Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis

Mkaddem, Sanae Ben; Hayem, Gilles; Jönsson, Friederike; Rossato, Elisabetta; Boedec, Erwan; Boussetta, Tarek; Benna, Jamel El; Launay, Pierre; Goujon, Jean-Michel; Benhamou, Marc; Bruhns, Pierre; Monteiro, Renato C.

doi:10.1172/jci74572

Cited by 84 publications

(126 citation statements)

References 48 publications

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“…In contrast, freeze-thawed L. major did not induce Akt activation in WT mice (Figure S6E). We hypothesized that DC activation by L. major might be antagonized by Mincle through the recruitment of SHP1 in an inhibitory ITAM (ITAMi) configuration (Aloulou et al, 2012; Ben Mkaddem et al, 2014; Hamerman et al, 2009; Pasquier et al, 2005). Consistent with this notion, treatment with the SHP1/2 phosphatase inhibitor NSC-87877 increased DC activation by L. major (Figure S6F), contrasting with the absence of an effect with the Akt inhibitor VIII.…”

Section: Resultsmentioning

confidence: 99%

“…This inhibitory axis involved transient Syk activation that mediated coupling of SHP1 to FcRγ chain and dampened DC activation. Recruitment of SHP1 to the ITAM and mediating inhibitory signaling toward heterologous receptors (inhibitory ITAM, ITAMi) have been described for Fc receptors binding monomeric immunoglobulins (Aloulou et al, 2012; Ben Mkaddem et al, 2014; Hamerman et al, 2009; Pasquier et al, 2005), but not downstream of pattern recognition receptors. Our results reveal the relevance of the ITAMi pathway activated via Mincle after detection of a pathogen and as a mechanism of immune evasion by L. major .…”

Section: Introductionmentioning

confidence: 99%

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Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection

et al. 2016

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Summary C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation, migration and priming by Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. Selective loss of SHP1 in CD11c+ cells phenocopies enhanced adaptive immunity to Leishmania. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM (ITAMi) configuration that impairs DC activation. Thus, ITAMi can be exploited for immune evasion by a pathogen and may represent a paradigm for ITAM-coupled receptors sensing self and non-self.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection

et al. 2016

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“…1F) . This phenomenon likely accounts for the clinical benefits of IVIG therapy in treating patients with rheumatoid arthritis 185 , idiopathic thrombocytopenic purpura (ITP) 186 , and other autoimmune disorders 187, 188 . Our understanding of Fc-FcR interactions and their involvements in numerous biological processes, however, is far from complete, and their complexities are only now beginning to be unraveled.…”

Section: Mechanistic Contributions Of Fc-fcr Interactionsmentioning

confidence: 99%

Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

Ryan

Wasser

Adler

et al. 2016

Expert Opinion on Biological Therapy

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Introduction Monoclonal antibodies (mAbs) targeting checkpoint inhibitors have demonstrated clinical benefit in treating patients with cancer and have paved the way for additional immune-modulating mAbs such as those targeting costimulatory receptors. The full clinical utility of these agents, however, is hampered by immune-related adverse events (irAEs) that can occur during therapy. Areas covered We first provide a general overview of tumor immunity, followed by a review of the two major classes of immunomodulatory mAbs being developed as cancer therapeutics: checkpoint inhibitors and costimulatory receptor agonists. We then discuss therapy-associated adverse events. Finally, we describe in detail the mechanisms driving their therapeutic activity, with an emphasis on interactions between antibody fragment crystallizable (Fc) domains and Fc receptors (FcR). Expert Opinion Given that Fc-FcR interactions appear critical in facilitating the ability of immunomodulatory mAbs to elicit both therapeutically useful as well as adverse effects, the engineering of mAbs that can effectively engage their targets while limiting interaction with FcRs might represent a promising future avenue for developing the next generation of immune-enhancing tumoricidal agents with increased safety and retention of efficacy.

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“…by guest www.bloodjournal.org From inhibited CD32a-mediated arthritis in experimental mice. 30 However, the in vivo use of whole IgG CD32a-blocking mAbs and their effects on platelets in the context of native FcgRs has not previously been described. Whole IgG mAbs are generally superior to F(ab9) 2 fragments as therapeutics because they are less susceptible to degradation and have greater bioavailability.…”

Section: Discussionmentioning

confidence: 99%

“…Our study did not address the emerging biology of inducedinhibitory functions of CD32a, 1,30 in which CD32a engagement may induce a bias toward inhibitory (eg, inhibitory immunoreceptor tyrosine-based activation motif [ITAMi]) rather than activating (eg, ITAM) cellular reactions. Future studies addressing whether AT-10, IV.3, or MDE-8 may induce CD32a-ITAMi function in platelets are warranted.…”

Section: Discussionmentioning

confidence: 99%

CD32a antibodies induce thrombocytopenia and type II hypersensitivity reactions in FCGR2A mice

Meyer¹,

Robles‐Carrillo²,

Dávila³

et al. 2015

Blood

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Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis

Cited by 84 publications

References 48 publications

Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection

Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection

Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

CD32a antibodies induce thrombocytopenia and type II hypersensitivity reactions in FCGR2A mice

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