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?
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