期刊
JCI INSIGHT
卷 7, 期 11, 页码 1-23出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.158193
关键词
-
资金
- NIH [R01 A1084898]
- CA [P30 CA016058]
- NCI [T30CA16058]
ME/CFS patients showed elevated levels of activin A and IL-21, which were associated with antibodies against EBV and HHV-6 proteins. Impaired T-FH cell function was observed in ME/CFS patients, potentially contributing to the progression of the disease. The study also suggests that viral dUTPases may lead to abnormal germinal center activity.
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 (T-FH) cell differentiation and for the generation of high-affinity antibodies and long-lived plasma cells. Notably, ME/CFS serum was sufficient to drive T-FH cell differentiation via an activin A-dependent mechanism. The lack of simultaneous CXCL13 increase with IL-21 indicates impaired T-FH 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.
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