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The kidney glomerular capillaries are frequent sites of immune complex deposition and subsequent neutrophil accumulation in post-infectious and rapidly progressive glomerulonephritis. However, the mechanisms of neutrophil recruitment remain enigmatic, and there is no targeted therapeutic to avert this proximal event in glomerular inflammation. The uniquely human activating Fc receptor Fc[gamma]RIlA promotes glomerular neutrophil accumulation and damage in anti-glomerular basement membrane-induced (anti-GBM-induced) glomerulonephritis when expressed on murine neutrophils. Here, we found that neutrophils are directly captured by immobilized IgG antibodies under physiological flow conditions in vitro through Fc[gamma]RIIA dependent, Abl/Src tyrosine kinase-mediated F-actin polymerization. Biophysical measurements showed that the lifetime of Fc[gamma]RIIA-IgG bonds increased under mechanical force in an F-actin-dependent manner, which could enable the capture of neutrophils under physiological flow. Kidney intravital microscopy revealed that circulating neutrophils, which were similar in diameter to glomerular capillaries, abruptly arrested following anti-GBM antibody deposition via neutrophil Fc[gamma]RIIA and Abl/Src kinases. Accordingly, inhibition of Abl/Src with bosutinib reduced Fc[gamma]RIIA-mediated glomerular neutrophil accumulation and renal injury in experimental, crescentic anti-GBM nephritis. These data identify a pathway of neutrophil recruitment within glomerular capillaries following IgG deposition that may be targeted by bosutinib to avert glomerular injury., Introduction Infiltration of myeloid-derived cells in the glomerulus of the kidney is a key pathogenic event in autoantibody-mediated glomerulonephritis (GN), a leading cause of end-stage renal disease (1-4). Glomerular neutrophil [...]

YTE YTE 0.95 4.61 4.82, To protect against human immunodeficiency virus (HIV-1) infection, broadly neutralizing antibodies (bnAbs) must be active at the portals of viral entry in the gastrointestinal or cervicovaginal tracts. The localization and [...]

The phase III RV144 HIV-1 vaccine trial estimated vaccine efficacy (VE) to be 31.2%. This trial demonstrated that the presence of HIV-1-specific IgG-binding Abs to envelope (Env) V1V2 inversely correlated with infection risk, while the presence of Env-specific plasma IgA Abs directly correlated with risk of HIV-1 infection. Moreover, Ab-dependent cellular cytotoxicity responses inversely correlated with risk of infection in vaccine recipients with low IgA; therefore, we hypothesized that vaccine-induced Fc receptor-mediated (FcR-mediated) Ab function is indicative of vaccine protection. We sequenced exons and surrounding areas of FcR-encoding genes and found one FCGR2C tag SNP (rs114945036) that associated with VE against HIV-1 subtype CRF01_AE, with lysine at position 169 (169K) in the V2 loop (CRF01_AE 169K). Individuals carrying CC in this SNP had an estimated VE of 15%, while individuals carrying CT or TT exhibited a VE of 91%. Furthermore, the rs114945036 SNP was highly associated with 3 other FCGR2CSNPs (rs138747765, rs78603008, and rs373013207). Env-specific IgG and IgG3 Abs, IgG avidity, and neutralizing Abs inversely correlated with CRF01_AE 169K HIV-1 infection risk in the CT- or TT carrying vaccine recipients only. These data suggest a potent role of Fc-γ receptors and Fc-mediated Ab function in conferring protection from transmission risk in the RV144 VE trial., Introduction The Thai phase III RV144 vaccine trial, which tested the ALVACHIV (vCP1521) prime and bivalent clade B/E recombinant gp120 boost vaccine regimen, showed an estimated vaccine efficacy (VE) of [...]

The effector activity of antibodies is dependent on engagement with Fey receptors (FcγRs) and activation of the associated intracellular signaling pathways. Preclinical evaluation of therapeutic humanized or chimeric mAbs to study the interactions of their Fc regions with FcγRs is hampered by substantial structural and functional FcγR diversity among species. In this report, we used mice expressing only human FcγRs to evaluate the contribution of FcγR-mediated pathways to the neutralizing activity of an anti-anthrax toxin chimeric mAb. We observed that the protective activity of this mAb was highly dependent upon FcγR engagement, with minimal protection against anthrax toxin observed in FcγR-deficient mice following mAb administration. We generated anti-anthrax toxin mAbs with specific Fc domain variants with selectively enhanced affinity for particular human FcγRs and assessed their activity in FcγR-humanized mice. We determined that Fc domain variants that were capable of selectively engaging activating FcγRs substantially enhanced the in vitro and in vivo activity of anthrax toxin-neutralizing antibodies. These findings indicate that the application of Fc domain engineering is a feasible strategy to enhance toxin-neutralizing activity and suggest that engineered antitoxin antibodies will have improved therapeutic efficacy., Introduction The development of hybridoma technology has revolutionized medicinal therapeutics, making possible the generation of highly specific mAbs with efficacy against a wide range of diseases. While Fab-antigen interactions play [...]

