Abstract
The biological activities of human IgG antibodies predominantly rely on a family of receptors for the Fc portion of IgG, FcγRs: FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, FcγRIIIB, FcRL5, FcRn, and TRIM21. All FcγRs bind IgG at the cell surface, except FcRn and TRIM21 that bind IgG once internalized. The affinity of FcγRs for IgG is determined by polymorphisms of human FcγRs and ranges from 2 × 104 to 8 × 107 M−1. The biological functions of FcγRs extend from cellular activation or inhibition, IgG-internalization/endocytosis/phagocytosis to IgG transport and recycling. This review focuses on human FcγRs and intends to present an overview of the current understanding of how these receptors may contribute to various pathologies. It will define FcγRs and their polymorphic variants, their affinity for human IgG subclasses, and review the associations found between FcγR polymorphisms and human pathologies. It will also describe the human FcγR-transgenic mice that have been used to study the role of these receptors in autoimmune, inflammatory, and allergic disease models.
Highlights
ON HUMAN FcγRs: DEFINITION AND BASIC FUNCTIONSHuman myeloid cells, NK cells, and B cells are equipped with a variety of receptors that enable their interaction with monomeric or aggregated immunoglobulins, antigen–antibody immune complexes, and opsonized particles, cells, or surfaces
A polymorphism resulting in the presence of a histidine or In 20% of individuals FCGR2C encodes for a glutamine at posian arginine residue at position 131 may be referred to tion 13 (Q13 or ORF) and FcγRIIC is expressed; but in 80% of www.frontiersin.org hFcγRs: polymorphisms, transgenic mice, and disease
- The NA1 allotypic variant of FcγRIIIB confers increased phagocytosis of IgG-immune complexes, and is associated with thrombocytopenia in humans; whereas FcγRIIIB-NA2 and copy number variation (CNV) are associated with inflammatory and autoimmune conditions characterized by immune complex deposition
Summary
NK cells, and B cells are equipped with a variety of receptors that enable their interaction with monomeric or aggregated immunoglobulins, antigen–antibody immune complexes, and opsonized (antibody-coated) particles, cells, or surfaces. FcγRs were categorized as either low-affinity receptors that can only bind IgG when present in an immune complex, aggregated, or opsonized; or highaffinity receptors that can bind free or monomeric IgG This terminology has become rather obsolete considering reports of high- and low-affinity interactions for a single receptor toward different Ig subclasses. The prevailing belief was that occupancy of high-affinity receptors with pre-bound monomeric IgG prevents their participation in immediate IgGdependent reactions; this has recently been refuted in vivo [9] Adding to this complexity, human FcγR polymorphisms that modulate affinity for some human IgG subclasses have been described [8] (refer to part 2; Figure 1). Receptors that bind IgG only when it has already been internalized, FcRn (the topic of this review series) and the ubiquitously expressed intracellular receptor TRIM21, may possibly contribute to this phenomenon [reviewed in Ref. [20]]
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