Plasmacytoid dendritic cells (pDCs) and
regulatory T (Treg) cells may be the key
to viral reactivation in drug-induced
hypersensitivity syndrome (DIHS)
Yi-Chun Chen, MD, MS, Michael D. Rosenblum, MD, PhD, and Kanade Shinkai, MD, PhD
San Francisco, California
Key words: drug-induced hypersensitivity syndrome; drug reaction with eosinophilia and systemic
symptoms; plasmacytoid dendritic cells; regulatory T cells; viral reactivation.
D rug-induced hypersensitivity syndrome
(DIHS) or drug reaction with eosinophilia
and systemic symptoms is a poorly under-
stood and clinically challenging syndrome. Its
cutaneous and systemic presentation can be varied,
often making an accurate diagnosis difficult. The
pathogenesis of DIHS involves a complex interplay
of drug sensitization, human herpesvirus (HHV)
reactivation, and dysregulation of the host immune
response. Currently, the pathogenesis of DIHS
is only partially understood and many disease
mechanisms are debated. Sequential reactivation of
several HHVs (HHV-6, HHV-7, Epstein-Barr virus,
cytomegalovirus) has been suggested to play a
central role in the pathogenesis of DIHS.1 HHV-6
reactivation correlates to more severe disease,
prolonged illness as a result of flaring courses, and
increased mortality.2 Multiple and/or sequential
HHV reactivation is also proposed to correlate with
autoimmune sequelae of DIHS.3 However, the
dominant factors that induce HHV reactivation in
these patients remain unknown. Systemic steroids
have been implicated in promoting viral reactivation
in DIHS because the incidence of viral reactivation
appears to be significantly higher after treatment.4
However, systemic steroids cannot be the sole
facilitator of viral induction, as HHV reactivation is
also observed in patients with DIHS in the absence of
corticosteroid therapy.5 Importantly, it is difficult to
exclude the possibility that patients had viral
reactivation because of worsening disease severity.
From the Department of Dermatology, University of California, San
Francisco.
Funding sources: None.
Conflicts of interest: None declared.
Reprint requests: Kanade Shinkai, MD, PhD, Department of Dermato-
logy, University of California, San Francisco, 1701 Divisadero St,
Third Floor, San Francisco, CA 94115. E-mail: kanade.shinkai@ucsf.
edu.
1288
Abbreviations used:
DC:
DIHS:
HHV:
dendritic cell
drug-induced hypersensitivity syndrome
human herpesvirus
pDC: plasmacytoid dendritic cell
Treg: regulatory T
HHV reactivation has also been postulated to be both
a trigger and a consequence of cytokine storm in
patients with DIHS.
Two cutaneous immune cell subsets, plasmacytoid
dendritic cells (pDCs) and regulatory T (Treg) cells,
have recently been implicated in DIHS pathogenesis.
The frequency and/or function of both cell types
change dynamically during the course of DIHS. In
early stages of DIHS, Treg cells expand but then later
contract with deficient function upon resolution.6
These findings may explain some important clinical
features of DIHS, including prolonged latency of
onset, HHV reactivation, and autoimmune sequelae
long after resolution. Direct evidence correlating viral
reactivations with changes in Treg cell numbers and/
or function is lacking. More frequent blood samplings
and assessment of lymphocytes in affected organs
(ie, skin) are required to discern dynamic changes of
Treg cells during different stages of DIHS.
pDCs are a distinct subset of human dendritic cells
(DCs) notable for their specialized antiviral function
and central role in activating host innate and
adaptive immune responses.7 Upon viral infection,
J Am Acad Dermatol 2016;74:1288-9.
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2015 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2015.11.031
J AM ACAD DERMATOL
VOLUME 74, NUMBER 6
pDCs produce large amounts of type 1 interferons,
and subsequently undergo differentiation into
mature DCs. Type 1 interferons have potent antiviral
effects not only through activating natural killer (NK)
cells, but also by augmenting T-cell function,
promoting B-cell differentiation, and inducing
effector cytokine production.8 pDCs are also potent
producers of chemokines, which preferentially
recruit T helper (TH)1 type effector cells.
The significance of dynamic changes in cytokines
noted in patients with DIHS throughout the course of
illness remains poorly understood. The recent obser-
vation that patients with DIHS and HHV-6 reactivation
had lower levels of many proinflammatory cytokines
and chemokines in their blood when compared with
those without HHV-6 reactivation highlights a poten-
tially important role for pDCs in viral reactivation in
DIHS. Key proinflammatory cytokine/chemokine
levels nadir during viral reactivation and are elevated
thereafter.9 Based on the striking finding that circu-
lating pDCs are decreased in patients with DIHS,
especially around the time of viral reactivation,10 we
may now be able to explain several critical features of
DIHS, including the tendency of viral reactivation,
transient hypogammaglobulinemia, and profound
cytokine/chemokine reduction during viral reactiva-
tion. Because virus-activated pDCs preferentially elicit
TH1 polarization, increased eosinophilia observed in
patients with DIHS may be partially explained by a
shift of the TH1/TH2 balance, as evidenced by or a
consequence of diminished pDC numbers.
Importantly, the decrease of pDCs and reciprocal
cytokine/chemokine changes highlight the unique
features of patients with DIHS and HHV-6 reactivation,
significantly different when compared with what
is seen in patients with DIHS who do not reactivate
virus.
Better understanding of the roles of pDCs and
Treg cells in DIHS may inform future treatment, both
as important predictors of HHV reactivation and as
potential targets for immunotherapy to prevent
long-term sequelae.11 One important question that
remains is whether the changes of pDCs and Treg
Chen, Rosenblum, and Shinkai 1289
cells are part of a coordinated immune dysfunction
or whether these are independent events for viral
reactivation. Monitoring dynamic changes in the
numbers and function of pDCs and Treg cells in
both blood and skin of patients with DIHS
and correlating these with HHV reactivation and
cytokine changes should be a top priority. This work
will provide the foundation for establishing better
treatments to improve the outcomes, both short-term
and long-term, for patients with DIHS.
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