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\title{Consideration of serum IL-36\selectlanguage{greek}α \selectlanguage{english}and \selectlanguage{greek}β \selectlanguage{english}levels trends in two patients with
chikungunya fever\selectlanguage{english}}



\author[1]{Makoto Kondo}%
\author[2]{Yoshiaki  Matsushima}%
\author[2]{Takehisa  Nakanishi}%
\author[2]{Shohei  Iida}%
\author[2]{Koji  Habe}%
\author[2]{Keiichi Yamanaka}%
\affil[1]{Mie University}%
\affil[2]{Mie Univ}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\textbf{1. Introduction}

Chikungunya fever is a persistent joint pain disease caused by
mosquito-borne arboviruses: chikungunya virus (CHIKV). In Chikungunya
fever, inflammatory cytokines such as IL-6, Il-17, IL-22, and IL-23
[1,2] are involved in chronic joint pain, but there are no reports on
whether IL-36 is specified as a cause of joint pain. This case study
compares the changes in IL-36\selectlanguage{greek}α \selectlanguage{english}and \selectlanguage{greek}β \selectlanguage{english}levels during infected chikungunya
fever and the recovery. This article highlights the relationship between
chikungunya fever and IL-36.

\textbf{2. Case Presentation}

We previously reported two cases with chikungunya fever after traveling
to Cook Island.\textsuperscript{3} The elevated serum IL-6, IL-17,
IL-21, and IL-23 levels have been reported in patient with chronic
arthritis after chikungunya fever [1,2]. Recent findings in psoriatic
arthritis revealed the elevated serum IL-36 during arthritis
[4].\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}IL-36 is a relatively newly found cytokine belonging to the IL-1
family, whose involvement in various diseases is still poorly
understood. In the current study, to evaluate the involvement of IL-36
in patients with chikungunya fever, stocked serum from the previously
reported two cases [1] at the initial visit, 7 days, and 56 days later
were used to measure IL-36\selectlanguage{greek}α \selectlanguage{english}and IL-36\selectlanguage{greek}β\selectlanguage{english}concentration. Two cases were
siblings, and the brother developed pain in his neck and ankle joints on
the second day back to Japan, but fever was not detected. Sister
developed fever soon after returning to Japan, with severe arthralgia
and leg edema. The arthralgia persisted for about a year. IL-36\selectlanguage{greek}α \selectlanguage{english}and
IL-36\selectlanguage{greek}β \selectlanguage{english}were measured in the patient's serum using human IL-36\selectlanguage{greek}α/\selectlanguage{english}IL-1F6
and IL-36\selectlanguage{greek}β/\selectlanguage{english}IL-1F8 DuoSet ELISA\selectlanguage{ngerman}\textsuperscript{®} (R\&D Systems,
Minneapolis, MN, USA). At the initial visit, IL-36\selectlanguage{greek}α \selectlanguage{english}was higher in the
sister, who had more fever and arthralgia symptoms than her brother. 7
days later, both had higher levels than at the initial visit, but the
brother, whose symptoms of Chikungunya fever appeared later, had a
larger increase than at the initial visit. After 56 days, both decreased
to about half of the peak value. IL-36\selectlanguage{greek}β \selectlanguage{english}was highest at the first visit
for both patients and gradually decreased (Figure 1).

