Article
Elevated maternal soluble checkpoint molecules predict autoimmune congenital heart block
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Authors
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Ana-Luisa Stefanski
- Charité – Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology, Berlin; Deutsches Rheumaforschungszentrum (DRFZ), Berlin
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Hector Rincon-Arevalo
- Charité – Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology, Berlin; Deutsches Rheumaforschungszentrum (DRFZ), Berlin; Charité – Universitätsmedizin Berlin, Department of Nephrology and Intensive Medical Care, Berlin; Universidad de Antioquia UdeA, Grupo de Inmunología Celular e Inmunogenética, Facultad de Medicina, Instituto de Investigaciones Médicas, Medellin
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Nadja Nomovi
- Ernst von Bergmann Clinic, Department of Obstetrics, Potsdam; Charité – Universitätsmedizin Berlin, Department of Obstetrics, Berlin
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Arman Aue
- Charité – Universitätsmedizin Berlin, Department of Nephrology and Intensive Medical Care, Berlin
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Jacob Casimir Ritter
- Charité – Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology, Berlin; Deutsches Rheumaforschungszentrum (DRFZ), Berlin
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Annika Glenzer
- Charité – Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology, Berlin; Deutsches Rheumaforschungszentrum (DRFZ), Berlin
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Franziska Szelinski
- Charité – Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology, Berlin; Deutsches Rheumaforschungszentrum (DRFZ), Berlin
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Eva V. Schrezenmeier
- Deutsches Rheumaforschungszentrum (DRFZ), Berlin; Charité – Universitätsmedizin Berlin, Department of Nephrology and Intensive Medical Care, Berlin
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Andreia Lino
- Deutsches Rheumaforschungszentrum (DRFZ), Berlin
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Thomas Dörner
- Charité – Universitätsmedizin Berlin, Department of Rheumatology and Clinical Immunology, Berlin; Deutsches Rheumaforschungszentrum (DRFZ), Berlin
| Published: | September 18, 2024 |
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Outline
Text
Introduction: Type I interferon signature is a known risk factor for the development of autoimmune congenital heart block (CHB) after exposure to maternal anti-Ro/La autoantibodies [1]. However, only about 2% of children born to mothers with the respective antibodies are affected, indicating that further risk factors exist, which are not yet fully understood. Recent findings suggest a significant involvement of immune checkpoint molecules (CPM) in the induction of feto-maternal tolerance in healthy pregnancy [2]. This study aims to evaluate maternal levels of soluble checkpoint molecules in CHB affected and at-risk mothers positive for anti-Ro/SS-A +/- anti-La/SS-B autoantibodies.
Methods: We analyzed plasma samples, clinical data and serological parameters from 12 pregnant women with CHB pregnancy, 23 with antibodies against Ro/SS-A +/- La/SS-B without a CHB complication (at-risk) and 15 healthy pregnant women without respective autoantibodies as controls (healthy donors, HD), who presented in our outpatient clinic during the last 5 years. Plasma levels of various CPM were assessed via a bead-based multiplex immunoassay, including sCD86, s4-1BB, sCD25, sCD27, sCTLA-4, sPD-1, sPD-L1, sPD-L2, sTim-3, sLAG-3 and sGal-9. Expression of SIGLEC-1 on CD14+ monocytes as surrogate for type I IFN signature was also measured.
Results: Mothers of CHB affected children had significantly higher circulating levels of sPD-L1, sCD86 and s4-1BB compared to the at-risk patient group and healthy pregnancies (Figure 1A [Fig. 1]). We found no correlations between sPD-L1, s4-1BB and CD86 with Siglec-1 expression on monocytes. Moreover, higher levels of sPD-L1 and sCD86 could differentiate between pregnancies at-risk with high type I IFN signature and CHB pregnancies (Figure 1B [Fig. 1]). While sPD-L1 levels significantly declined postpartum, s4-1BB and sCD86 values persisted at a high level after delivery (Figure 1C [Fig. 1]).
Conclusion: This study identified elevated maternal sPD-L1, sCD86 and s4-1BB as potential CHB risk biomarkers in addition to IFN signature. While sCD86 and s4-1BB seem to reflect the inflammatory environment independent of the pregnancy, the decrease in sPD-L1 postpartum suggests elevated modulatory effects by the PD-1/PD-L1 axis on feto-maternal tolerance in mothers with CHB offspring.
References
- 1.
- Lisney AR, Szelinski F, Reiter K, Burmester GR, Rose T, Dörner T. High maternal expression of SIGLEC1 on monocytes as a surrogate marker of a type I interferon signature is a risk factor for the development of autoimmune congenital heart block. Ann Rheum Dis. 2017 Aug;76(8):1476-80. DOI: 10.1136/annrheumdis-2016-210927
- 2.
- Okuyama M, Mezawa H, Kawai T, Urashima M. Elevated Soluble PD-L1 in Pregnant Women's Serum Suppresses the Immune Reaction. Front Immunol. 2019 Feb 18;10:86. DOI: 10.3389/fimmu.2019.00086
