EBV/HHV-6A dUTPases contribute to myalgic encephalomyelitis/chronic fatigue syndrome pathophysiology by enhancing TFH cell differentiation and extrafollicular activities

• Published in: JCI insight Vol. 7; no. 11
• Main Authors: Cox, Brandon S, Alharshawi, Khaled, Mena-Palomo, Irene, Lafuse, William P, Ariza, Maria Eugenia
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 08.06.2022; American Society for Clinical investigation
• Subjects: Cell Differentiation; Epstein-Barr Virus Infections - enzymology; Epstein-Barr Virus Infections - virology; Fatigue Syndrome, Chronic - diagnosis; Fatigue Syndrome, Chronic - enzymology; Fatigue Syndrome, Chronic - virology; Herpesvirus 4, Human - enzymology; Herpesvirus 6, Human - enzymology; Humans; Infectious disease; Pyrophosphatases - metabolism; Roseolovirus Infections - enzymology; Roseolovirus Infections - virology; T-Lymphocytes, Helper-Inducer - enzymology; T-Lymphocytes, Helper-Inducer - pathology; T-Lymphocytes, Helper-Inducer - virology; Infectious disease; NKT cells; Cytokines; Cellular immune response
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.158193

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, debilitating, multisystem illness of unknown etiology for which no cure and no diagnostic tests are available. Despite increasing evidence implicating EBV and human herpesvirus 6A (HHV-6A) as potential causative infectious agents in a subset of patients with ME/CFS, few mechanistic studies address a causal relationship. In this study we examined a large ME/CFS cohort and controls and demonstrated a significant increase in activin A and IL-21 serum levels, which correlated with seropositivity for antibodies against the EBV and HHV-6 protein deoxyuridine triphosphate nucleotidohydrolase (dUTPases) but no increase in CXCL13. These cytokines are critical for T follicular helper (TFH) cell differentiation and for the generation of high-affinity antibodies and long-lived plasma cells. Notably, ME/CFS serum was sufficient to drive TFH cell differentiation via an activin A-dependent mechanism. The lack of simultaneous CXCL13 increase with IL-21 indicates impaired TFH function in ME/CFS. In vitro studies revealed that virus dUTPases strongly induced activin A secretion while in vivo, EBV dUTPase induced the formation of splenic marginal zone B and invariant NKTFH cells. Together, our data indicate abnormal germinal center (GC) activity in participants with ME/CFS and highlight a mechanism by which EBV and HHV6 dUTPases may alter GC and extrafollicular antibody responses.