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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 17028

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Special Issue Editor

Dr. Markus Biburger

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Guest Editor

1. Division of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erlangen, Germany
2. Medical Immunology Campus Erlangen, University of Erlangen-Nürnberg, Erlangen, Germany
Interests: antibody effector functions; myeloid effector cells; immunological tumor targeting; novel CAR immunotherapy strategies; imaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Antibodies are central mediators of immunological defense mechanisms, are used as therapeutic agents in the clinics, but are also functionally involved in various immune-mediated disorders. Whereas antibodies accomplish some of their biological functions autonomously, many effector functions strictly depend on the interaction with distinct receptors (FcR) that bind antibody Fc domains. The purpose of this Special Issue on “Fc Receptors” is to report the recent progress achieved in the exceedingly complex topic of the interaction between these receptors and their antibody ligands.

Due to the multitude of:

Molecular partners that can be involved in antibody–Fc receptor interactions;
Patterns of glycosylation which affect binding affinities;
Biological functions, such as IgG homeostasis and transcytosis by FcRn, proteasomal degradation of intracellular antibody load via cytosolic TRIM21, killing or phagocytosis of opsonized target cells via Fcγ receptors, activation of the immune system e.g. by histamine release upon FcεR triggering on mast cells, and much more;
Members of the rather novel family of FcR-like (FCRL) molecules;
Clinical manifestations of adverse FcR engagement such as type I and some type II hypersensitivity reactions and autoimmune diseases;
Clinical applications of FcR-mediated antibody effector functions, e.g., in cancer immunotherapy;
The various effector cell types involved in these processes;
Genetic polymorphisms in human FcRs, which are associated with susceptibility to various diseases and/or differences in the effectiveness of therapeutic antibodies;

there is a correspondingly broad field of topics that will fit into this Special Issue. In addition to biological, preclinical, and clinical research, also work that focusses on mathematical and structural models is welcome to be submitted.

This Special Issue on “Fc Receptors” invites original research and—since the International Journal of Molecular Sciences may additionally reach an audience beyond that of common Immunology journals—also review articles in the field.

Dr. Markus Biburger
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

FcγR
FcεR
FcμR
FcαR
FcRn
neonatal Fc receptor
TRIM21
cytosolic Fc receptor
antibody effector functions
Fc–Fc receptor interaction
immune regulation
inflammation
immunotherapy
antibody-dependent cellular cytotoxicity
antibody-dependent cellular phagocytosis
mast cells
neutrophils
macrophages
monocytes
natural killer cells

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Published Papers (6 papers)

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Research

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14 pages, 4081 KiB

Open AccessArticle

Inhibition of BET Proteins Regulates Fcγ Receptor Function and Reduces Inflammation in Rheumatoid Arthritis

by Divya Shankar, Giovanna Merchand-Reyes, Nathaniel J. Buteyn, Ramasamy Santhanam, Huiqing Fang, Krishan Kumar, Xiaokui Mo, Latha P. Ganesan, Wael Jarjour, Jonathan P. Butchar and Susheela Tridandapani

Int. J. Mol. Sci. 2023, 24(8), 7623; https://doi.org/10.3390/ijms24087623 - 21 Apr 2023

