Fetal Inflammatory Response Syndrome (FIRS) is a disease that manifests during fetal life and is strongly associated with neonatal morbidity and mortality. FIRS can be classified as type I or type II, which are clinically considered as distinct syndromes. However, the molecular underpinnings of these fetal inflammatory responses are not well understood due to their low prevalence and the difficulty of diagnosis. To help fill this gap in knowledge, PRB researchers applied RNA sequencing and systems immunobiology approaches to investigate the cord blood transcriptome in neonates diagnosed with FIRS type I or FIRS type II compared to neonates without these conditions.
The team reported that FIRS type I was characterized by upregulation of host immune responses, including neutrophil and monocyte function, together with a pro-inflammatory cytokine storm and a downregulation of T-cell processes. In contrast, FIRS type II comprised a mild chronic inflammatory response involving perturbation of HLA transcripts, suggestive of fetal semi-allograft rejection. Integrating single-cell RNAseq-derived signatures with bulk transcriptomic data confirmed that FIRS type I immune responses were mainly driven by monocytes, macrophages, and neutrophils. Lastly, tissue- and cell-specific signatures derived from the BioGPS Gene Atlas further corroborated the role of myeloid cells originating from the bone marrow in FIRS type I. Collectively, these data provide evidence that FIRS type I and FIRS type II are driven by distinct immune mechanisms: while the former involves the innate limb of immunity consistent with host defense, the latter resembles a state of semi-allograft rejection. These findings shed light on the fetal immune responses caused by infection or alloreactivity that can lead to deleterious consequences in neonatal life.