IgE-Mediated Allergen Presentation via Fc Epsilon Rl on Antigen-Presenting Cells

Abstract

In atopic individuals, cutaneous antigen-presenting cells (APC), i.e. Langerhans’ cells (LC) and dermal dendritic cells (DDC), frequently display anti-IgE reactivity. While earlier observations suggested that this phenomenon results from the binding of (complexed) IgE to the low affinity IgE receptor (FcεRII/CD23), recent evidence exists that LC and DDC, as well as peripheral blood dendritic cells and monocytes from atopic individuals, can bind monomeric IgE via the high-affinity receptor for IgE (FcεRI). We have now found that FcεRI, both quantitatively and qualitatively, is the pivotal serum IgE-binding structure on APC of atopic individuals, that FcεRI on APC functions as allergen-focusing molecule and that allergens are more efficiently taken up, processed and presented to T cells following targeting to APC via FcεRI compared to allergen binding to APC in the conventional manner. In vivo, FcεRI-IgE-dependent allergen presentation may critically lower atopic individuals’ threshold to mount allergen-specific T cell responses. This would result in the perpetuation of allergen-specific IgE production (type I reactions) and perhaps even in the occurrence of T-cell-mediated delayed-type hypersensitivity reactions in allergen-exposed tissues.

Engagement of the FcεRI Stimulates the Production of IL-16 in Langerhans Cell-Like Dendritic Cells

“…More importantly, we show that LLDC derived from monocytes of AD patients carry high levels of Fc⑀RI and low levels of CD23 (the low affinity IgE receptor), similar to LC isolated from AD lesions, while LLDC derived from monocytes of healthy subjects expressed only low levels of Fc⑀RI, similar to LC isolated from normal skin (28). There was also evidence that LLDC express only the ␣-and ␥-chains, not the ␤-chain, of Fc⑀RI, a characteristic of LC (19).…”

“…Importantly, the development of a positive test reaction has been shown to strictly depend on the presence og IgE-bearing epidermal LC, circulating specific IgE Abs, and allergen-reactive T cells (20). The current explanation is that LC capture allergen via specific IgE molecules bound to the high affinity IgE receptor and subsequently induce an allergen-specific cutaneous T cell response (19). Because allergen-dependant LC activation and CD4 ϩ T cell infiltration are key elements of the atopy patch test reaction, we used this model to investigate whether Fc⑀RI-dependant induction of IL-16 would also occur in LC in vivo.…”

“…A current concept is that epidermal LC in AD overexpress Fc⑀RI and use this structure for the selective and highly efficient uptake of IgE-bound Ags. Preferential presentation of these Ags subsequently leads to the induction of allergen-specific T cell responses that are capable of promoting IgE production and DTH responses (19). This understanding is supported by the clinical observation that DTH-like skin lesions can be provoked in a subset of AD patients by epicutaneous application of allergen (atopy patch test), with positive patch test reactions depending on the presence of IgE-bearing LC in the epidermis (20).…”

Impact of CD40 Ligand, B Cells, and Mast Cells in Peanut-Induced Anaphylactic Responses

“…This is relevant to our findings because we observed that absence of the FcRI ␣-chain did not entirely abrogate anaphylactic responses. It has been reported that mouse macrophages do not express FcRI (40,44,45) and, in addition, there is evidence that both IgE and IgG1 can bind to the Fc␥RIII on MCs (46 -49). Hence, the partial protection observed in FcRI-deficient mice may suggest that the remaining anaphylactic response may be mediated via IgG1-dependent activation of Fc␥RIII on MCs.…”

The immunoglobulin-like modules Cε3 and α2 are the minimal units necessary for human IgE-FcεRI interaction

“…The interaction of IgE antibodies with FcεRI on effector cells (e.g., mast cells, basophils, eosinophils) (2, 3) and inducer cells (monocytes, dendritic cells) (4,5) of the allergic reaction represents the key event responsible for the acute and chronic manifestations of type I allergy. Despite the central role of the IgE-FcεRI interaction in the pathogenesis of atopy, the precise mode of the IgEFcεRI interaction is not fully understood, and the minimal domains required for this interaction have not yet been produced as active recombinant proteins.…”