Cited by 4 | Viewed by 2175

Abstract

Overactivation of immune responses is a hallmark of autoimmune disease pathogenesis. This includes the heightened production of inflammatory cytokines such as Tumor Necrosis Factor α (TNFα), and the secretion of autoantibodies such as isotypes of rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA). Fcγ receptors (FcγR) expressed on the surface of myeloid cells bind Immunoglobulin G (IgG) immune complexes. Recognition of autoantigen-antibody complexes by FcγR induces an inflammatory phenotype that results in tissue damage and further escalation of the inflammatory response. Bromodomain and extra-terminal protein (BET) inhibition is associated with reduced immune responses, making the BET family a potential therapeutic target for autoimmune diseases such as rheumatoid arthritis (RA). In this paper, we examined the BET inhibitor PLX51107 and its effect on regulating FcγR expression and function in RA. PLX51107 significantly downregulated expression of FcγRIIa, FcγRIIb, FcγRIIIa, and the common γ-chain, FcϵR1-γ, in both healthy donor and RA patient monocytes. Consistent with this, PLX51107 treatment attenuated signaling events downstream of FcγR activation. This was accompanied by a significant decrease in phagocytosis and TNFα production. Finally, in a collagen-induced arthritis model, PLX51107-treatment reduced FcγR expression in vivo accompanied by a significant reduction in footpad swelling. These results suggest that BET inhibition is a novel therapeutic approach that requires further exploration as a treatment for patients with RA. Full article

(This article belongs to the Special Issue Fc Receptors 2.0)

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14 pages, 8950 KiB

Open AccessArticle

Evidence for Extensive Duplication and Subfunctionalization of FCRL6 in Armadillo (Dasypus novemcinctus)

by Maria Carolina Matos, Ana Pinheiro, Randall S. Davis and Pedro J. Esteves

Int. J. Mol. Sci. 2023, 24(5), 4531; https://doi.org/10.3390/ijms24054531 - 25 Feb 2023

Cited by 1 | Viewed by 1849

Abstract

The control of infections by the vertebrate adaptive immune system requires careful modulation to optimize defense and minimize harm to the host. The Fc receptor-like (FCRL) genes encode immunoregulatory molecules homologous to the receptors for the Fc portion of immunoglobulin (FCR). To date, nine different genes (FCRL1–6, FCRLA, FCRLB and FCRLS) have been identified in mammalian organisms. FCRL6 is located at a separate chromosomal position from the FCRL1-5 locus, has conserved synteny in mammals and is situated between the SLAMF8 and DUSP23 genes. Here, we show that this three gene block underwent repeated duplication in Dasypus novemcinctus (nine-banded armadillo) resulting in six FCRL6 copies, of which five appear functional. Among 21 mammalian genomes analyzed, this expansion was unique to D. novemcinctus. Ig-like domains that derive from the five clustered FCRL6 functional gene copies show high structural conservation and sequence identity. However, the presence of multiple non-synonymous amino acid changes that would diversify individual receptor function has led to the hypothesis that FCRL6 endured subfunctionalization during evolution in D. novemcinctus. Interestingly, D. novemcinctus is noteworthy for its natural resistance to the Mycobacterium leprae pathogen that causes leprosy. Because FCRL6 is chiefly expressed by cytotoxic T and NK cells, which are important in cellular defense responses against M. leprae, we speculate that FCRL6 subfunctionalization could be relevant for the adaptation of D. novemcinctus to leprosy. These findings highlight the species-specific diversification of FCRL family members and the genetic complexity underlying evolving multigene families critical for modulating adaptive immune protection. Full article

(This article belongs to the Special Issue Fc Receptors 2.0)

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18 pages, 2872 KiB

Open AccessArticle

Fcα Receptor-1-Activated Monocytes Promote B Lymphocyte Migration and IgA Isotype Switching

by Amélie V. Bos, Melissa M. J. van Gool, Annelot C. Breedveld, Richard van der Mast, Casper Marsman, Gerd Bouma, Mark A. van de Wiel, S. Marieke van Ham, Reina E. Mebius and Marjolein van Egmond

Int. J. Mol. Sci. 2022, 23(19), 11132; https://doi.org/10.3390/ijms231911132 - 22 Sep 2022

