Expression and regulation of Siglec-6 (CD327) on human mast cells and basophils

Smiljkovic, Dubravka; Herrmann, Harald; Sadovnik, Irina; Gamperl, Susanne; Berger, Daniela; Stefanzl, Gabriele; Eisenwort, Gregor; Hoermann, Gregor; Kopanja, Sonja; Dorofeeva, Yulia; Focke‐Tejkl, Margarete; Jaksch, Péter; Höetzenecker, Konrad; Szépfalusi, Zsolt; Valenta, Rudolf; Arock, Michel; Valent, Peter

doi:10.1016/j.jaci.2022.07.018

Cited by 15 publications

(9 citation statements)

References 73 publications

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“…In the case of BM samples, erythrocyte lysis was performed by adding lysis buffer (Becton Dickinson; 1:10 diluted in dH2O) for 15 min. Stained cells were examined using multicolor flow cytometry as reported in [35,43,44]. To assess the expression of CoV-R on PB EO (Siglec-8+ cells) and PB BA (CD203c+/CD123+/CD45+/CD14− cells), whole blood samples were examined as reported [44,45].…”

Section: Evaluation Of Surface Expression Of Cov-r On Cell Lines and ...mentioning

confidence: 99%

Coronavirus Receptor Expression Profiles in Human Mast Cells, Basophils, and Eosinophils

Degenfeld-Schonburg,

Sadovnik,

Smiljkovic

et al. 2024

Cells

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A major problem in SARS-CoV-2-infected patients is the massive tissue inflammation in certain target organs, including the lungs. Mast cells (MC), basophils (BA), and eosinophils (EO) are key effector cells in inflammatory processes. These cells have recently been implicated in the pathogenesis of SARS-CoV-2 infections. We explored coronavirus receptor (CoV-R) expression profiles in primary human MC, BA, and EO, and in related cell lines (HMC-1, ROSA, MCPV-1, KU812, and EOL-1). As determined using flow cytometry, primary MC, BA, and EO, and their corresponding cell lines, displayed the CoV-R CD13 and CD147. Primary skin MC and BA, as well as EOL-1 cells, also displayed CD26, whereas primary EO and the MC and BA cell lines failed to express CD26. As assessed using qPCR, most cell lines expressed transcripts for CD13, CD147, and ABL2, whereas ACE2 mRNA was not detectable, and CD26 mRNA was only identified in EOL-1 cells. We also screened for drug effects on CoV-R expression. However, dexamethasone, vitamin D, and hydroxychloroquine did not exert substantial effects on the expression of CD13, CD26, or CD147 in the cells. Together, MC, BA, and EO express distinct CoV-R profiles. Whether these receptors mediate virus–cell interactions and thereby virus-induced inflammation remains unknown at present.

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Section: Evaluation Of Surface Expression Of Cov-r On Cell Lines and ...mentioning

confidence: 99%

Coronavirus Receptor Expression Profiles in Human Mast Cells, Basophils, and Eosinophils

Degenfeld-Schonburg,

Sadovnik,

Smiljkovic

et al. 2024

Cells

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“…121,122 In contrast to Siglec-8, is upregulated in IgE-and SCF-activated MCs, suggesting Siglec-6 may play a greater role in activated MCs. 120 Anti-Siglec-6 mAbs appear to mediate broad inhibition of IgE-dependent and -independent MC activation and degranulation through multiple routes, including FcεRI, complement component 5a receptor, and MRGPRX2 pathways. 121 Consistent with the inhibitory function of Siglec-6, mutation of both the ITIM and ITIM-like domains abrogate anti-Siglec-6-mediated MC inhibition by preventing SHP-1 and SHP-2 phosphatase recruitment.…”

Section: Ak006 a Siglec-6 Agonist Antibodymentioning

confidence: 99%

“…Siglec‐6 is constitutively expressed on mucosal and connective tissue MC subtypes 121,122 . In contrast to Siglec‐8, is upregulated in IgE‐ and SCF‐activated MCs, suggesting Siglec‐6 may play a greater role in activated MCs 120 . Anti‐Siglec‐6 mAbs appear to mediate broad inhibition of IgE‐dependent and ‐independent MC activation and degranulation through multiple routes, including FcεRI, complement component 5a receptor, and MRGPRX2 pathways 121 .…”

Section: Silencers In Clinical Developmentmentioning

confidence: 99%

“…Siglec-6 is an inhibitory receptor expressed predominantly on MCs, and at lower levels on basophils, select populations of B cells, and placental trophoblasts. 120,121 Siglec-6 is constitutively expressed on mucosal and connective tissue MC subtypes. 121,122 In contrast to Siglec-8, is upregulated in IgE-and SCF-activated MCs, suggesting Siglec-6 may play a greater role in activated MCs.…”

Section: Ak006 a Siglec-6 Agonist Antibodymentioning

confidence: 99%

“…Siglec‐6 is an inhibitory receptor expressed predominantly on MCs, and at lower levels on basophils, select populations of B cells, and placental trophoblasts 120,121 . Siglec‐6 is constitutively expressed on mucosal and connective tissue MC subtypes 121,122 .…”

Section: Silencers In Clinical Developmentmentioning

confidence: 99%

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Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell‐mediated diseases

Metz,

Kolkhir,

Altrichter

et al. 2023

Allergy

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Chronic urticaria (CU) is a mast cell (MC)‐dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE‐mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation—including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators—strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid‐binding immunoglobulin‐like lectin8 ‐[Siglec‐8] [lirentelimab/AK002], Siglec‐6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on‐ or off‐target, immunosuppressive adverse effects.

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