Ins and outs of the IgA receptor, FcαRI

Abstract

The interaction between immunoglobulins and Fc receptors has been recognized as a key element of the body's natural defense, and play a crucial role in FcR-mediated immunotherapy. FcαRI, the receptor for IgA, represents a transmembrane receptor consisting of two extracellular Ig-like domains, a 19 amino acid transmembrane region and a short (41 amino acid) cytoplasmic tail devoid of any recognized signaling motifs. Notably, most FcαRI research has focussed on the receptors found in complex with the ITAM (immunoreceptor tyrosine-based activation motif)-bearing FcR γ-chains, which was found crucial for coupling FcR to cellular activation, including phagocytosis, antigen presentation, ADCC, superoxide production and cytokine release. Cytokine induced inside-out signaling refers to the ability of cytokines to increase the binding capacity of FcαRI for IgA-immune complexes without effects on receptor expression levels, a process critically dependent on the FcαRI intracellular domain but not on the FcR γ-chains. In the present thesis, the emphasis was placed on the biological role of the FcαRI α-chain, which lead to a better insight in IgA receptor complex formation, FcαRI protein turn-over and cytokine-induced FcαRI activation, a critical step in FcαRI functioning. We addressed the molecular basis of the FcαRI-FcR γ-chain transmembrane interaction important for cellular activation, identified new mediators in FcαRI signaling for which two showed their functional importance in regulating the molecular switch for FcαRI activation. The third novel identified protein displayed its role in modulation of FcαRI-FcR γ-chain complex formation on protein levels. Last, we investigated the contribution of receptor avidity but also affinity in IgA immune complex binding. Thorough understanding of the role of IgA and its receptor will contribute to our insight in both normal and pathological immunity. These novel findings and future work contributing to the IgA receptor biology may furthermore unravel FcαRI signaling and regulation, and may well catalyze the development of novel strategies to modulate FcαRI function for immunotherapy.