Unconventional cell death in erythroid cells.

Abstract

deglycosylation. A pilot study in 2009 confirmed the activity of 3G8 and GMA161 in ITP; however, both antibodies were associated with a similar toxicity profile. These studies provided proof of principle that FcgRIII contributed to clearance of antibody-coated platelets in ITP. However, toxicity from FcgRIII activation halted their further consideration as ITP therapeutics. Humans express several Fcg receptors in a cell-specific manner. FcgR1, FcgRIIa, FCgRIIc, and FcgRIIIa are “activating” receptors, whereas FcgRIIb is inhibitory. FcgRI and FcgRIIIa contain a ligand-bindinga chain, but signal through the associated g chain dimer, which contains an immunoreceptor tyrosine-based activation motif. FcgRIIIa is a low-affinity receptor that preferentially binds immune complexes; ligation of FcgRIIIa leads to phosphorylation of the immunoreceptor tyrosine-based activation motif, recruitment of SYK, and activation of downstream targets including SOS, RAS, and phosphatidylinositol 3-kinase, causing cellular activation, phagocytosis, and cytokine release. Though it had been assumed that the toxicity of 3G8 was a consequence of FcgR activation by the Fc region, Yu et al reasoned that the parallel toxicity of GMA161 suggested that these responses were due instead to ligation of FcgRIIIA by the bivalent F(ab9)2 region. To test this hypothesis, they produced a monovalent 3G8 single chain variable region (scFv) fused to human serum albumin (HSA) (see figure). This fusion protein specifically bound and blocked binding of human immunoglobulin G to the extracellular domain of human FcgRIIIa. The investigators then created a murine counterpart of the 3G8 scFv-HSA fusion protein using an scFv from monoclonal antibody 2.4G2, which targets murine FcgRIII/IIb, and murine serum albumin (MSA). This construct specifically bound its target and inhibited development of thrombocytopenia in mice treated with the antiplatelet antibody MWReg30, which induces thrombocytopenia by stimulating platelet clearance through FcgRIII. In contrast, 2.4G2 scFv-MSA did not impair platelet clearance in response to 6A6, a murine antiplatelet antibody that mediates clearance through FcgRIV. Importantly, the 2.4G2 scFv-MSA fusion protein had an extended half-life and did not cause the systemic drop in temperature or activation of basophils seen with the bivalent parental antibody, which resulted from activation of FcgRIII. This study extends previous work demonstrating the role of FcgRIII in ITP and suggests the feasibility of a monovalent FcgRIII scFv-fusion protein as an ITP therapeutic. However, many questions remain. For example, human ITP is a complex disorder with a heterogeneous array of antiplatelet antibodies that may cause platelet clearance through different Fcg receptors. Moreover, a recent report suggests a role for an entirely different receptor, the hepatocyte AshwellMorell receptor, in clearance of platelets bound by antibodies to GP1ba that cause Fcgindependent activation and desialylation. Finally, it is likely that inhibition of platelet production is of primary importance in at least some cases of ITP. The late baseball legend, Yogi Berra, was famous for his “Yogi-isms,” the most wellknown of which is “It ain’t over ’til it’s over,” meaning that a baseball game was not over until the last out, and there was always a chance for a comeback. In this report,Yu et al show that this also applies to treatment of ITP through inhibition of FcgRIII. Future studies of the 3G8 scFv-HSA fusion protein or its derivatives in human ITP will be of great interest. Conflict-of-interest disclosure: The author declares no competing financial interests. n

DOI: 10.1182/blood-2015-11-677229

Cite this paper

@article{Bruce2016UnconventionalCD, title={Unconventional cell death in erythroid cells.}, author={Lesley J Bruce and David J Anstee}, journal={Blood}, year={2016}, volume={127 1}, pages={12-4} }