Secretion of mediators from basophils is an important component of the allergic response. How this secretion is regulated by two low affinity IgG receptors (CD32a and CD32b) is the focus of this proposal. Specific immunotherapy (SIT) is a mainstay approach in the treatment of allergic diseases. While there are several strong hypotheses that provide an explanation for the success (or lack thereof) of this therapeutic approach, most of these hypotheses are incompletely examined in humans. One of the longstanding observations is that SIT induces enhanced production of specific IgG antibodies but the mechanism by which these antibodies may contribute to the efficacy of SIT is not well understood. This proposal will test the hypothesis that blocking IgG exerts an influence on the human basophil response through cell surface CD32b (FcgRIIb). The limited existing literature testing this hypothesis is contradictory but there is new information that may help to explore this question and account for potential biological variation that may occur in a clinical study of SIT. Studies in this laboratory demonstrate that the relative proportion of CD32a and CD32b can be altered with cytokine exposure.
The first aim of this proposal is to expand our knowledge of the regulation of CD32 expression, with a particular emphasis on whether there are genotypes of CD32a and CD32b and IgG subclass profiles that allow for CD32a-mediated secretion. Some of this knowledge will be used to further improve on the design and interpretation of a clinical study of SIT that is proposed in the second aim of the proposal. The purpose of the clinical study is to provide the patients needed to explore the proposed hypothesis but we will couple the results from the in vitro testing of basophil function to the clinical outcomes of SIT as measured by experimental nasal allergen challenges.
The third aim explores a unique new observation that regulation of IgE-mediated secretion from basophils by CD32b allows for suppression of mediator release but maintenance of down-regulatory processes such as the loss in the expression of syk. This circumstance may provide an explanation for the important variable expression of syk seen in the general population, variation that is now known to be linked to the efficacy of at least one new asthma therapeutic, omalizumab.
The third aim will determine whether CD32b can modulate the IgE-mediated down-regulation of syk expression in basophils maturing from their CD34+ progenitors and examine the basis for this process.

Public Health Relevance

Treatment of allergic diseases often includes specific immunotherapy (SIT) but the mechanisms responsible for success using this treatment are not yet well understood. Since there is considerable effort to improve SIT, it would stand to reason that a better understanding of its mechanisms would be helpful. This proposal will examine a longstanding hypothesis of SIT that has yet to be studied and validated in humans and it will explore other mechanisms of human basophil responsiveness.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Dong, Gang
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
MacGlashan, Donald (2018) Auto-antibodies to IgE and FceRI and the Natural Variability of SYK Expression in Basophils. J Allergy Clin Immunol :
Lewis, A; MacGlashan Jr, D W; Suvarna, S K et al. (2017) Recovery from desensitization of IgE-dependent responses in human lung mast cells. Clin Exp Allergy 47:1022-1031
MacGlashan Jr, Donald W; Saini, Sarbjit S (2017) Syk expression and IgE-mediated histamine release in basophils as biomarkers for predicting the clinical efficacy of omalizumab. J Allergy Clin Immunol 139:1680-1682.e10
MacGlashan Jr, Donald (2017) FceRI density and spontaneous secretion from human basophils. PLoS One 12:e0179734
MacGlashan Jr, Donald (2016) Stability of Syk protein and mRNA in human peripheral blood basophils. J Leukoc Biol 100:535-43
MacGlashan Jr, Donald; Hamilton, Robert G (2016) Parameters determining the efficacy of CD32 to inhibit activation of Fc?RI in human basophils. J Allergy Clin Immunol 137:1256-1258.e11
MacGlashan Jr, Donald (2015) Expression profiling of human basophils: modulation by cytokines and secretagogues. PLoS One 10:e0126435
Alexander, V; MacGlashan Jr, D (2015) The relationship between total cellular content of CD203c and cell surface expression on human basophils. Clin Exp Allergy 45:1138-41
Macglashan Jr, D; Moore, G; Muchhal, U (2014) Regulation of IgE-mediated signalling in human basophils by CD32b and its role in Syk down-regulation: basic mechanisms in allergic disease. Clin Exp Allergy 44:713-23