Evolutionary Story of the Low/Medium-Affinity IgG Fc Receptor Gene Cluster.

Julien Lejeune,Hervé Watier,Guillaume Brachet

doi:10.3389/fimmu.2019.01297

Abstract

Low/intermediate affinity Fc-gamma receptors (FcγR) are crucial for the recognition of immune complexes and IgG-sensitized microorganisms by phagocytic and cytotoxic effector cells. In all mammalian species studied so far, their genes are clustered in a single locus. However, this locus differs between humans and mice, both in the number of genes and the structure/function of the encoded receptors. We show that murine fcgr3 evolved through several steps into FCGR2A, its ortholog, which is specific to primates. One of these steps was the insertion of a retroviral element bringing a new intracellular exon comprising a non-canonical ITAM motif. We also show that the fcgr3-hspa6-fcgr4-fcgr2b module in mammals that has evolved in a FCGR2A-HSPA6-FCGR4-FCGR2B module in primates, was subsequently duplicated in apes through a Non-Allelic Homologous Recombination (NAHR), giving birth to FCGR2C, a hybrid gene between FCGR2B and FCGR2A. The FCGR4 duplication, which occurred simultaneously, eventually resulted in the emergence of FCGR3B, while FCGR3A remained the true FCGR4 ortholog. FCGR2C and FCGR3B, markers of this NAHR, are present in gorillas and chimpanzees, whereas they are absent in orangutans and more distant primates, such as gibbons and macaques. These data need to be taken into account when testing IgG-based therapies in animal species.

Highlights

Receptors for the Fc portion of IgG (FcγR) play an important role by connecting innate and adaptive immunity
Mouse Fcgr3 and Fcgr2b show no homology except between their EC1 and EC2 exons, human FCGR2A aligns with FCGR2B at the level of EC1 and EC2 exons, and on a large stretch extending for the 5′ part of EC2 to the 3′ part of IC3 of FCGR2B
We searched the genomes of non-human primates for low/medium affinity FCGR orthologs, amplified the corresponding genes using a longPCR approach, characterized the products and deduced the evolutionary history of this locus between mice and humans

Summary

Introduction

Receptors for the Fc portion of IgG (FcγR) play an important role by connecting innate and adaptive immunity. This is true for receptors of low/intermediate affinity which are specialized in the recognition of immune complexes and IgG-sensitized microorganisms or target cells by phagocytic and cytotoxic effector cells. In all mammalian species studied so far, all the genes encoding these low/intermediate affinity FcγRs are clustered in a single locus This clustering probably allows gene plasticity and rapid evolution to maintain adequate binding of the different FcγR to their different ligands (IgG subclasses), which are themselves in continuous evolution, and to maintain the immune functions conferred to the effector cells. FcγRIII and FcγRIV, as well as the high affinity FcγRI (gene located on chromosome 3), are associated with the FcR-γ chain, which carries an Immunoreceptor Tyrosine-based Activation Motif (ITAM) required for cell activation [2, 3]

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Conclusion