The multiple facets of FcRn in immunity.

The neonatal Fc receptor, FcRn, is best known for its role in transporting IgG in various tissues, providing newborns with humoral immunity, and for prolonging the half-life of IgG. Recent findings implicate the involvement of FcRn in a far wider range of biological and immunological processes, as FcRn has been found to bind and extend the half-life of albumin; to be involved in IgG transport and antigen sampling at mucosal surfaces; and to be crucial for efficient IgG-mediated phagocytosis. Herein, the function of FcRn will be reviewed, with emphasis on its recently documented significance for IgG polymorphisms affecting the half-life and biodistribution of IgG3, on its role in phagocyte biology, and the subsequent role for the presentation of antigens to lymphocytes.

Staphylococcus aureus formyl peptide receptor-like 1 inhibitor (FLIPr) and its homologue FLIPr-like are potent FcγR antagonists that inhibit IgG-mediated effector functions.

To evade opsonophagocytosis, Staphylococcus aureus secretes various immunomodulatory molecules that interfere with effective opsonization by complement and/or IgG. Immune-evasion molecules targeting the phagocyte receptors for these opsonins have not been described. In this study, we demonstrate that S. aureus escapes from FcγR-mediated immunity by secreting a potent FcγR antagonist, FLIPr, or its homolog FLIPr-like. Both proteins were previously reported to function as formyl peptide receptor inhibitors. Binding of FLIPr was mainly restricted to FcγRII receptors, whereas FLIPr-like bound to different FcγR subclasses, and both competitively blocked IgG-ligand binding. They fully inhibited FcγR-mediated effector functions, including opsonophagocytosis and subsequent intracellular killing of S. aureus by neutrophils and Ab-dependent cellular cytotoxicity of tumor cells by both neutrophils and NK cells. In vivo, treatment of mice with FLIPr-like prevented the development of an immune complex-mediated FcγR-dependent Arthus reaction. This study reveals a novel immune-escape function for S. aureus-secreted proteins that may lead to the development of new therapeutic agents in FcγR-mediated diseases.

Proximity to livestock farms and COVID-19 in the Netherlands, 2020-2021.

OBJECTIVES: In the Netherlands, during the first phase of the COVID-19 epidemic, the hotspot of COVID-19 overlapped with the country's main livestock area, while in subsequent phases this distinct spatial pattern disappeared. Previous studies show that living near livestock farms influence human respiratory health and immunological responses. This study aimed to explore whether proximity to livestock was associated with SARS-CoV-2 infection. METHODS: The study population was the population of the Netherlands excluding the very strongly urbanised areas and border areas, on January 1, 2019 (12, 628, 244 individuals). The cases are the individuals reported with a laboratory-confirmed positive SARS-CoV-2 test with onset before January 1, 2022 (2, 223, 692 individuals). For each individual, we calculated distance to nearest livestock farm (cattle, goat, sheep, pig, poultry, horse, rabbit, mink). The associations between residential (6-digit postal-code) distance to the nearest livestock farm and individuals' SARS-CoV-2 status was studied with multilevel logistic regression models. Models were adjusted for individuals' age categories, the social status of the postal code area, particulate matter (PM10)- and nitrogen dioxide (NO2)-concentrations. We analysed data for the entire period and population as well as separately for eight time periods (Jan-Mar, Apr-Jun, Jul-Sep and Oct-Dec in 2020 and 2021), four geographic areas of the Netherlands (north, east, west and south), and for five age categories (0-14, 15-24, 25-44, 45-64 and > 65 years). RESULTS: Over the period 2020-2021, individuals' SARS-CoV-2 status was associated with living closer to livestock farms. This association increased from an Odds Ratio (OR) of 1.01 (95% Confidence Interval [CI] 1.01-1.02) for patients living at a distance of 751-1000 m to a farm to an OR of 1.04 (95% CI 1.04-1.04), 1.07 (95% CI 1.06-1.07) and 1.11 (95% CI 1.10-1.12) for patients living in the more proximate 501-750 m, 251-500m and 0-250 m zones around farms, all relative to patients living further than 1000 m around farms. This association was observed in three out of four quarters of the year in both 2020 and 2021, and in all studied geographic areas and age groups. CONCLUSIONS: In this exploratory study with individual SARS-CoV-2 notification data and high-resolution spatial data associations were found between living near livestock farms and individuals' SARS-CoV-2 status in the Netherlands. Verification of the results in other countries is warranted, as well as investigations into possible underlying exposures and mechanisms.

Competition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential.

