PMID- 35482424
OWN - NLM
STAT- MEDLINE
DCOM- 20220609
LR  - 20220716
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 7
IP  - 11
DP  - 2022 Jun 8
TI  - EBV/HHV-6A dUTPases contribute to myalgic encephalomyelitis/chronic fatigue 
      syndrome pathophysiology by enhancing TFH cell differentiation and 
      extrafollicular activities.
LID - 10.1172/jci.insight.158193 [doi]
LID - e158193
AB  - 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.
FAU - Cox, Brandon S
AU  - Cox BS
AD  - Department of Cancer Biology and Genetics.
FAU - Alharshawi, Khaled
AU  - Alharshawi K
AD  - Department of Cancer Biology and Genetics.
FAU - Mena-Palomo, Irene
AU  - Mena-Palomo I
AD  - Department of Cancer Biology and Genetics.
FAU - Lafuse, William P
AU  - Lafuse WP
AD  - Department of Microbial Infection and Immunity, and.
FAU - Ariza, Maria Eugenia
AU  - Ariza ME
AD  - Department of Cancer Biology and Genetics.
AD  - Institute for Behavioral Medicine Research, The Ohio State University Wexner 
      Medical Center, Columbus, Ohio, USA.
LA  - eng
GR  - P30 CA016058/CA/NCI NIH HHS/United States
GR  - R01 AI084898/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220608
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - EC 3.6.1.- (Pyrophosphatases)
RN  - EC 3.6.1.23 (dUTP pyrophosphatase)
SB  - IM
MH  - Cell Differentiation
MH  - Epstein-Barr Virus Infections/enzymology/virology
MH  - *Fatigue Syndrome, Chronic/diagnosis/enzymology/virology
MH  - *Herpesvirus 4, Human/enzymology
MH  - *Herpesvirus 6, Human/enzymology
MH  - Humans
MH  - *Pyrophosphatases/metabolism
MH  - Roseolovirus Infections/enzymology/virology
MH  - *T-Lymphocytes, Helper-Inducer/enzymology/pathology/virology
PMC - PMC9220958
OTO - NOTNLM
OT  - Cellular immune response
OT  - Cytokines
OT  - Infectious disease
OT  - NKT cells
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2022/04/29 06:00
MHDA- 2022/06/10 06:00
PMCR- 2022/06/08
CRDT- 2022/04/28 12:03
PHST- 2022/01/04 00:00 [received]
PHST- 2022/04/26 00:00 [accepted]
PHST- 2022/04/29 06:00 [pubmed]
PHST- 2022/06/10 06:00 [medline]
PHST- 2022/04/28 12:03 [entrez]
PHST- 2022/06/08 00:00 [pmc-release]
AID - 158193 [pii]
AID - 10.1172/jci.insight.158193 [doi]
PST - epublish
SO  - JCI Insight. 2022 Jun 8;7(11):e158193. doi: 10.1172/jci.insight.158193.