POS0245 SOLUBLE CHECKPOINT MOLECULES AS PREDICTIVE BIOMARKERS FOR AUTOIMMUNE CONGENITAL HEART BLOCK
Authors: A. L. Stefanski, H. Rincon-Arevalo, N. Nomovi, A. Aue, J. Ritter, A. Wiedemann, F. Szelinski, E. Schrezenmeier, A. C. Lino, T. Dörner
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Autoimmune congenital heart block (CHB) is a severe manifestation of neonatal lupus syndrome due to placental transfer of maternal anti-Ro/SS-A ± anti-La/SS-B autoantibodies. Substantial type I interferon (IFN) activation is a known risk factor for CHB development [1], however, there is a lack of predictive biomarkers for CHB in pregnant women at risk. Recent findings suggest a significant involvement of immune checkpoint molecules in the induction of feto-maternal tolerance [2]. <h3>Objectives:</h3> 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, who presented in our outpatient clinic during the last 5 years. <h3>Methods:</h3> We enrolled 12 pregnant women with CHB pregnancy, 23 with antibodies against Ro/SS-A±La/SS-B without a CHB complication (at-risk) and another 15 healthy pregnant women without respective autoantibodies (healthy donors, HD). Plasma levels of various checkpoint molecules were analyzed 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. We also assessed the expression of SIGLEC-1 on CD14+ monocytes as surrogate for type I IFN signature. <h3>Results:</h3> Pregnant females with CHB pregnancies had significantly higher circulating levels of sPD-L1, sCD86 and s4-1BB compared to the at-risk patient group and healthy pregnancies (Figure 1A, B). Striking correlations were observed between these soluble checkpoints. In a next step, we analyzed the relationship between type I IFN signature and the identified checkpoint molecules. sPD-L1 and sCD86 were unrelated to Siglec-1 expression on monocytes and could differentiate between pregnancies at-risk with high type I IFN signature and CHB pregnancies. While sPD-L1 levels significantly declined postpartum, s4-1BB and sCD86 values persisted at a high level after delivery. <h3>Conclusion:</h3> The data indicate the value of checkpoint molecules sPD-L1, sCD86 and s4-1BB as potential CHB risk biomarkers. 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. <h3>REFERENCES:</h3> [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;76(8):1476-80. [2] Okuyama M, Mezawa H, Kawai T, Urashima M. Elevated Soluble PD-L1 in Pregnant Women's Serum Suppresses the Immune Reaction. Frontiers in Immunology. 2019;10(86). <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> Ana-Luisa Stefanski: None declared, Hector Rincon-Arevalo: None declared, Nadja Nomovi: None declared, Arman Aue: None declared, Jacob Ritter: None declared, Annika Wiedemann: None declared, Franziska Szelinski: None declared, Eva Schrezenmeier: None declared, Andreia C. Lino: None declared, Thomas Dörner AbbVie, Eli Lilly, Roche/Genentech, Janssen, Novartis.