These types of studies can bring us closer to SLE transcriptional signatures and precision medicine possibilities, the study researchers concluded. This is an example of how the results from studies done in children with SLE should be applicable to adults as well, Dr. Pascual explained.
Another study Dr. Pascual reviewed, by Caielli et al. and published this year, focused on mitochondrial dysfunction within SLE pathogenesis.2 Specifically, researchers showed that programmed mitochondrial removal in the red blood cell lineage is defective in a group of SLE patients.
Caielli et al. demonstrated that when human erythroid cell maturation takes place, a hypoxia-inducible factor-mediated metabolic switch leads to the activation of the ubiquitin-proteasome system. This is needed to induce mitophagy and final mitochondrial removal, but a defect in this pathway can lead to mature red blood cells that carry mitochondria. When internalized by macrophages, these red blood cells induce a strong interferon response. SLE patients displaying red blood cells carrying mitochondria as well as anti-red blood cell antibodies, which facilitate their opsonization by macrophages, have the highest levels of blood interferon-stimulated gene signatures. This is yet another example of a unique collaboration between lupus autoantibodies and unusual endogenous nucleic acids contributing to lupus pathogenesis, the researchers concluded.
Future Possibilities
These studies provide insights into potential markers toward precision medicine avenues for lupus, and research continues to find promising lupus targets and biomarkers that might enable precision medicine in the near future. “In the meantime, while some of the therapies currently in development will hopefully show success in phase 3 clinical trials, failures might result from the enrollment of highly heterogeneous patients within the same trial,” Dr. Pascual said.
A rational trial design based on patient molecular and overall immune stratification will lead the way toward precision medicine for lupus, Dr. Pascual said. Contributions from granulocytes, erythroid lineage cells, dysregulated metabolic pathways and novel autoantibodies will remain part of the quest.
“What we’ve witnessed in the past five years is an explosion of information in the right direction,” Dr. Pascual said.
Vanessa Caceres is a medical writer in Bradenton, Fla.
References
- Nehar-Belaid D, Hong S, Marches R, et al. Mapping systemic lupus erythematosus heterogeneity at the single-cell level. Nat Immunol. 2020 Sep;21:1094–1106.
- Caielli S, Cardenas J, Almeida de Jesus, et al. Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE. Cell. 2021 Aug 19;184:4464–4479.
