Basophil and mast cell mediator release is a central feature of both acute and chronic allergic reactions. Future therapeutic approaches that depend on regulating secretion from these two cell types will require a detailed knowledge of the mechanisms that regulate the response of these cells to stimulation. This proposal will focus on IgE-mediated secretion from human basophils, examining patient populations in aims 2 and 4 and elucidating signaling pathways in these cells in aims 1 and 3. With the large number of possible signaling pathways suggested by studies in mast cell/basophil cell lines, we have chosen to focus on those which specifically down-regulate ongoing IgE-mediated secretion. There are four aims.
Aim 1 will address the issue of the loss of signaling elements as a result of activation, a form of long term down-regulation. The loss of syk kinase has already been documented in our recent studies and this aim will expand these observations, leading to tests in aim 2 of whether a chronic state of down-regulation can be induced in maturing basophils and whether clinical desensitization (such as used to prepare patients for penicillin use) results from a similar process. In the third aim, we will examine the process of late down-regulation we have called nonspecific desensitization. This form of down-regulation appears to involve regulation of phosphatidyl inositol 3,4,5 phosphate (PIPS).
Sub aims will determine the signaling elements that connect the presence of PIPS to the activation of p21ras/Raf-1, determine the activation and regulation of SHIP1/2, and determine the mechanisms underlying the long term memory (or prior activation) that appear related to SHIP.
In aim 4, a synthesis of our current understanding suggests syk and SHIP expression will be two predictors of two independent characteristics of the IgE-mediated response in human basophils, the cells' sensitivity to stimulation and the maximum release obtainable. A population of subjects will be examined for this relationship.
|MacGlashan Jr, Donald W; Savage, Jessica H; Wood, Robert A et al. (2012) Suppression of the basophil response to allergen during treatment with omalizumab is dependent on 2 competing factors. J Allergy Clin Immunol 130:1130-1135.e5|
|MacGlashan Jr, Donald (2012) Marked differences in the signaling requirements for expression of CD203c and CD11b versus CD63 expression and histamine release in human basophils. Int Arch Allergy Immunol 159:243-52|
|MacGlashan Jr, Donald; Honigberg, Lee A; Smith, Ashley et al. (2011) Inhibition of IgE-mediated secretion from human basophils with a highly selective Bruton's tyrosine kinase, Btk, inhibitor. Int Immunopharmacol 11:475-9|
|Ishmael, Susan S; MacGlashan Jr, Donald W (2010) Syk expression in peripheral blood leukocytes, CD34+ progenitors, and CD34-derived basophils. J Leukoc Biol 87:291-300|
|Zaidi, Asifa K; Saini, Sarbjit S; Macglashan Jr, Donald W (2010) Regulation of Syk kinase and FcRbeta expression in human basophils during treatment with omalizumab. J Allergy Clin Immunol 125:902-908.e7|
|MacGlashan Jr, D (2010) Expression of CD203c and CD63 in human basophils: relationship to differential regulation of piecemeal and anaphylactic degranulation processes. Clin Exp Allergy 40:1365-77|
|Zaidi, Asifa K; MacGlashan, Donald W (2010) Regulation of Fc epsilon RI expression during murine basophil maturation: the interplay between IgE, cell division, and Fc epsilon RI synthetic rate. J Immunol 184:1463-74|
|Mora, Juanita; Riggs, Emily K; Fu, Jun et al. (2009) Expression of the high affinity IgE receptor by neutrophils of individuals with allergic asthma is both minimal and insensitive to regulation by serum IgE. Clin Immunol 132:132-40|
|MacGlashan Jr, Donald; Vilariño, Natalia (2009) Polymerization of actin does not regulate desensitization in human basophils. J Leukoc Biol 85:627-37|
|MacGlashan Jr, Donald; Undem, Bradley J (2008) Inducing an anergic state in mast cells and basophils without secretion. J Allergy Clin Immunol 121:1500-6, 1506.e1-4|
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