Importance of mast cell histamine secretion in IgG-mediated systemic anaphylaxis

Abstract

Background

IgG can mediate murine and human systemic anaphylaxis (SA). The roles of mast cells (MCs) and histamine in IgG-mediated anaphylaxis are controversial for mice and have not been studied in vivo for humans. We are now investigating these issues.

Methods

Actively or passively sensitized wild-type and immune-deficient mice were induced to develop anaphylaxis by intravenous antigen challenge. Anaphylaxis was characterized by evaluating hypothermia, hypomobility, histamine, and MC protease responses.

Results

In contrast to our previous results with protein-immunized mice from a conventional colony, IgG-mediated passive SA in our specific pathogen-free colony mice depended considerably on histamine produced by connective tissue MCs (CTMCs) in response to FcγRIII crosslinking. This was found for C57BL/6 and young male and female BALB/c mice, including BALB/c mice newly arrived from 3 vendors. IgG-mediated anaphylaxis was less histamine dependent in old than young mice. Although both mucosal MC (MMC) and CTMC responses were severely depleted in c-kit–deficient mice, MMC responses depended considerably more than CTMC responses on c-kit for maintenance. In immunologically naive mice, FcγRIII crosslinking strongly activated a subset of CTMCs but had little ability to activate MMCs. In vivo LPS + poly I:C treatment decreased histamine dependence of IgG-mediated anaphylaxis, while a strong T_H2 immune response increased FcγRIII crosslinking-induced MMC activation. IgG-mediated activation of human MCs in reconstituted immunodeficient mice induced histamine-dependent anaphylaxis.

Conclusion

IgG-dependent SA can be mediated largely by histamine released by mouse CTMCs and human MCs; histamine dependence is influenced by mouse age, sex, and immune and infectious history, as well as the anaphylaxis model studied.