Human IgG3 displays the strongest effector functions of all IgG subclasses but has a short half-life for unresolved reasons. Here we show that IgG3 binds to IgG-salvage receptor (FcRn), but that FcRn-mediated transport and rescue of IgG3 is inhibited in the presence of IgG1 due to intracellular competition between IgG1 and IgG3. We reveal that this occurs because of a single amino acid difference at position 435, where IgG3 has an arginine instead of the histidine found in all other IgG subclasses. While the presence of R435 in IgG increases binding to FcRn at neutral pH, it decreases binding at acidic pH, affecting the rescue efficiency-but only in the presence of H435-IgG. Importantly, we show that in humans the half-life of the H435-containing IgG3 allotype is comparable to IgG1. H435-IgG3 also gave enhanced protection against a pneumococcal challenge in mice, demonstrating H435-IgG3 to be a candidate for monoclonal antibody therapies.

FcRn: an IgG receptor on phagocytes with a novel role in phagocytosis.

Here, we report that the MHC class I-related neonatal Fc receptor (FcRn) is expressed within azurophilic and specific granules of neutrophils and relocates to phagolysosomes on phagocytosis of IgG-opsonized bacteria. We found FcRn to enhance phagocytosis in a pH-dependent manner which was independent of IgG recycling. IgG-opsonized bacteria were inefficiently phagocytosed by neutrophils from beta2M knock-out or FcRn alpha-chain knock-out mice, which both lack expression of FcRn. Similarly, low phagocytic activity was also observed with mutated IgG (H435A), which is incapable of binding to FcRn, while retaining normal binding to classical leukocyte Fcgamma receptors. Finally, a TAT peptide representing intracellular endocytosis and transport motifs within FcRn strongly inhibited IgG-mediated phagocytosis. These findings support a novel concept in which FcRn fulfills a major role in IgG-mediated phagocytosis.

Working mechanism of immunoglobulin A1 (IgA1) protease: cleavage of IgA1 antibody to Neisseria meningitidis PorA requires de novo synthesis of IgA1 Protease.

Neisseria meningitidis secretes a protease that specifically cleaves the hinge region of immunoglobulin A1 (IgA1), releasing the effector (Fc) domain of IgA1 from the antigen binding (Fab) determinants. Theoretically, the remaining Fab fragments can block pathogen receptors or toxins and still provide protection. Here, we describe binding of V-gene-matched human IgA1 and IgA2 to PorA of strain H44/76. On live meningococci, efficient cleavage of IgA1, but not cleavage of IgA2, was observed, and up to approximately 80% of the IgA1 Fc tails were lost from the meningococcal surface within 30 min. No cleavage of IgA1 was found on an isogenic H44/76 strain lacking IgA1 protease. Furthermore, our data indicate that PorA-bound IgA1 is masked by the serogroup B polysaccharide capsule, rendering the IgA1 less accessible to degradation by secreted IgA1 protease present in the bacterial surroundings. Experiments with protein synthesis inhibitors showed that de novo production of IgA1 protease was responsible for cleavage of PorA-bound IgA1 on encapsulated bacteria. Finally, our data suggest that cleavage of IgA1 by IgA1 protease releases a significant proportion of Fab fragments from the bacterium, probably as a result of their reduced avidity compared to that of whole antibodies.

Central role of complement in passive protection by human IgG1 and IgG2 anti-pneumococcal antibodies in mice.

Streptococcus pneumoniae is an important cause of morbitity and mortality worldwide. Capsule-specific IgG1 and IgG2 Abs are induced upon vaccination with polysaccharide-based vaccines that mediate host protection. We compared the protective capacity of human recombinant serogroup 6-specific IgG1 and IgG2 Abs in mice deficient for either leukocyte FcR or complement factors. Human IgG1 was found to interact with mouse leukocyte FcR in vitro, whereas human IgG2 did not. Both subclasses induced complement activation, resulting in C3c deposition on pneumococcal surfaces. Passive immunization of C57BL/6 mice with either subclass before intranasal challenge with serotype 6A induced similar degrees of protection. FcgammaRI- and III-deficient mice, as well as the combined FcgammaRI, II, and III knockout mice, were protected by passive immunization, indicating FcR not to be essential for protection. C1q or C2/factor B knockout mice, however, were not protected by passive immunization. Passively immunized C2/factor B(-/-) mice displayed higher bacteremic load than C1q(-/-) mice, supporting an important protective role of the alternative complement pathway. Spleens from wild-type and C1q(-/-) mice showed hyperemia and thrombotic vessel occlusion, as a result of septicemic shock. Notably, thrombus formation was absent in spleens of C2/factor B(-/-) mice, suggesting that the alternative complement pathway contributes to shock-induced intravascular coagulation. These studies demonstrate complement to play a central role in Ab-mediated protection against pneumococcal infection in vivo, as well as in bacteremia-associated thrombotic complications.