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Protein Fv produced during viral hepatitis is an endogenous immunoglobulin superantigen activating human heart mast
Arturo Genovese1, Guglielmo Borgia, Jean-Pierre Bouvet
1Division of Clinical Immunology and Allergy, University of Naples Federico II, Naples, Italy.
Abstract:
Protein Fv, an endogenous protein produced in the liver, is released in biological fluids during viral hepatitis. Acute and chronic viral hepatitis can be associated with cardiovascular derangements. Protein Fv induced the release of histamine, tryptase and the de novo synthesis of prostaglandin D(2) and cysteinyl leukotriene C(4) from mast cells isolated from human heart tissue (HHMC). Protein Fv absorbed with protein A-Sepharose coated with polyclonal IgG did not induce histamine secretion. The maximal percent histamine secretion induced by protein Fv correlated (r(s) = 0.60; p < 0.05) with that induced by anti-IgE, whereas there was no correlation between the release caused by proteins Fv and C5a. Preincubation of HHMC with protein Fv or anti-IgE caused complete cross-desensitization to subsequent challenge with heterologous stimulus. HHMC from which IgE had been dissociated no longer released histamine in response to anti-IgE and protein Fv. A human monoclonal IgE blocked both anti-IgE- and protein Fv-induced release. Three human monoclonal IgM V(H)3(+) inhibited protein-Fv-induced secretion of histamine from HHMC, whereas monoclonal IgM V(H)6(+) did not inhibit the release induced by protein Fv. Protein Fv acts as an endogenous immunoglobulin superantigen by interacting with the V(H)3 domain of IgE to induce the release of mediators from HHMC.
Insights
Protein Fv, released during viral hepatitis, triggers histamine release from human heart mast cells. This protein acts as an immunoglobulin superantigen, interacting with IgE to mediate cardiovascular effects.
Area of Science:
- Immunology
- Cardiovascular Medicine
- Hepatology
Background:
- Protein Fv is an endogenous liver protein released during viral hepatitis.
- Viral hepatitis is linked to cardiovascular complications.
- Mast cells in human heart tissue (HHMC) are implicated in inflammatory responses.
Purpose of the Study:
- To investigate the role of Protein Fv in mast cell activation.
- To determine the mechanism by which Protein Fv induces mediator release from HHMC.
- To explore the potential link between Protein Fv, IgE, and cardiovascular derangements in viral hepatitis.
Main Methods:
- Isolation and culture of human heart mast cells (HHMC).
- Stimulation of HHMC with Protein Fv and measurement of mediator release (histamine, tryptase, prostaglandin D2, cysteinyl leukotriene C4).
- Immune complex assays, including absorption with Protein A-Sepharose and IgE dissociation experiments.
- Cross-desensitization studies with anti-IgE.
- Inhibition assays using monoclonal antibodies (IgE and IgM V(H)3/V(H)6).
Main Results:
- Protein Fv induced the release of histamine, tryptase, prostaglandin D2, and cysteinyl leukotriene C4 from HHMC.
- Histamine secretion induced by Protein Fv correlated with that induced by anti-IgE, suggesting an IgE-dependent mechanism.
- Cross-desensitization experiments indicated that Protein Fv and anti-IgE act via a common pathway involving IgE.
- Dissociation of IgE from HHMC abolished responses to both Protein Fv and anti-IgE.
- Monoclonal IgE blocked Protein Fv-induced histamine release.
- Specific monoclonal IgM V(H)3(+) antibodies inhibited Protein Fv-induced histamine release, while V(H)6(+) antibodies did not.
Conclusions:
- Protein Fv acts as an endogenous immunoglobulin superantigen.
- It interacts with the V(H)3 domain of IgE on human heart mast cells.
- This interaction triggers the release of inflammatory mediators, potentially contributing to cardiovascular derangements in viral hepatitis.
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