Siglec-1 macrophages and the contribution of IFN to the development of autoimmune congenital heart block

Robert M. Clancy, Marc K Halushka, Sara E. Rasmussen, Tenzin Lhakhang, Miao Chang, Jill P. Buyon

Research output: Contribution to journalArticle

Abstract

Given that diseases associated with anti-SSA/Ro autoantibodies, such as systemic lupus erythematosus and Sjögren syndrome, are linked with an upregulation of IFN and type I IFN-stimulated genes, including sialic acid-binding Ig-like lectin 1 (Siglec-1), a receptor on monocytes/macrophages, recent attention has focused on a potential role for IFN and IFN-stimulated genes in the pathogenesis of congenital heart block (CHB). Accordingly, three approaches were leveraged to address the association of IFN, IFN-stimulated genes, and the phenotype of macrophages in affected fetal cardiac tissue: 1) cultured healthy human macrophages transfected with hY3, an anti-SSA/Ro-associated ssRNA, 2) RNA isolated from freshly sorted human leukocytes/macrophages after Langendorff perfusion of three fetal hearts dying with CHB and three healthy gestational age-matched hearts, and 3) autopsy tissue from three additional human CHB hearts and one healthy heart. TLR ligation of macrophages with hY3 led to the upregulation of a panel of IFN transcripts, including SIGLEC1, a result corroborated using quantitative PCR. Using independent and agnostic bioinformatics approaches, CD45+CD11c+ and CD45+CD11c2 human leukocytes flow sorted from the CHB hearts highly expressed type I IFN response genes inclusive of SIGLEC1. Furthermore, Siglec-1 expression was identified in the septal region of several affected fetal hearts. These data now provide a link between IFN, IFN-stimulated genes, and the inflammatory and possibly fibrosing components of CHB, positioning Siglec-1-positive macrophages as integral to the process.

Original languageEnglish (US)
Pages (from-to)48-55
Number of pages8
JournalJournal of Immunology
Volume202
Issue number1
DOIs
StatePublished - Jan 1 2019

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Sialic Acid Binding Ig-like Lectin 1
Macrophages
Fetal Heart
Genes
Leukocytes
Up-Regulation
Septum of Brain
Computational Biology
Systemic Lupus Erythematosus
Autoantibodies
Gestational Age
Ligation
Congenital heart block
Monocytes
Autopsy
Fetus
Perfusion
RNA
Phenotype
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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Siglec-1 macrophages and the contribution of IFN to the development of autoimmune congenital heart block. / Clancy, Robert M.; Halushka, Marc K; Rasmussen, Sara E.; Lhakhang, Tenzin; Chang, Miao; Buyon, Jill P.

In: Journal of Immunology, Vol. 202, No. 1, 01.01.2019, p. 48-55.

Research output: Contribution to journalArticle

Clancy, Robert M. ; Halushka, Marc K ; Rasmussen, Sara E. ; Lhakhang, Tenzin ; Chang, Miao ; Buyon, Jill P. / Siglec-1 macrophages and the contribution of IFN to the development of autoimmune congenital heart block. In: Journal of Immunology. 2019 ; Vol. 202, No. 1. pp. 48-55.
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