Genetic Variation in Low-To-Medium-Affinity Fcγ Receptors: Functional Consequences, Disease Associations, and Opportunities for Personalized Medicine

Abstract

Fc-gamma receptors (FcγR) are the cellular receptors for Immunoglobulin G (IgG). Upon binding of complexed IgG, FcγRs can trigger various cellular immune effector functions, thereby linking the adaptive and innate immune systems. In humans, six classic FcγRs are known: one high-affinity receptor (FcγRI) and five low-to-medium-affinity FcγRs (FcγRIIA, -B and -C, FcγRIIIA and -B). In this review we describe the five genes encoding the low-to-medium -affinity FcγRs (FCGR2A, FCGR2B, FCGR2C, FCGR3A, and FCGR3B), including well-characterized functionally relevant single nucleotide polymorphisms (SNPs), haplotypes as well as copy number variants (CNVs), which occur in distinct copy number regions across the locus. The evolution of the locus is also discussed. Importantly, we recommend a consistent nomenclature of genetic variants in the FCGR2/3 locus. Next, we focus on the relevance of genetic variation in the FCGR2/3 locus in auto-immune and auto-inflammatory diseases, highlighting pathophysiological insights that are informed by genetic association studies. Finally, we illustrate how specific FcγR variants relate to variation in treatment responses and prognosis amongst autoimmune diseases, cancer and transplant immunology, suggesting novel opportunities for personalized medicine.

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

“…- 13 -Monocytes and monocyte subsets can also be identified based on CD14 expression (discussed in Section 1.1.1), a cell surface co-receptor for LPS [23,95], and whether they express Fc-gamma receptor IIIa (CD16a); see Section 1.2.3 for further subset definitions. CD16a (FcγRIIIA) consists of (i) two extracellular Ig-like domains that bind to IgG, (ii) a transmembrane domain that associates with adaptor proteins containing an immunoreceptor tyrosine-based activating motif (ITAM) and induces downstream intracellular signalling, and finally, (iii) a short intracellular domain [96]. CD16a associated γ-chains are essential for signalling and stable expression, as well as targeting the receptor on the monocyte cell membrane [96].…”

“…CD16a (FcγRIIIA) consists of (i) two extracellular Ig-like domains that bind to IgG, (ii) a transmembrane domain that associates with adaptor proteins containing an immunoreceptor tyrosine-based activating motif (ITAM) and induces downstream intracellular signalling, and finally, (iii) a short intracellular domain [96]. CD16a associated γ-chains are essential for signalling and stable expression, as well as targeting the receptor on the monocyte cell membrane [96]. Humans seem to express two FcγRIIIa (CD16a) allotypes that differ in a single amino acid residue at position 158;…”

Antibody effector functions in malaria and other parasitic diseases: a few needles and many haystacks

“…Genetic variation in Fcγ receptors can result in functional changes including differing affinities of FcγR for Ig or different FcγR expression levels (reviewed by Nagelkerke et al ) and can influence how antibodies toward malaria antigens interact with immune cells expressing these receptors . While clinical significance is not always established, in Asian and African populations a prevalent FcγRIIB mutation has likely been selected for by malaria and a variation in FcγRIIA appears to protect against clinical malaria …”

The therapeutical approaches for rare diseases through the immune processes of IgG Fc Receptors

“…Studies showed such genetic variations affecting immune functions, increasing individual's susceptibility and impacting therapeutical response of disorders/diseases [50][51][52]. Studies also showed that there are many different kinds of disorders/ disease linked with such genetic variations associated dysfunctions of FcRs (gain or loss) with different consequences occurring with heterogeneity among different ethnic groups [53][54][55]. [66].…”