Cited by 3 | Viewed by 2449

Abstract

Patients with inflammatory bowel disease (IBD) produce enhanced immunoglobulin A (IgA) against the microbiota compared to healthy individuals, which has been correlated with disease severity. Since IgA complexes can potently activate myeloid cells via the IgA receptor FcαRI (CD89), excessive IgA production may contribute to IBD pathology. However, the cellular mechanisms that contribute to dysregulated IgA production in IBD are poorly understood. Here, we demonstrate that intestinal FcαRI-expressing myeloid cells (i.e., monocytes and neutrophils) are in close contact with B lymphocytes in the lamina propria of IBD patients. Furthermore, stimulation of FcαRI-on monocytes triggered production of cytokines and chemokines that regulate B-cell differentiation and migration, including interleukin-6 (IL6), interleukin-10 (IL10), tumour necrosis factor-α (TNFα), a proliferation-inducing ligand (APRIL), and chemokine ligand-20 (CCL20). In vitro, these cytokines promoted IgA isotype switching in human B cells. Moreover, when naïve B lymphocytes were cultured in vitro in the presence of FcαRI-stimulated monocytes, enhanced IgA isotype switching was observed compared to B cells that were cultured with non-stimulated monocytes. Taken together, FcαRI-activated monocytes produced a cocktail of cytokines, as well as chemokines, that stimulated IgA switching in B cells, and close contact between B cells and myeloid cells was observed in the colons of IBD patients. As such, we hypothesize that, in IBD, IgA complexes activate myeloid cells, which in turn can result in excessive IgA production, likely contributing to disease pathology. Interrupting this loop may, therefore, represent a novel therapeutic strategy. Full article

(This article belongs to the Special Issue Fc Receptors 2.0)

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17 pages, 7972 KiB

Open AccessArticle

The Neonatal Fc Receptor Is Elevated in Monocyte-Derived Immune Cells in Pancreatic Cancer

by Justin Thomas, Molly A. Torok, Kriti Agrawal, Timothy Pfau, Trang T. Vu, Justin Lyberger, Hsiaochi Chang, Alyssa Marie M. Castillo, Min Chen, Bryan Remaily, Kyeongmin Kim, Zhiliang Xie, Mary E. Dillhoff, Samuel K. Kulp, Gregory K. Behbehani, Zobeida Cruz-Monserrate, Latha P. Ganesan, Dwight H. Owen, Mitch A. Phelps, Christopher C. Coss and Thomas A. Mace Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(13), 7066; https://doi.org/10.3390/ijms23137066 - 25 Jun 2022

Cited by 4 | Viewed by 3654

Abstract

The neonatal Fc receptor (FcRn) is responsible for recycling of IgG antibodies and albumin throughout the body. This mechanism has been exploited for pharmaceutic delivery across an array of diseases to either enhance or diminish this function. Monoclonal antibodies and albumin-bound nanoparticles are examples of FcRn-dependent anti-cancer therapeutics. Despite its importance in drug delivery, little is known about FcRn expression in circulating immune cells. Through time-of-flight mass cytometry (CyTOF) we were able to characterize FcRn expression in peripheral blood mononuclear cell (PBMC) populations of pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer donors. Furthermore, we were able to replicate these findings in an orthotopic murine model of PDAC. Altogether, we found that in both patients and mice with PDAC, FcRn was elevated in migratory and resident classical dendritic cell type 2 (cDC2) as well as monocytic and granulocytic myeloid-derived suppressor cell (MDSC) populations compared to tumor-free controls. Furthermore, PBMCs from PDAC patients had elevated monocyte, dendritic cells and MDSCs relative to non-cancer donor PBMCs. Future investigations into FcRn activity may further elucidate possible mechanisms of poor efficacy of antibody immunotherapies in patients with PDAC. Full article

(This article belongs to the Special Issue Fc Receptors 2.0)

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Review

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17 pages, 2270 KiB

Open AccessReview

Physiological and Pathophysiological Roles of IgM Fc Receptor (FcµR) Isoforms

by Hiromi Kubagawa, Caren Clark, Christopher M. Skopnik, Pedram Mahmoudi Aliabadi, Khlowd Al-Qaisi, Ruth Teuber, Peter K. Jani, Andreas Radbruch, Fritz Melchers, Niklas Engels and Jürgen Wienands

