Publications

Publications 2019 – Partner 1

Understanding Fc Receptor Involvement in Inflammatory Diseases: From Mechanisms to New Therapeutic Tools. Icon for Frontiers Media SA Icon for PubMed Central Related Articles

Understanding Fc Receptor Involvement in Inflammatory Diseases: From Mechanisms to New Therapeutic Tools.

Front Immunol. 2019;10:811

Authors: Ben Mkaddem S, Benhamou M, Monteiro RC

Abstract
Fc receptors (FcRs) belong to the ITAM-associated receptor family. FcRs control the humoral and innate immunity which are essential for appropriate responses to infections and prevention of chronic inflammation or auto-immune diseases. Following their crosslinking by immune complexes, FcRs play various roles such as modulation of the immune response by released cytokines or of phagocytosis. Here, we review FcR involvement in pathologies leading notably to altered intracellular signaling with functionally relevant consequences to the host, and targeting of Fc receptors as therapeutic approaches. Special emphasis will be given to some FcRs, such as the FcαRI, the FcγRIIA and the FcγRIIIA, which behave like the ancient god Janus depending on the ITAM motif to inhibit or activate immune responses depending on their targeting by monomeric/dimeric immunoglobulins or by immune complexes. This ITAM duality has been recently defined as inhibitory or activating ITAM (ITAMi or ITAMa) which are controlled by Src family kinases. Involvement of various ITAM-bearing FcRs observed during infectious or autoimmune diseases is associated with allelic variants, changes in ligand binding ability responsible for host defense perturbation. During auto-immune diseases such as rheumatoid arthritis, lupus or immune thrombocytopenia, the autoantibodies and immune complexes lead to inflammation through FcR aggregation. We will discuss the role of FcRs in autoimmune diseases, and focus on novel approaches to target FcRs for resolution of antibody-mediated autoimmunity. We will finally also discuss the down-regulation of FcR functionality as a therapeutic approach for autoimmune diseases.

PMID: 31057544 [PubMed - in process]

CD89 Is a Potent Innate Receptor for Bacteria and Mediates Host Protection from Sepsis. Icon for Elsevier Science Related Articles

CD89 Is a Potent Innate Receptor for Bacteria and Mediates Host Protection from Sepsis.

Cell Rep. 2019 Apr 16;27(3):762-775.e5

Authors: de Tymowski C, Heming N, Correia MDT, Abbad L, Chavarot N, Le Stang MB, Flament H, Bex J, Boedec E, Bounaix C, Soler-Torronteras R, Denamur E, Galicier L, Oksenhendler E, Fehling HJ, Pinheiro da Silva F, Benhamou M, Monteiro RC, Ben Mkaddem S

Abstract
Direct bacterial recognition by innate receptors is crucial for bacterial clearance. Here, we show that the IgA receptor CD89 is a major innate receptor that directly binds bacteria independently of its cognate ligands IgA and c-reactive protein (CRP). This binding is only partially inhibited by serum IgA and induces bacterial phagocytosis by CD11c+ dendritic cells and monocytes and/or macrophages, suggesting a physiological role in innate host defense. Blood phagocytes from common variable immunodeficiency patients bind, internalize, and kill bacteria in a CD89-dependent manner, confirming the IgA independence of this mechanism. In vivo, CD89 transgenic mice are protected in two different models of sepsis: a model of pneumonia and the cecal ligation and puncture (CLP) polymicrobial model of infection. These data identify CD89 as a first-line innate receptor for bacterial clearance before adaptive responses can be mounted. Fc receptors may emerge as a class of innate receptors for various bacteria with pleiotropic roles.

PMID: 30995475 [PubMed - in process]

Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice. Icon for Silverchair Information Systems Related Articles

Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice.

Nephrol Dial Transplant. 2019 Jul 01;34(7):1135-1144</p>

Authors: Chemouny JM, Gleeson PJ, Abbad L, Lauriero G, Boedec E, Le Roux K, Monot C, Bredel M, Bex-Coudrat J, Sannier A, Daugas E, Vrtovsnik F, Gesualdo L, Leclerc M, Berthelot L, Ben Mkaddem S, Lepage P, Monteiro RC

Abstract
BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgA is mainly produced by the gut-associated lymphoid tissue (GALT). Both experimental and clinical data suggest a role of the gut microbiota in this disease. We aimed to determine if an intervention targeting the gut microbiota could impact the development of disease in a humanized mouse model of IgAN, the α1KI-CD89Tg mice.
METHODS: Four- and 12-week old mice were divided into two groups to receive either antibiotics or vehicle control. Faecal bacterial load and proteinuria were quantified both at the beginning and at the end of the experiment, when blood, kidneys and intestinal tissue were collected. Serum mouse immunoglobulin G (mIgG) and human immunoglobulin A1 (hIgA1)-containing complexes were quantified. Renal and intestinal tissue were analysed by optical microscopy after haematoxylin and eosin colouration and immunohistochemistry with anti-hIgA and anti-mouse CD11b antibodies.
RESULTS: Antibiotic treatment efficiently depleted the faecal microbiota, impaired GALT architecture and impacted mouse IgA production. However, while hIgA1 and mIgG serum levels were unchanged, the antibiotic treatment markedly prevented hIgA1 mesangial deposition, glomerular inflammation and the development of proteinuria. This was associated with a significant decrease in circulating hIgA1-mIgG complexes. Notably, final faecal bacterial load strongly correlated with critical clinical and pathophysiological features of IgAN such as proteinuria and hIgA1-mIgG complexes. In addition, treatment with broad-spectrum antibiotics reverted established disease.
CONCLUSIONS: These data support an essential role of the gut microbiota in the generation of mucosa-derived nephrotoxic IgA1 and in IgAN development, opening new avenues for therapeutic approaches in this disease.

PMID: 30462346 [PubMed - in process]

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