A commentary by Andrew Grimson about the single-cell RNA-seq preprint from his lab
When we started this project, our goal was to ask which components of the immune system are most altered in ME/CFS (and which are not). If we could answer this question, we hoped that it would give us a clear path towards understanding some of the molecular underpinnings of ME/CFS, which is likely to be an essential step towards therapies. We used a technique called single-cell RNA sequencing to answer this question, an approach that looks at the genes expressed in thousands of individual cells from each ME/CFS individual (and control). When we look at the data (which in aggregate contains about 0.5 million immune cells found in peripheral blood, sampled from 30 ME/CFS individuals and 28 controls), the strongest signal of dysregulation is found in classical monocytes, a type of innate immune cell with diverse roles. There are three fundamental observations we can make about monocytes in ME/CFS. First, within individuals with ME/CFS, the proportion of monocytes that are dysregulated is variable, with a mixture of relatively normal cells and those that are altered. Second, comparing between individuals, the proportion of altered monocytes is also variable, with individuals with a higher fraction of altered monocytes tending to have more serious cases of ME/CFS. Third, by looking at the genes mis-expressed in altered monocytes, we can find patterns that suggest what might be different about the biology of the altered monocytes. In essence, what we see is that monocytes in individuals with ME/CFS appear to be triggered to migrate to tissues, where they become macrophages. This migration and differentiation pathway is a normal function of monocytes – we think the pathway is more active in ME/CFS, and this increased activity could contribute to many of the symptoms of ME/CFS. This work sets up lots of questions that motivate our work now – where are the monocytes going in ME/CFS individuals, what is causing them to be dysregulated, and ultimately, can we reverse this dysregulation?
Beyond changes in gene expression in monocytes in ME/CFS, we also find changes in expression in other immune cells, which will be an invaluable resource for both us and other researchers as we build towards a comprehensive understanding of immune alterations in ME/CFS. For example, certain subsets of T cells also show a strong signature of dysregulation in ME/CFS. We also found some intriguing changes in expression in platelets: unique to platelets, the genes expressed look very different at baseline and when patients are experiencing post-exertional malaise (PEM), a hallmark symptom of ME/CFS. It is too early to understand what this means, but it strongly suggests that PEM induces a change in the platelet population in circulation in ME/CFS individuals, which we do not see in controls.
We would like to thank the individuals with ME/CFS and healthy controls who participated in this study, and support from NIH, which underpins this work. Finally, I would also like acknowledge the contributions from a large and collaborative team – we would not have been able to complete this work without such a strong interdisciplinary group of dedicated researchers.
The above commentary was written by Andrew Grimson, co-PI of the Cornell NIH ME/CFS Research Center and Associate Director of the Cornell Center for Enervating Neuroimmune Disease.
FarazAhmed, Luyen TienVu, HongyaZhu, David Shing HukIu, Elizabeth A.Fogarty, YeonuiKwak, WeizhongChen, Carl J.Franconi, Paul R.Munn, Susan M.Levine, JaredStevens, XianglingMao, Dikoma C.Shungu, Geoffrey E.Moore, Betsy A.Keller, Maureen R.Hanson, Jennifer K.Grenier, AndrewGrimson
Note: articles on bioRxiv are not peer-reviewed before being posted online. This manuscript has been submitted for peer-review and the process is ongoing.