Int. J. Mol. Sci. 2023, 24(6), 5728; https://doi.org/10.3390/ijms24065728 - 17 Mar 2023

Cited by 1 | Viewed by 2638

Abstract

IgM is the first antibody to emerge during phylogeny, ontogeny, and immune responses and serves as a first line of defense. Effector proteins interacting with the Fc portion of IgM, such as complement and its receptors, have been extensively studied for their functions. IgM Fc receptor (FcµR), identified in 2009, is the newest member of the FcR family and is intriguingly expressed by lymphocytes only, suggesting the existence of distinct functions as compared to the FcRs for switched Ig isotypes, which are expressed by various immune and non-hematopoietic cells as central mediators of antibody-triggered responses by coupling the adaptive and innate immune responses. Results from FcµR-deficient mice suggest a regulatory function of FcµR in B cell tolerance, as evidenced by their propensity to produce autoantibodies of both IgM and IgG isotypes. In this article, we discuss conflicting views about the cellular distribution and potential functions of FcµR. The signaling function of the Ig-tail tyrosine-like motif in the FcµR cytoplasmic domain is now formally shown by substitutional experiments with the IgG2 B cell receptor. The potential adaptor protein associating with FcµR and the potential cleavage of its C-terminal cytoplasmic tail after IgM binding are still enigmatic. Critical amino acid residues in the Ig-like domain of FcµR for interacting with the IgM Cµ4 domain and the mode of interaction are now defined by crystallographic and cryo-electron microscopic analyses. Some discrepancies on these interactions are discussed. Finally, elevated levels of a soluble FcµR isoform in serum samples are described as the consequence of persistent B cell receptor stimulation, as seen in chronic lymphocytic leukemia and probably in antibody-mediated autoimmune disorders. Full article

(This article belongs to the Special Issue Fc Receptors 2.0)

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20 pages, 2322 KiB

Open AccessReview

FcγRs and Their Relevance for the Activity of Anti-CD40 Antibodies

by Isabell Lang, Olena Zaitseva and Harald Wajant

Int. J. Mol. Sci. 2022, 23(21), 12869; https://doi.org/10.3390/ijms232112869 - 25 Oct 2022

Cited by 3 | Viewed by 3522

Abstract

Inhibitory targeting of the CD40L-CD40 system is a promising therapeutic option in the field of organ transplantation and is also attractive in the treatment of autoimmune diseases. After early complex results with neutralizing CD40L antibodies, it turned out that lack of Fcγ receptor (FcγR)-binding is the crucial factor for the development of safe inhibitory antibodies targeting CD40L or CD40. Indeed, in recent years, blocking CD40 antibodies not interacting with FcγRs, has proven to be well tolerated in clinical studies and has shown initial clinical efficacy. Stimulation of CD40 is also of considerable therapeutic interest, especially in cancer immunotherapy. CD40 can be robustly activated by genetically engineered variants of soluble CD40L but also by anti-CD40 antibodies. However, the development of CD40L-based agonists is biotechnologically and pharmacokinetically challenging, and anti-CD40 antibodies typically display only strong agonism in complex with FcγRs or upon secondary crosslinking. The latter, however, typically results in poorly developable mixtures of molecule species of varying stoichiometry and FcγR-binding by anti-CD40 antibodies can elicit unwanted side effects such as antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) of CD40 expressing immune cells. Here, we summarize and compare strategies to overcome the unwanted target cell-destroying activity of anti-CD40-FcγR complexes, especially the use of FcγR type-specific mutants and the FcγR-independent cell surface anchoring of bispecific anti-CD40 fusion proteins. Especially, we discuss the therapeutic potential of these strategies in view of the emerging evidence for the dose-limiting activities of systemic CD40 engagement. Full article

(This article belongs to the Special Issue Fc Receptors 2.0)

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