Markers of Autoimmunity in ME/CFS and Post-COVID Syndrome (PCS)

Prof. Dr. Birgit Sawitzki presented recent work on identifying biologically defined endotypes in Long COVID-associated ME/CFS. Her research is based on the observation that Long COVID-ME/CFS is a heterogeneous condition in which distinct disease mechanisms can lead to similar clinical symptoms. To identify treatable subgroups—so-called endotypes—and lay the groundwork for more precise patient stratification, her team is employing a comparative approach involving multiple cohorts. These include an unselected Long COVID-ME/CFS cohort; a cohort with elevated GPCR autoantibodies and known responders or non-responders to immunoadsorption; Sjögren’s patients as an autoimmune reference group; individuals with acute SARS-CoV-2 infection as a model of a non-autoimmune inflammatory response; and healthy controls. Using mass cytometry, plasma proteomics, and machine learning, the team identified three immunological endotypes. Two of these endotypes were characterised by elevated plasma concentrations of soluble mediators associated with B cell activation and T cell/B cell communication. To further characterise these immune profiles, the team developed an autoimmunity score based on soluble mediators capable of distinguishing Sjögren’s from acute SARS-CoV-2 infection. The two endotypes with high and intermediate mediator concentrations exhibited elevated autoimmunity scores, whereas a third patient group was characterised by low autoimmunity scores. This endotype was found exclusively within the unselected Long COVID-ME/CFS cohort. Although these patients did not exhibit the T-B cell communication signatures typical of the other two groups, they nonetheless showed signs of distinct immunological dysregulation, suggesting different underlying disease mechanisms. A key focus of the presentation was the distinction between two B cell activation pathways. While patients who responded to immunoadsorption displayed characteristics of a germinal center-dependent immune response, non-responders were more frequently characterised by extrafollicular B cell activation and additional activation of the innate immune system. These differences indicate that autoimmune disease mechanisms in Long COVID-ME/CFS can vary not only in magnitude but also in nature. To improve clinical applicability, the team employed machine learning to identify minimal marker sets capable of assigning patients to the various endotypes and stratifying them based on their response to immunoadsorption. Sawitzki concluded that Long COVID-ME/CFS comprises at least three biologically distinct endotypes. Comparative analysis of an autoantibody-enriched cohort and an unselected cohort makes it possible to distinguish shared disease mechanisms from endotype-specific ones, thereby laying the foundation for biomarker-based patient stratification and future personalised treatment.