MECHANISMS OF HUMAN BASOPHIL & MAST CELL DESENSITIZATION

Summary

Principal Investigator: D MacGlashan
Affiliation: Johns Hopkins University
Country: USA
Abstract: Basophil and mast cell mediator release is a central feature of both acute and chronic allergic reactions. However, little is known of the biochemical nature of signal transduction in the human cells of this type. This proposal focuses on studies which will elucidate some of the important biochemical events in both IgE mediated and univalent hormone induced secretion. The primary goals of these studies is to elucidate the mechanisms of desensitization although significant effort will also be applied towards understanding activation events. In particular, the role of cytosolic calcium elevations and protein kinase C in activation and desensitization will be further examined. We have demonstrated that IgE-mediated histamine release in both human basophils and lung mast cells is accompanied by the increased activity of membrane associated protein kinase C and elevations in cytosolic calcium. Detailed studies suggest that desensitization processes are specific for the mediator being examined and that for regulating the extent of degranulation (histamine release), the basophil and mast cell regulate the activation of protein kinase C rather than elevations in cytosolic calcium. Therefore, part of this proposal seeks to understand in greater detail the relationship between PKC activation and histamine release, the multiple roles PKC may play in regulating mediator release and whether the transient activation in PKC activity results from the specific regulation of diacylglycerol levels. A series of exploratory experiments are proposed to determine whether tyrosine kinase activity plays a role in desensitization. Preliminary evidence also suggests that leukotriene release, unlike histamine release, is controlled by the down-regulation of the calcium response. The proposed studies will initially examine the relationship between down-regulation of the calcium response and down- regulation of leukotriene release. A second primary area of study will be on the relationship between calcium oscillations observed in single cells and subsequent mediator release. Several methods are proposed to measure single cell degranulation in an effort to correlate this end point with the early oscillatory changes in cytosolic calcium. In addition, the relationship between calcium oscillations and leukotriene release will be examined. A third aim of this proposal is to study the relationship between desensitization events that affect the early mediators (histamine and leukotrienes) and cytokine secretion which occurs much later in the secretory response. Since cytokine release appears dependent on mRNA accumulation, initial studies will focus on the mechanisms of mRNA accumulation.
Funding Period: 1984-12-01 - 1994-08-31
more information: NIH RePORT

Top Publications

  1. pmc Suppression of the basophil response to allergen during treatment with omalizumab is dependent on 2 competing factors
    Donald W Macglashan
    Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
    J Allergy Clin Immunol 130:1130-1135.e5. 2012
  2. pmc Marked differences in the signaling requirements for expression of CD203c and CD11b versus CD63 expression and histamine release in human basophils
    Donald MacGlashan
    Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA dmacglas jhmi edu
    Int Arch Allergy Immunol 159:243-52. 2012
  3. pmc Inhibition of IgE-mediated secretion from human basophils with a highly selective Bruton's tyrosine kinase, Btk, inhibitor
    Donald MacGlashan
    Johns Hopkins University, Asthma and Allergy Center, Baltimore, MD 21224, USA
    Int Immunopharmacol 11:475-9. 2011
  4. pmc Expression of CD203c and CD63 in human basophils: relationship to differential regulation of piecemeal and anaphylactic degranulation processes
    D MacGlashan
    Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA
    Clin Exp Allergy 40:1365-77. 2010
  5. pmc Regulation of Syk kinase and FcRbeta expression in human basophils during treatment with omalizumab
    Asifa K Zaidi
    Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA
    J Allergy Clin Immunol 125:902-908.e7. 2010
  6. ncbi Regulation of Fc epsilon RI expression during murine basophil maturation: the interplay between IgE, cell division, and Fc epsilon RI synthetic rate
    Asifa K Zaidi
    Division of Allergy and Clinical Immunology, Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
    J Immunol 184:1463-74. 2010
  7. pmc Syk expression in peripheral blood leukocytes, CD34+ progenitors, and CD34-derived basophils
    Susan S Ishmael
    Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA
    J Leukoc Biol 87:291-300. 2010
  8. pmc Expression of the high affinity IgE receptor by neutrophils of individuals with allergic asthma is both minimal and insensitive to regulation by serum IgE
    Juanita Mora
    The Department of Immunology Microbiology, Section of Allergy and Immunology, Rush University Medical Center, Chicago, IL 60612, USA
    Clin Immunol 132:132-40. 2009
  9. pmc Polymerization of actin does not regulate desensitization in human basophils
    Donald MacGlashan
    Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA
    J Leukoc Biol 85:627-37. 2009
  10. doi Inducing an anergic state in mast cells and basophils without secretion
    Donald MacGlashan
    Asthma and Allergy Center, Johns Hopkins University, Baltimore, MD 21224, USA
    J Allergy Clin Immunol 121:1500-6, 1506.e1-4. 2008

Scientific Experts

  • D MacGlashan
  • Asifa K Zaidi
  • Natalia VilariƱo
  • Susan S Ishmael
  • Juanita Mora
  • Becky M Vonakis
  • Sarbjit S Saini
  • Emily K Riggs
  • Larry L Thomas
  • Jun Fu
  • Mary C Tobin
  • Byung Yu
  • Susan A Fox
  • Jacqueline M Langdon
  • Susan M MacDonald
  • Rebecca S Scott
  • Katsushi Miura

