FCER1

Abstract: Background Dendritic cells (DCs) are potent antigen-presenting cells that express FceRI, the high-affinity IgE receptor. Although the downregulation of basophil FceRI during anti-IgE therapy with omalizumab is well documented, its effect on FceRI expression by DCs has not been reported. Objective We hypothesized that IgE regulates surface FceRI expression by DCs in vivo and that, consequently, anti-IgE therapy decreases FceRI expression by DCs. Methods In a randomized, double-blind, placebo-controlled clinical trial 24 subjects (16 receiving omalizumab and 8 receiving placebo) with seasonal allergic rhinitis received the study drug on days 0 and 28. Serial blood samples drawn on days 0, 7, 14, 28, and 42 were analyzed for precursor DC1 (pDC1) and pDC2 surface expression of FceRIα by using flow cytometry. Results Omalizumab caused a significant decrease in surface FceRI expression at all time points examined in both the pDC1 and pDC2 subsets. No significant change was seen with placebo. The maximum decrease in FceRI expression in the omalizumab group was 52% and 83%, respectively, for the pDC1 and pDC2 subsets. The decrease in FceRI expression by both pDC subsets correlated with the decrease in serum-free IgE and was of a similar magnitude to that found in basophils. A 10-fold decrease in IgE corresponded to a 42% and 54% decrease in surface FceRI expression by the pDC1 and pDC2 subsets, respectively. Conclusion These results demonstrate that anti-IgE therapy causes a rapid decrease in DC surface FceRI expression and establish that IgE is an important regulator of FceRI expression by DCs.

Abstract: Mast cells (MCs) are portions of the innate and adaptive immune system derived from bone marrow (BM) progenitors that are rich in cytoplasmic granules. MC maturation, phenotype, and function are determined by their microenvironment. MCs accumulate at inflammatory sites associated with atopy, wound healing, and malignancies. They interact with the external environment and are predominantly located in close proximity of blood vessels and sensory nerves. MCs are key initiators and modulators of allergic, anaphylactic, and other inflammatory reactions, by induction of vasodilation, promoting of vascular permeability, recruitment of inflammatory cells, facilitation of adaptive immune responses, and modulation of angiogenesis, and fibrosis. They express a wide range of receptors, e.g., for IgE (FceRI), IgG (FcγR), stem cell factor (SCF) (KIT receptor or CD117), complement (including C5aR), and cytokines, that upon activation trigger various signaling pathways. The final consequence of such ligand receptor–based activation of MCs is the release of a broad array of mediators which are classified in three categories. While some mediators are preformed and remain stored in granules such as heparin, histamine, and enzymes mainly chymase and tryptase, others are de novo synthesized only after activation including LTB4, LTD4, PDG2, and PAF, and the cytokines IL-10, IL-8, IL-5, IL-3, IL-1, GM-CSF, TGF-β, VEGF, and TNF-α. Depending on the stimulus, MCs calibrate their pattern of mediator release, modulate the amplification of allergic inflammation, and are involved in the resolution of the immune responses. Here, we review recent findings and reports that help to understand the MC biology, pathology, and physiology of diseases with MC involvement.

Abstract: IgE has a key role in the pathogenesis of allergic responses through its ability to activate mast cells via the receptor FceR1. In addition to mast cells, many cell types implicated in atherogenesis express FceR1, but whether IgE has a role in this disease has not been determined. Here, we demonstrate that serum IgE levels are elevated in patients with myocardial infarction or unstable angina pectoris. We found that IgE and the FceR1 subunit FceR1α were present in human atherosclerotic lesions and that they localized particularly to macrophage-rich areas. In mice, absence of FceR1α reduced inflammation and apoptosis in atherosclerotic plaques and reduced the burden of disease. In cultured macrophages, the presence of TLR4 was required for FceR1 activity. IgE stimulated the interaction between FceR1 and TLR4, thereby inducing macrophage signal transduction, inflammatory molecule expression, and apoptosis. These IgE activities were reduced in the absence of FceR1 or TLR4. Furthermore, IgE activated macrophages by enhancing Na+/H+ exchanger 1 (NHE1) activity. Inactivation of NHE1 blocked IgE-induced macrophage production of inflammatory molecules and apoptosis. Cultured human aortic SMCs (HuSMCs) and ECs also exhibited IgE-induced signal transduction, cytokine expression, and apoptosis. In human atherosclerotic lesions, SMCs and ECs colocalized with IgE and TUNEL staining. This study reveals what we believe to be several previously unrecognized IgE activities that affect arterial cell biology and likely other IgE-associated pathologies in human diseases.