Abstract
Immunoglobulin E (IgE) activates mast cells (MCs). It remains unknown whether IgE also activates other inflammatory cells, and contributes to the pathogenesis of abdominal aortic aneurysms (AAAs). This study demonstrates that CD4+ T cells express IgE receptor FcεR1, at much higher levels than do CD8+ T cells. IgE induces CD4+ T-cell production of IL6 and IFN-γ, but reduces their production of IL10. FcεR1 deficiency (Fcer1a−/−) protects apolipoprotein E-deficient (Apoe−/−) mice from angiotensin-II infusion-induced AAAs and reduces plasma IL6 levels. Adoptive transfer of CD4+ T cells (but not CD8+ T cells), MCs, and macrophages from Apoe−/− mice, but not those from Apoe−/− Fcer1a−/− mice, increases AAA size and plasma IL6 in Apoe−/− Fcer1a−/− recipient mice. Biweekly intravenous administration of an anti-IgE monoclonal antibody ablated plasma IgE and reduced AAAs in Apoe−/− mice. Patients with AAAs had significantly higher plasma IgE levels than those without AAAs. This study establishes an important role of IgE in AAA pathogenesis by activating CD4+ T cells, MCs, and macrophages and supports consideration of neutralizing plasma IgE in the therapeutics of human AAAs.
Highlights
Mast cells (MCs) contribute importantly to the pathogenesis of atherosclerosis and abdominal aortic aneurysms (AAAs) (Kovanen, 2007; Sun et al, 2007a,b; Bot & Biessen, 2011; Swedenborg et al, 2011)
Using angiotensin-II (Ang-II) infusioninduced experimental AAAs in apolipoprotein E-deficient (ApoeÀ/À) mice, we tested whether immunoglobulin E (IgE) actions on T cells, MCs, and macrophages contribute to AAA pathogenesis and whether inhibition of IgE activity using FceR1-deficient mice or ablation of plasma IgE using anti-IgE monoclonal antibody ameliorates AAA development
Using Ang-II infusion-induced experimental AAAs in ApoeÀ/À mice, FceR1-deficient mice, adoptive transfer of leukocyte populations, and anti-IgE monoclonal antibody (mAb) administration, we demonstrated that IgE actions on CD4+ T cells, MCs, and macrophages, and possibly other inflammatory and vascular cells contribute to AAA pathogenesis
Summary
Mast cells (MCs) contribute importantly to the pathogenesis of atherosclerosis and abdominal aortic aneurysms (AAAs) (Kovanen, 2007; Sun et al, 2007a,b; Bot & Biessen, 2011; Swedenborg et al, 2011). Multiple mechanisms— including lipoproteins, immunoglobulins, neurotrophic factors (e.g. substance P and neuron growth factor), stem cell factor, complements (e.g. C3a and C5a), endotoxin, inflammatory cytokines (e.g. IL1 and TNF-a) (Xu & Shi, 2012), or even acute restraint stress (Huang et al, 2002)—can mediate MC activation. Among these MC activators, immunoglobulin E (IgE) is probably the best known (Ishizaka et al, 1978; Razin et al, 1983; Dvorak et al, 1985). Using angiotensin-II (Ang-II) infusioninduced experimental AAAs in apolipoprotein E-deficient (ApoeÀ/À) mice, we tested whether IgE actions on T cells, MCs, and macrophages contribute to AAA pathogenesis and whether inhibition of IgE activity using FceR1-deficient mice or ablation of plasma IgE using anti-IgE monoclonal antibody (mAb) ameliorates AAA development
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