Detail Information

Publications15

  1. pmc Suppression of the basophil response to allergen during treatment with omalizumab is dependent on 2 competing factors
    Donald W Macglashan
    Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
    J Allergy Clin Immunol 130:1130-1135.e5. 2012
    ..However, there were differences that provided additional insight into the nature of the cellular responses in allergic subjects...
  2. pmc Marked differences in the signaling requirements for expression of CD203c and CD11b versus CD63 expression and histamine release in human basophils
    Donald MacGlashan
    Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA dmacglas jhmi edu
    Int Arch Allergy Immunol 159:243-52. 2012
    ....
  3. pmc Inhibition of IgE-mediated secretion from human basophils with a highly selective Bruton's tyrosine kinase, Btk, inhibitor
    Donald MacGlashan
    Johns Hopkins University, Asthma and Allergy Center, Baltimore, MD 21224, USA
    Int Immunopharmacol 11:475-9. 2011
    ..These results suggest that btk is specifically required for IgE-mediated activation of human basophils...
  4. pmc Expression of CD203c and CD63 in human basophils: relationship to differential regulation of piecemeal and anaphylactic degranulation processes
    D MacGlashan
    Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA
    Clin Exp Allergy 40:1365-77. 2010
    ..The markers CD63 and CD203c have been used in recent years to assess basophil activation but there have been many studies that demonstrate that expression of these markers can be dissociated from histamine release...
  5. pmc Regulation of Syk kinase and FcRbeta expression in human basophils during treatment with omalizumab
    Asifa K Zaidi
    Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA
    J Allergy Clin Immunol 125:902-908.e7. 2010
    ..This observation raised the possibility that the stoichiometry of FcRbeta/FcepsilonRIalpha is not fixed to a 1:1 ratio and might be modifiable during changes in the basophil's environment...
  6. ncbi Regulation of Fc epsilon RI expression during murine basophil maturation: the interplay between IgE, cell division, and Fc epsilon RI synthetic rate
    Asifa K Zaidi
    Division of Allergy and Clinical Immunology, Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
    J Immunol 184:1463-74. 2010
    ..The studies also support a model whereby receptor expression is limited by cell division and that basophils, once mature, slow their rate of receptor synthesis...
  7. pmc Syk expression in peripheral blood leukocytes, CD34+ progenitors, and CD34-derived basophils
    Susan S Ishmael
    Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA
    J Leukoc Biol 87:291-300. 2010
    ....
  8. pmc Expression of the high affinity IgE receptor by neutrophils of individuals with allergic asthma is both minimal and insensitive to regulation by serum IgE
    Juanita Mora
    The Department of Immunology Microbiology, Section of Allergy and Immunology, Rush University Medical Center, Chicago, IL 60612, USA
    Clin Immunol 132:132-40. 2009
    ....
  9. pmc Polymerization of actin does not regulate desensitization in human basophils
    Donald MacGlashan
    Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA
    J Leukoc Biol 85:627-37. 2009
    ..These studies demonstrate that desensitization is not the result of two signaling pathways once considered relevant to down-regulation of IgE-mediated signaling...
  10. doi Inducing an anergic state in mast cells and basophils without secretion
    Donald MacGlashan
    Asthma and Allergy Center, Johns Hopkins University, Baltimore, MD 21224, USA
    J Allergy Clin Immunol 121:1500-6, 1506.e1-4. 2008
    ..IgE-mediated secretion from mast cells or basophils depends on the activity of both spleen tyrosine kinase (syk) and phosphatidyl inositol 3' kinase (PI3K), but several specific downregulatory pathways (eg, loss of syk expression) do not...
  11. pmc Distinct characteristics of signal transduction events by histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP)-induced priming and activation of human basophils
    Becky M Vonakis
    The Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA
    Blood 111:1789-96. 2008
    ..This finding is different from IL-3, which also primes basophils for histamine release, but does show phosphorylation of these events. We conclude that priming induced by HRF/TCTP is distinct from that induced by IL-3...
  12. ncbi Endocytosis, recycling, and degradation of unoccupied FcepsilonRI in human basophils
    Donald W Macglashan
    Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA
    J Leukoc Biol 82:1003-10. 2007
    ..These studies establish that the unoccupied receptor is lost by a process of endocytosis, partially recycled to the cell surface, and ultimately degraded by a lysosomal mechanism...
  13. ncbi Relationship between spleen tyrosine kinase and phosphatidylinositol 5' phosphatase expression and secretion from human basophils in the general population
    Donald W Macglashan
    Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA
    J Allergy Clin Immunol 119:626-33. 2007
    ..Previous studies have suggested that expression levels of spleen tyrosine kinase (syk) or phosphatidylinositol 5' phosphatase (SHIP) may explain certain extreme human basophil phenotypes...
  14. ncbi Nonspecific desensitization, functional memory, and the characteristics of SHIP phosphorylation following IgE-mediated stimulation of human basophils
    Donald MacGlashan
    Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Center, Baltimore, MD 21224, USA
    J Immunol 177:1040-51. 2006
    ....
  15. ncbi Acute IL-3 priming up-regulates the stimulus-induced Raf-1-Mek-Erk cascade independently of IL-3-induced activation of Erk
    Natalia VilariƱo
    Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA
    J Immunol 175:3006-14. 2005
    ..This type of preactivation can be mimicked by incubation with the Ser-Thr kinase inhibitors, Ro-81-3220, or bisindoylmaleimide II...