Interferon-complement loop in transplant-associated thrombotic microangiopathy
Open Access
- 24 March 2020
- journal article
- research article
- Published by American Society of Hematology in Blood Advances
- Vol. 4 (6), 1166-1177
- https://doi.org/10.1182/bloodadvances.2020001515
Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.This publication has 49 references indexed in Scilit:
- Genome-Wide Signatures of Transcription Factor Activity: Connecting Transcription Factors, Disease, and Small MoleculesPLoS Computational Biology, 2013
- TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusionsGenome Biology, 2013
- The spectrum of renal thrombotic microangiopathy in lupus nephritisArthritis Research & Therapy, 2013
- Netting Neutrophils Are Major Inducers of Type I IFN Production in Pediatric Systemic Lupus ErythematosusScience Translational Medicine, 2011
- Validation of Recently Proposed Consensus Criteria for Thrombotic Microangiopathy After Allogeneic Hematopoietic Stem-Cell TransplantationTransplantation, 2010
- Transcription factor regulation can be accurately predicted from the presence of target gene signatures in microarray gene expression dataNucleic Acids Research, 2010
- CLEAN: CLustering Enrichment ANalysisBMC Bioinformatics, 2009
- Mapping and quantifying mammalian transcriptomes by RNA-SeqNature Methods, 2008
- Random-set methods identify distinct aspects of the enrichment signal in gene-set analysisThe Annals of Applied Statistics, 2007
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005