. B cells were required to expand IL-4-committed Tfh cells during the sensitization phase, but did not directly contribute to disease. Impairment of Tfh cell responses during the sensitization phase or Tfh cell depletion prevented Th2 cell-mediated responses following challenge. Thus, our data demonstrate that Tfh cells are precursors of HDM-specific Th2 cells and reveal an unexpected role of B cells and Tfh cells in the pathogenesis of allergic asthma.
Henry EK, Sy CB, Inclan-Rico JM, Espinosa V, Ghanny SS, Dwyer DF, Soteropoulos P, Rivera A, Siracusa MC.
Carbonic anhydrase enzymes regulate mast cell-mediated inflammation.
J Exp Med. 2016 Aug 22;213(9):1663-73.
Committee's reason for recommendation: Type 2 cytokine responses are necessary for the development of protective immunity to helminth parasites but also cause the inflammation associated with allergies and asthma. Here the authors identify a previously unrecognized role for carbonic anhydrase (Car) enzymes in regulating mast cell lineage commitment and suggest that Car enzyme inhibitors may be used to treat mast cell-mediated inflammation.
Type 2 cytokine responses are necessary for the development of protective immunity to helminth parasites but also cause the inflammation associated with allergies and asthma. Recent studies have found that peripheral hematopoietic progenitor cells contribute to type 2 cytokine-mediated inflammation through their enhanced ability to develop into mast cells. In this study, we show that carbonic anhydrase (Car) enzymes are up-regulated in type 2-associated progenitor cells and demonstrate that Car enzyme inhibition is sufficient to prevent mouse mast cell responses and inflammation after Trichinella spiralis infection or the induction of food allergy-like disease. Further, we used CRISPR/Cas9 technology and illustrate that genetically editing Car1 is sufficient to selectively reduce mast cell development. Finally, we demonstrate that Car enzymes can be targeted to prevent human mast cell development. Collectively, these experiments identify a previously unrecognized role for Car enzymes in regulating mast cell lineage commitment and suggest that Car enzyme inhibitors may possess therapeutic potential that can be used to treat mast cell-mediated inflammation.