\textbf{3. Discussion}

Chikungunya fever causes arthritis, which often persists for a long time
in many cases. The sibling patients also suffered from arthralgia even
with taking non-steroidal anti-inflammatory drugs. The sister in
particular had severe symptoms of arthralgia that persisted for about a
year. Based on the results of serum IL-36\selectlanguage{greek}α \selectlanguage{english}and IL-36\selectlanguage{greek}β \selectlanguage{english}levels, the
association between IL-36 and chikungunya fever was discussed. Both
IL-36\selectlanguage{greek}α \selectlanguage{english}and IL-36\selectlanguage{greek}β \selectlanguage{english}were reduced by 56 days. In the case of psoriatic
arthritis, IL-36 activates dendritic cells inducing Th17 cells to
generate IL-17 and IL-22, resulting in persistent arthritis. Therefore,
the mechanism of chronic arthritis caused by psoriatic arthritis is
different from that of chronic arthritis in chikungunya fever and IL-36
may not be involved in the chronic arthritis of chikungunya fever.
IL-36\selectlanguage{greek}α \selectlanguage{english}is produced by monocytes, B cells, and T cells. IL-36\selectlanguage{greek}β \selectlanguage{english}is
produced by dendritic cells and induces proinflammatory cytokines,
including IL-12, IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6, and TNF-\selectlanguage{greek}α. \selectlanguage{english}Both IL-36\selectlanguage{greek}α \selectlanguage{english}and IL-36\selectlanguage{greek}β \selectlanguage{english}play an
important role in host immunity, and it has been suggested that one
physiological function of IL-36 may be to counteract microbial immune
evasion [5]. IL-36\selectlanguage{greek}β \selectlanguage{english}was highest at the initial visit, indicating that
inflammatory cytokines may have been induced during the infection
control process. And IL-36\selectlanguage{greek}α \selectlanguage{english}was persistently high or increased from the
time of initial visit to one week, suggesting that the acquired immune
mechanism may be the peak. IL-36 might act as an immunological defense
mechanism during chikungunya virus infection.

\textbf{Conflicts of Interests}

The authors have declared that no competing interests exist.

\textbf{Ethics Statement}

We had received permission and written informed consent from siblings to
use the extra serum for additional testing and publish the current case
report.

\textbf{Funding Statement}

The authors did not receive any financial support for this study.

\textbf{Authors' contributions}

Take care of the patient: M.K. Conceptualization and data measurement:
M.K. methodology: Y.M. S.I. and T.N. Writing---original draft
preparation: M.K. Writing---review and editing: K.H. and K.Y. All
authors have read and agreed to the published version of the manuscript.

\textbf{Data availability Statement}

The original contributions presented in this study are included in the
article. Further inquiries can be directed to the corresponding authors.



\textbf{References}

[1] Kondo M, Akachi S, Ando K, er al., ``Two Japanese siblings
affected with Chikungunya fever with different clinical courses:
Imported infections from the Cook Islands'', \emph{J Dermatol} , vol.43,
no. 6, pp697-700, 2016.

[2] Chow A, Her Z, Ong EK, et al., ``Persistent arthralgia induced by
Chikungunya virus infection is associated with interleukin-6 and
granulocyte macrophage colony-stimulating factor'', \emph{J Infect Dis}
, vol.203, no.2, pp149-157, 2011.

[3] Liu X, Poo YS, Alves JC, et al., ``Interleukin-17 Contributes to
Chikungunya Virus-Induced Disease'', \emph{mBio} , vol.13, no.2,
e0028922, 2022.

[4] Boutet MA, Nerviani A, Lliso-Ribera G, et al., ``Interleukin-36
family dysregulation drives joint inflammation and therapy response in
psoriatic arthritis'', \emph{Rheumatology (Oxford)} , vol.59, no.4,
pp828-838, 2020.

[5] L. E. Jensen, ``Interleukin-36 cytokines may overcome microbial
immune evasion strategies that inhibit interleukin-1 family
signaling'',\emph{Sci Signal,} vol.10, no.492, eaan3589, 2017.

\textbf{Figure legend}

\textbf{FIGURE 1} : The graphs show the changes in serum levels of
IL-36\selectlanguage{greek}α \selectlanguage{english}and IL-36\selectlanguage{greek}β \selectlanguage{english}measured on day1 (at first visit), day7, and day56
from the brother and sister. A 20-fold dilution serum was used for the
assay.\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/figIL-36/figIL-36}

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\end{figure}

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