The importance of mast cell histamine secretion in IgG-mediated systemic anaphylaxis.

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 now investigate these issues.

Methods: Actively or passively sensitized wild-type and immune-deficient mice were induced to develop anaphylaxis by i.v. antigen challenge. Anaphylaxis was characterized by evaluating hypothermia, hypomobility, histamine, and mast cell protease responses.

Results: In contrast to our previous results with protein-immunized mice from a conventional colony, IgG-mediated passive SA in our SPF 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 freshly 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 naïve 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 Th2 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, immune and infectious history, and the anaphylaxis model studied.