IgE antibodies bind the high-affinity IgE Fc receptor (FcζRI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response (1,2). Inhibitors of IgE-FcζRI binding have [...]

ABSTRACT Autologous cellular immunotherapies have been used experimentally in humans to treat many types of cancer. These therapies are divided into two principal types: active cellular immunotherapies that rely on [...]

Interactions between IgG Fc and its receptors (Fc[gamma]Rs) have been shown to augment broadly neutralizing Ab-mediated (BnAb-mediated) protection from simian-human immunodeficiency virus (SHIV) challenge. In the current issue of the JCI, Parsons and collaborators compared the BnAb PGT121 with a version engineered to have impaired Fc[gamma]R binding for their ability to protect macaques from an intravenous challenge with SHIV-infected cells as well as to treat already infected animals. Unexpectedly, and in contrast to previous studies, both versions of the Ab were equally able to prevent infection and decrease viral loads in infected animals. Thus, Fc[gamma]R engagement does not always improve the in vivo antiviral activity of BnAbs., Need for non-neutralizing Abs with antiviral activityAbs are highly effective at preventing viral infections. For most viruses, including the lentiviruses human immunodeficiency virus type 1 (HIV-1) and the simian-HIV-1 (SHIV) [...]

The Fc receptor FcRn traffics immunoglobulin G (IgG) in both directions across polarized epithelial cells that line mucosal surfaces, contributing to host defense. We show that FcRn traffics IgG from either apical or basolateral membranes into the recycling endosome (RE), after which the actin motor myosin Vb and the GTPase Rab25 regulate a sorting step that specifies transcytosis without affecting recycling. Another regulatory component of the RE, Rab11a, is dispensable for transcytosis, but regulates recycling to the basolateral membrane only. None of these proteins affect FcRn trafficking away from lysosomes. Thus, FcRn transcytotic and recycling sorting steps are distinct. These results are consistent with a single structurally and functionally heterogeneous RE compartment that traffics FcRn to both cell surfaces while discriminating between recycling and transcytosis pathways polarized in their direction of transport.

In autoimmune disease, Fc receptors (FcRs) form the interface between immune effector cells and their antibody-coated targets, and as such are attractive targets for immunomodulatory therapy. In this issue of the JCI, two highly novel studies of Fc--FcR interactions provide new insights into the role of FcRs in immune thrombocytopenia. Asahi et al. utilized a comprehensive platform of immunological assays to examine the mechanism underlying Helicobacter pylori--associated immune thrombocytopenic purpura, and Ghevaert et al. describe a specially designed antibody that saturates binding sites on fetal platelets without initiating Fc[gamma]R-mediated platelet phagocytosis, preventing the binding of pathological maternal anti-HLA antibodies that cause fetomaternal alloimmune thrombocytopenia (see the related articles beginning on pages 2939 and 2929, respectively). These reports illustrate how a remarkably detailed molecular understanding of the FcR network may translate into new therapeutic strategies with high clinical impact., A focus on the Fc receptor network present on macrophages The interactions between immune cells and their target cells in autoimmune diseases have been the focus of much attention, and [...]

Background Transplacental transfer of maternal immunoglobulin G (IgG) to the fetus helps to protect against malaria and other infections in infancy. Recent studies have emphasized the important role of malaria-specific IgG3 in malaria immunity, and its transfer may reduce the risk of malaria in infancy. Human IgGs are actively transferred across the placenta by binding the neonatal Fc receptor (FcRn) expressed within the endosomes of the syncytiotrophoblastic membrane. Histidine at position 435 (H435) provides for optimal Fc-IgG binding. In contrast to other IgG subclasses, IgG3 is highly polymorphic and usually contains an arginine at position 435, which reduces its binding affinity to FcRn in vitro. The reduced binding to FcRn is associated with reduced transplacental transfer and reduced half-life of IgG3 in vivo. Some haplotypes of IgG3 have histidine at position 435. This study examines the hypotheses that the IgG3-H435 variant promotes increased transplacental transfer of malaria-specific antibodies and a prolonged IgG3 half-life in infants and that its presence correlates with protection against clinical malaria during infancy. Methods and findings In Benin, 497 mother-infant pairs were included in a longitudinal birth cohort. Both maternal and cord serum samples were assayed for levels of IgG1 and IgG3 specific for MSP1.sub.19, MSP2 (both allelic families, 3D7 and FC27), MSP3, GLURP (both regions, R0 and R2), and AMA1 antigens of Plasmodium falciparum. Cord:maternal ratios were calculated. The maternal IgG3 gene was sequenced to identify the IgG3-H435 polymorphism. A multivariate logistic regression was used to examine the association between maternal IgG3-H435 polymorphism and transplacental transfer of IgG3, adjusting for hypergammaglobulinemia, maternal malaria, and infant malaria exposure. Twenty-four percent of Beninese women living in an area highly endemic for malaria had the IgG3-H435 allele (377 women homozygous for the IgG3-R435 allele, 117 women heterozygous for the IgG3-R/H alleles, and 3 women homozygous for the IgG3-H435 allele). Women with the IgG3-H435 allele had a 78% (95% CI 17%, 170%, p = 0.007) increased transplacental transfer of GLURP-R2 IgG3 compared to those without the IgG3-H435 allele. Furthermore, in infants born to mothers with the IgG3-H435 variant, a 28% longer IgG3 half-life was noted (95% CI 4%, 59%, p = 0.02) compared to infants born to mothers homozygous for the IgG3-R435 allele. Similar findings were observed for AMA1, MSP2-3D7, MSP3, GLURP-R0, and GLURP-R2 but not for MSP1.sub.19 and MSP2-FC27. Infants born to women with IgG3-H435 had a 32% lower risk of symptomatic malaria during infancy (incidence rate ratio [IRR] = 0.68 [95% CI 0.51, 0.91], p = 0.01) compared to infants born to mothers homozygous for IgG3-R435. We did not find a lower risk of asymptomatic malaria in infants born to women with or without IgG3-H435. Limitations of the study were the inability to determine (i) the actual amount of IgG3-H435 relative to IgG-R435 in serum samples and (ii) the proportion of malaria-specific IgG produced by infants versus acquired from their mothers. Conclusions An arginine-to-histidine replacement at residue 435 in the binding domain of IgG3 to FcRn increases the transplacental transfer and half-life of malaria-specific IgG3 in young infants and is associated with reduced risk of clinical malaria during infancy. The IgG3-H435 allele may be under positive selection, given its relatively high frequency in malaria endemic areas., Author(s): Celia Dechavanne 1,*, Sebastien Dechavanne 1, Ibrahim Sadissou 2,3,4, Adjimon Gatien Lokossou 2,3,5, Fernanda Alvarado 1, Magalie Dambrun 2,3, Kabirou Moutairou 6, David Courtin 2,3, Gregory Nuel 7, Andre [...]

