Type I IFN system activation in newborns exposed to Ro/SSA and La/SSB autoantibodies in utero

Abstract

ObjectiveIn utero exposure of the fetus to Ro/La autoantibodies may lead to congenital heart block (CHB). In the mother, these autoantibodies are associated with activation of the type I interferon (IFN)-system. As maternal autoantibodies are transferred to the fetus during pregnancy, we investigated whether the type I IFN-system is activated also in newborns of anti-Ro/La positive mothers, and whether fetal IFN activation is affected by maternal immunomodulatory treatment.MethodsBlood drawn at birth from anti-Ro/La positive mothers, their newborns and healthy control pairs was separated into plasma and peripheral blood mononuclear cells (PBMC). PBMC were analysed directly or cultured. mRNA expression was analysed by microarrays, cell surface markers by flow cytometry, and IFNα levels by immunoassays.ResultsWe observed increased expression of IFN-regulated genes and elevated plasma IFNα levels not only in anti-Ro/La positive women, but also in their newborns. CD14+ monocytes of both anti-Ro/La positive mothers and their neonates showed increased expression of Sialic acid-binding Ig-like lectin-1, indicating cellular activation. Notably, the IFN score of neonates born to mothers receiving immunomodulatory treatment was similar to that of controls, despite persistent IFN activation in the mothers. In both maternal and neonatal PBMC, IFNα production was induced when cells were cultured with anti-Ro/La positive plasma.ConclusionsRo/La autoantibody-exposed neonates at risk of CHB have signs of an activated immune system with an IFN signature. This study further demonstrates that neonatal cells can produce IFNα when exposed to autoantibody-containing plasma, and that maternal immunomodulatory treatment may diminish the expression of IFN-regulated genes in the fetus.

Activation of plasmacytoid dendritic cells and B cells with two structurally different Toll‐like receptor 7 agonists

“…IFN‐α was analysed in culture supernatants by a dissociation‐enhanced lanthanide fluoroimmunoassay (DELFIA) as previously described 34,35 . The DELFIA assay does not detect the IFN‐α subtype 2b which was used for priming.…”

A Broader Perspective on Anti-Ro Antibodies and Their Fetal Consequences—A Case Report and Literature Review

“…Moreover, data from in vitro studies show that anti-Ro–associated single-stranded RNA binds to macrophage Toll-like receptors (TLR) and thus triggers the aforementioned inflammatory and fibrosis cascade [ 46 ]. An important role seems to be played in this context by interferon (IFN), with highly expressed type I IFN response genes [ 46 , 47 ].…”

Interferons and innate immune activation in autoimmune congenital heart block

“…[54][55][56][57] Of note, the same study found that the levels of IP-10 (CXCL10), a protein induced by both type I and type II IFNs and also correlating with disease activity in SLE, 55 did not differ between CHB mothers and mothers of unaffected children. 53 Since this initial study, activation of the type I IFN system and increased expression of SIGLEC-1 have been reported both in cord blood mononuclear cells (CBMCs) from neonates of anti-Ro/La antibody-positive mothers 58 and in heart tissues from foetuses dying with autoimmune CHB. 59 Upregulation of IFN-stimulated genes (ISGs) was observed not only in leukocytes isolated from a CHB foetal heart compared with cells isolated from healthy, electively terminated foetal hearts, 59 but also in other cardiac-derived cell types, albeit to varying degrees.…”

“…CBMCs derived from newborns in pregnancies both with and without anti-Ro/La autoantibodies have indeed the capacity to produce IFNα following exposure to plasma containing anti-Ro/La antibodies. 58 As maternal antibodies start crossing the placenta around the 6-7th weeks of pregnancy, with 10% of maternal IgG concentrations transferred to the foetus by gestational weeks 17-22, 68 anti-Ro/La autoantibodies, in complex with apoptotic/necrotic material from cardiac cells dying during normal foetal heart remodelling, may activate foetal cardiac immune cells to produce type I IFN.…”

“…Supporting this idea is the fact that an activated type I IFN system was observed in clinically non-affected neonates of anti-Ro antibody-positive women in another study. 58 Furthermore, a recent study demonstrated elevated serum levels of various cytokines in the newborns of mothers with rheumatic diseases. 69 Activation of the type I IFN system may thus simply be part of a more general innate immune activation present in neonates of mothers with rheumatic disease rather than a specific risk factor for autoimmune CHB.…”