Acta Dermato-Venereologica 2018, No. 6 98-6CompleteContent | Page 18

SHORT COMMUNICATION
Up-regulation of Human Herpesvirus 6B-derived microRNAs in the Serum of Patients with Drug-
induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms
Kazuya MIYASHITA, Fumi MIYAGAWA, Yuki NAKAMURA, Rie OMMORI, Hiroaki AZUKIZAWA and Hideo ASADA*
Department of Dermatology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan. *E-mail: asadah@
naramed-u.ac.jp
Accepted Mar 15, 2018; Epub ahead of print Mar 15, 2018
200
0
DIHS
(n=10)
b
MPE
(n=10)
H e a l t h y c o n t r o l
(n=10)
1000
r= 0.65
800
p= 0.02
600
400
200
0
-200
0
//
4
5
6
7
DRESS score
8
hhv6b-miR-Ro6-3
1200
400
https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-2925
1
800
400
0
DIHS
(n=10)
MPE
(n=10)
2000
H e a l t h y c o n t r o l
(n=10)
r= 0.77
p= 0.003
1500
1000
500
0
-500
0
//
4
5
DRESS score
6
7
8
800
400
600
300
400
200
200
0
hhv6b-miR-Ro6-4
500
100
DIHS
(n=10)
MPE
(n=10)
H e a l t h y c o n t r o l
(n=10)
1000 r= 0.60
800 p= 0.04
600
400
200
0
-200
0
//
4
5
DRESS score
6
7
8
1600
600
The maximum levels of hhv6b-miR-Ro6-1, -2, -3, and -4
in serum were significantly higher in patients with DIHS/
DRESS than in those with MPE and healthy controls
(p < 0.05, respectively) (Fig. 1a).
The time course of HHV-6B miRNA expression was
examined in the serum of patients with DIHS/DRESS.
In case 1, HHV-6B reactivation was confirmed by de-
tecting HHV-6B DNA in peripheral blood mononuclear
cells (PBMCs) on day 25 after onset. The expression
of hhv6b-miR-Ro6-2 in serum was detected on day 19,
while hhv6b-miR-Ro6-4 and -1 were detected on days
25 and 33, respectively (Fig. S1a 1 ).
In case 2, HHV-6B reactivation was detected on day
16 after onset. Hhv6b-miR-Ro6-2 was expressed on day
10, while hhv6b-miR-Ro6-3 and -1 were expressed on
the same day as HHV-6B DNA was detected (Fig. S1b 1 ).
1000
2000
800
hhv6b-miR-Ro6-2
RESULTS
1000
MATERIALS AND METHODS (see Appendix S1 1 )
hhv6b-miR-Ro6-1
a
levels of the 4 HHV-6B miRNAs in the serum of patients
with DIHS/DRESS during the acute and subacute stages.
Drug-induced hypersensitivity syndrome/drug reaction
with eosinophilia and systemic symptoms (DIHS/DRESS)
is a life-threatening multi-organ hypersensitivity reaction.
Reactivation of human herpesvirus 6B (HHV-6B), which
typically occurs 2–3 weeks after its onset, has been im-
plicated in DIHS/DRESS (1). Reactivation of HHV-6 has
been reported to correlate with flaring of symptoms such
as fever and hepatitis (2) and renal failure (3) in patients
with DIHS/DRESS, indicating that virus reactivation
could contribute to some symptoms or complications
in DIHS/DRESS. However, it has also been reported
that reactivation of HHV-6 could be merely a result of a
strong drug-specific immune response and not contribute
to DRESS symptoms and severity (4).
MicroRNAs (miRNAs) play important roles in biolo-
gical processes such as immune responses and cell dif-
ferentiation. Herpesviruses express their own miRNAs
and may regulate key viral genes (5). HHV-6A encodes
miR-U86 that regulates viral lytic replication (6), while
HHV-6B encodes at least 4 miRNAs: hhv6b-miR-Ro6-1,
-2, -3 and -4 (7). However, the precise roles of these 4
miRNAs in the regulation of HHV-6B latency and reac-
tivation remain largely unknown. Moreover, the roles of
individual miRNAs in DIHS/DRESS have not yet been
elucidated. The present study investigated the expression
612
0
DIHS
(n=10)
H e a l t h y c o n t r o l
(n=10)
MPE
(n=10)
500
r= 0.21
p= 0.51
400
300
200
100
0
0
//
4
5
DRESS score
6
7
8
Fig. 1. (a) Up-regulation of human herpesvirus 6B (HHV-6B)-derived miRNAs in the serum of patients with drug-induced hypersensitivity
syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS). The maximum levels of HHV6b-miR-Ro6-1, -2, -3, and -4
in serum were significantly higher in patients with DIHS/DRESS than in those with maculo-papular eruption (MPE) and healthy controls. *p  < 0.05. (b)
Correlation between DRESS scores and HHV-6B miRNAs in the serum of patients with DIHS/DRESS. DRESS scores correlated with the serum
levels of hhv6b-miR-Ro6-1, -2, and -3, respectively.
doi: 10.2340/00015555-2925
Acta Derm Venereol 2018; 98: 612–613
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Journal Compilation © 2018 Acta Dermato-Venereologica.