Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS, by Milica Milivojevic, Xiaoyu Che, Lucinda Bateman, Aaron Cheng, Benjamin A Garcia, Mady Hornig, Manuel Huber, Nancy G Klimas,Bohyun Lee, Hyoungjoo Lee, Susan Levine, Jose G Montoya, Daniel L Peterson, Anthony L Komaroff, W Ian Lipkin in PLoS One. 2020 Jul 21;15(7):e0236148 [doi:10.1371/journal.pone.0236148]
Research abstract:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an unexplained chronic, debilitating illness characterized by fatigue, sleep disturbances, cognitive dysfunction, orthostatic intolerance and gastrointestinal problems. Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed the plasma proteomes of 39 ME/CFS patients and 41 healthy controls.
Logistic regression models, with both linear and quadratic terms of the protein levels as independent variables, revealed a significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30. Stratifying the ME/CFS group based on self-reported irritable bowel syndrome (sr-IBS) status revealed a significant quadratic effect of immunoglobulin lambda constant region 7 on its association with ME/CFS with sr-IBS whilst IGHV3-23/30 and immunoglobulin kappa variable region 3-11 were significantly associated with ME/CFS without sr-IBS.
In addition, we were able to predict ME/CFS status with a high degree of accuracy (AUC = 0.774-0.838) using a panel of proteins selected by 3 different machine learning algorithms: Lasso, Random Forests, and XGBoost. These algorithms also identified proteomic profiles that predicted the status of ME/CFS patients with sr-IBS (AUC = 0.806-0.846) and ME/CFS without sr-IBS (AUC = 0.754-0.780). Our findings are consistent with a significant association of ME/CFS with immune dysregulation and highlight the potential use of the plasma proteome as a source of biomarkers for disease.
Excerpt from Discussion
Whilst our exploratory study has identified a plasma protein biosignature using machine-learning algorithms that can predict ME/CFS status adequately, the clinical utility of these results remains to be shown. Validation of the panel of proteins in larger cohorts is needed to determine whether it would make a reliable biomarker. In addition, the specificity of the biosignature would need to be assessed to see if it could successfully distinguish ME/CFS cases, as well as ME/CFS cases with or without sr-IBS, from those with other fatiguing illnesses such as fibromyalgia and Gulf War Illness. Disease-specific specific biomarkers could provide an objective measure to aid in diagnosis of this heterogeneous disease. Previous proteomic studies in cerebrospinal fluid and saliva have identified protein signatures with predictive accuracies comparable to ours [11, 14], however, none have led to the development clinical biomarkers. In fact, no molecular biomarkers have been validated for ME/CFS diagnosis or prognosis [4], highlighting the challenges associated with this complex disease. Our work, whilst exploratory in nature, shows that the plasma proteome is a viable and untapped source of potential biomarkers in ME/CFS, and can provide insight into disease pathophysiology. In addition, we support previous results that ME/CFS patients with sr-IBS may constitute a subgroup with a distinct molecular profile [9, 26] and that considering subtypes of ME/CFS can lead to greater predictive accuracy in biomarker studies.
Our study is limited by small sample size, and the robustness of our findings needs to be verified in larger cohorts. Additionally, IBS status determination and stratification could be improved by an independent diagnosis at the time of participant recruitment. Nonetheless, our results comport with other work in ME/CFS that has found evidence in ME/CFS of immune dysregulation, B cell dysfunction, chronic inflammation, oxidative stress, and autoimmunity.
Comment:
A Proteomics Study from the Center: Searching for the Criminal, by Dr Anthony Komaroff, Jul 28 2020
What did the latest study from the Center show? Basically, two things:
- There appears to be a distinctive “signature” of a small group of proteins that distinguishes people with ME/CFS from healthy people;
- The proteins involved in that “signature” are primarily involved in the immune response—particularly the response of immune cells called B cells—to infections, and the response seen in autoimmune diseases.
