Revisiting IgG Antibody Reactivity to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Its Potential Application to Disease Diagnosis

Nuno Sepúlveda; João Malato; Franziska Sotzny; Anna D Grabowska; André Fonseca; Clara Cordeiro; Luís Graça; Przemyslaw Biecek; Uta Behrends; Josef Mautner; Francisco Westermeier; Eliana M Lacerda; Carmen Scheibenbogen

doi:10.3389/fmed.2022.921101

Revisiting IgG Antibody Reactivity to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Its Potential Application to Disease Diagnosis

Front Med (Lausanne). 2022 Jun 24:9:921101. doi: 10.3389/fmed.2022.921101. eCollection 2022.

Authors

Nuno Sepúlveda^{1

2}, João Malato^{2

3}, Franziska Sotzny⁴, Anna D Grabowska⁵, André Fonseca^{2

6}, Clara Cordeiro^{2

6}, Luís Graça³, Przemyslaw Biecek¹, Uta Behrends^{7

8}, Josef Mautner^{7

8}, Francisco Westermeier^{9

10}, Eliana M Lacerda¹¹, Carmen Scheibenbogen⁴

Affiliations

¹ Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland.
² CEAUL - Centro de Estatística e Aplicações da Universidade de Lisboa, Lisbon, Portugal.
³ Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
⁴ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Institute of Medical Immunology, Berlin, Germany.
⁵ Department of Biophysics, Physiology, and Pathophysiology, Medical University of Warsaw, Warsaw, Poland.
⁶ Faculdade de Ciências e Tecnologia, Universidade do Algarve, Faro, Portugal.
⁷ Technical University of Munich, School of Medicine, Childrens' Hospital, Munich, Germany.
⁸ German Center for Infection Research (DZIF), Braunschweig, Germany.
⁹ Department of Health Studies, Institute of Biomedical Science, FH Joanneum University of Applied Sciences, Graz, Austria.
¹⁰ Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O'Higgins, Santiago, Chile.
¹¹ Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Abstract

Infections by the Epstein-Barr virus (EBV) are often at the disease onset of patients suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, serological analyses of these infections remain inconclusive when comparing patients with healthy controls (HCs). In particular, it is unclear if certain EBV-derived antigens eliciting antibody responses have a biomarker potential for disease diagnosis. With this purpose, we re-analyzed a previously published microarray data on the IgG antibody responses against 3,054 EBV-related antigens in 92 patients with ME/CFS and 50 HCs. This re-analysis consisted of constructing different regression models for binary outcomes with the ability to classify patients and HCs. In these models, we tested for a possible interaction of different antibodies with age and gender. When analyzing the whole data set, there were no antibody responses that could distinguish patients from healthy controls. A similar finding was obtained when comparing patients with non-infectious or unknown disease trigger with healthy controls. However, when data analysis was restricted to the comparison between HCs and patients with a putative infection at their disease onset, we could identify stronger antibody responses against two candidate antigens (EBNA4_0529 and EBNA6_0070). Using antibody responses to these two antigens together with age and gender, the final classification model had an estimated sensitivity and specificity of 0.833 and 0.720, respectively. This reliable case-control discrimination suggested the use of the antibody levels related to these candidate viral epitopes as biomarkers for disease diagnosis in this subgroup of patients. To confirm this finding, a follow-up study will be conducted in a separate cohort of patients.

Keywords: Epstein-Barr virus; Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; antigen mimicry; biomarker discovery; patient stratification.