The Fc receptor-like protein 5 (FCRL5) on B cells has both an immunoreceptor tyrosine-based activation motif (ITAM)-like sequence and two consensus immunoreceptor tyrosine-based inhibitory motifs (ITIM) in its cytoplasmic region. To evaluate its signaling potential, we expressed constructs for chimeric molecules composed of the cytoplasmic region of FCRL5 and the extracellular and transmembrane regions of the IgG Fc receptor FcyRIIB in a B cell line lacking an endogenous Fc receptor. Coligation of this fusion protein with the B cell receptor (BCR) inhibited BCR-mediated calcium mobilization, intracellular tyrosine phosphorylation, and Erk kinase activation. Our mutational analysis indicated that, whereas tyrosines in both the inhibitory and activation motifs are phosphorylated after ligation, only those in ITIMs influence BCR-mediated signaling. This FCRL5 inhibitory effect was mediated through dual ITIM recruitment of the SH2-containing protein tyrosine phosphatase, SHP-1, which in turn dephosphorylates the ITAM-based tyrosines in BCR Ig[alpha]/Ig/[beta] heterodimers. An FCRL5 inhibitory effect on BCR signaling was likewise demonstrable for primary B cells. Although its ligand is presently unknown, we conclude that FCRL5 has the functional potential to serve as an inhibitory coreceptor on mature B cells in humans. B cell receptor | Fc receptor-like protein 5 | inhibitory | SH2 domain-containing tyrosine phosphatase 1

The neonatal Fc receptor for IgG (FcRn) plays a major role in regulating host IgG levels and transporting IgG and associated antigens across polarized epithelial barriers. Selective expression of FcRn [...]

It is now understood that the nonclassical major histocompatibility complex-I molecule FcRn binds albumin and retrieves it from an intracellular degradative fate. Whether FcRn in the liver modulates albumin turnover through effects on biosynthesis and production is not known. Thus we quantified the appearance of biosynthetically labeled albumin in plasma after an intravenous bolus injection of [[sup.3]H]leucine in FcRn-deficient mice. The production rates for both albumin (FcRn substrate) and transferrin (nonsubstrate) are increased by ~20% in FcRn-deficient mice compared with normal mice, likely compensating for the lowered plasma oncotic pressure caused by hypoalbuminemia in FcRn-deficient mice. Determining the magnitude of FcRn-mediated effects on albumin turnover, we then measured the steady-state plasma concentrations of biosynthetically labeled albumin and transferrin during [[sup.3]H]leucine infusion. The concentration of albumin was ~40% lower in FcRn-deficient mice compared with normal mice. Furthermore, the ~40% lower plasma albumin concentration in FcRn-deficient mice along with the ~20% increase in albumin production indicate, by the mass-balance equation, that albumin degradation in FcRn-deficient mice is twice that of normal mice. These studies of biosynthetically labeled, and thus native, albumin support our previous finding that FcRn protects albumin from degradation. Permitting quantification of the magnitude of FcRn-mediated recycling, they further indicate that FcRn has extraordinary capacity: the amount of albumin saved from degradation by FeRn-mediated recycling is the same as that produced by the liver. production; clearance; steady-state; kinetics; Fc receptor