Antigen-IgE desensitization in signal transducer and activator of transcription 6-deficient mast cells by suboptimal doses of antigen.
BACKGROUND
Rapid administration of suboptimal antigen induces transient unresponsiveness in patients with IgE antibodies to beneficial medications, but the molecular mechanisms of desensitization are poorly understood. Mast cells (MCs) have been implicated as the target cells.


OBJECTIVE
To establish a physiologic model of IgE-antigen desensitization using mouse bone marrow-derived MCs (mBMMCs) from wild-type and signal transducer and activator of transcription 6 (STAT6)-deficient mice.


METHODS
The mBMMCs were sensitized with dinitrophenyl (DNP) IgE or trinitrophenyl (TNP) IgE and activated with DNP/TNP-human serum albumin. For desensitization, suboptimal doses of DNP/TNP-human serum albumin were administered at fixed intervals.


RESULTS
Desensitized mBMMCs failed to respond to an optimal dose of antigen, indicating successful desensitization. Desensitization was time dependent, with 5 minutes of antigen exposure being optimal. Resensitization with DNP-IgE did not reverse the process. The desensitized cells were responsive to calcium ionophore and phorbol myristate acetate. Thus, the desensitization reaction alters an early event in the high-affinity IgE receptor (FcepsilonRI)-dependent signaling pathway in a nontoxic manner. The mBMMCs from STAT6-null mice could not be desensitized by suboptimal doses of antigen.


CONCLUSIONS
Mast cells can be rendered unresponsive by rapid administration of suboptimal doses of antigen in the presence of calcium, similar to in vivo desensitizations. The STAT6-null mBMMCs cannot be desensitized, providing the first molecular target in this inhibitory process.
Morales
Alexander Rodriguez
AR
Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Shah
Neil
N
Castells
Mariana
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology; D003888:Desensitization, Immunologic; D004136:Dinitrobenzenes / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D007114:Immunization; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C / Q000235:genetics; D008810:Mice, Inbred C57BL / Q000235:genetics; D010851:Picrates / Q000276:immunology; D050800:STAT6 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D000941:Antigens; D004136:Dinitrobenzenes; D010851:Picrates; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; C005858:picric acid