Immunological Medicine

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Murine models of idiopathic inflammatory

myopathy

Risa Konishi, Yuki Ichimura & Naoko Okiyama

To cite this article: Risa Konishi, Yuki Ichimura & Naoko Okiyama (2023) Murine
models of idiopathic inflammatory myopathy, Immunological Medicine, 46:1, 9-14, DOI:
10.1080/25785826.2022.2137968

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Group on behalf of the Japanese Society of
Clinical Immunology.

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IMMUNOLOGICAL MEDICINE
2023, VOL. 46, NO. 1, 9–14
https://doi.org/10.1080/25785826.2022.2137968

REVIEW ARTICLE

Murine models of idiopathic inflammatory myopathy

Risa Konishi , Yuki Ichimura and Naoko Okiyama
Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University,
Tokyo, Japan

ABSTRACT ARTICLE HISTORY

Idiopathic inflammatory myopathies (IIMs) are characterized by inflammation of muscles and Received 19 August 2022
other organs. Several myositis-specific autoantibodies (MSAs) have been identified in IIMs Accepted 16 October 2022
and were found to be associated with distinct clinical features. Although MSAs are valuable
KEYWORDS
for the diagnosis of IIMs, the pathogenic roles of these antibodies remain unknown. To
Murine model; idiopathic
investigate the pathogenesis of IIMs, several animal models of experimental myositis have inflammatory myopathy;
been established. Classical murine models of autoimmune myositis, experimental auto- dermatomyositis; myositis-
immune myositis, and C protein-induced myositis are established by immunization with specific autoantibody; TIF1c
muscle-specific antigens, myosin, and skeletal C protein, respectively. Furthermore, a murine
model of experimental myositis was generated by immunization with a murine recombinant
histidyl-tRNA synthetase, Jo-1, in which muscle and lung inflammation reflecting anti-synthe-
tase syndrome are induced depending on acquired immunity. Recently, the transfer of
human IgGs from patients with immune-mediated necrotizing myopathy, comprising anti-
signal recognition particles and anti-3-hydroxy-3-methylglutaryl coenzyme A reductase anti-
bodies, was found to induce complement-mediated myositis in recipient mice. CD8þ T cell-
mediated myositis can be established depending on autoimmunity against transcriptional
intermediary factor 1c (TIF1c), an autoantigen for MSAs induced by recombinant human
TIF1c immunization. These new murine models reflecting MSA-related IIMs are useful tools
for accurately understanding the pathological mechanisms underlying IIMs.

1. Introduction IIMs and are reportedly associated with distinct

Idiopathic inflammatory myopathies (IIMs), includ-
ing dermatomyositis (DM), polymyositis (PM),
immune-mediated necrotizing myopathy (IMNM),
inclusion body myositis (IBM), and anti-synthetase
syndrome (ASS), are characterized by inflammation
of the proximal arm and leg muscles, and other
organs, such as the skin, lung, and joints are fre-
quently affected [1].
DM is distinguished from other IIMs based on
its specific cutaneous manifestations, heliotrope
rash, and Gottron papules/signs. Perifascicular atro-
phy is the hallmark histopathological feature of DM,
along with the sarcoplasmic expression of myxovirus
resistance protein A (MxA) and sarcolemmal mem-
brane attack complex deposition [2]. Conversely,
IMNM is characterized by relatively severe proximal
weakness and myofiber necrosis with minimal
inflammatory cell infiltration on muscle biopsy [3],
the hallmark histological feature of IBM.
DM, IMNM, and ASS are characterized by the
presence of myositis-specific autoantibodies (MSAs).
Several MSAs have been identified in patients with
clinical features [4–6]. Almost all MSAs have been
identified in patients with DM: anti-Mi-2, anti-mel-
anoma differentiation-associated gene 5 (MDA5),
anti-transcriptional intermediary factor 1c (TIF1c),
anti-nuclear matrix protein 2 (NXP2), and anti-
small ubiquitin-like modifier activating enzyme
(SAE) antibodies, each of which was found to be
associated with characteristic clinical features [6].
Anti-MDA5 antibody exhibits high specificity for
clinically amyopathic DM, presenting with rapidly
progressive interstitial lung disease (ILD) [7]. Anti-
TIF1c antibody has been detected in juvenile and
adult patients with DM and is closely correlated
with internal malignancies, especially in elderly
patients [8]. Previously, we reported that the anti-
NXP2 antibody, also detected in juvenile and adult
patients with IIMs, is characterized by extensive
muscular involvement but occasionally lacks a typ-
ical rash [9]. In contrast, anti-SAE antibody-positive
patients with DM frequently display extensive
rash [10].
ASS is a subgroup of IIMs presenting a DM/PM
phenotype defined by the presence of autoantibodies

CONTACT Naoko Okiyama okiy.derm@tmd.ac.jp Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical
and Dental University, Tokyo, Japan
ß 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of the Japanese Society of Clinical Immunology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
10 R. KONISHI ET AL.

Table 1. Murine models of inflammatory myopathies.

Experimental Upregulation of Anti-SRP¶/HMGCR§
autoimmune MHC class I C protein-induced Jo-1- TIF1c-induced antibodies-
Model name myositis (EAM) in muscle myositis (CIM) immunized mice myositis (TIM) transferred mice
Related None None None Anti- Dermatomyositis Immune-mediated
human disease synthetase necrotizing
syndrome myopathy
Myositis-specific None None None Anti- Anti- Anti-SRP¶/
autoantibody (Some mice ARS† antibody TIF1c HMGCR§
have anti- antibody antibodies
ARS† antibody)
Clinical features of Not applicable Not applicable Not applicable Myositis, specific Myositis, specific Myositis
related rash, ILD‡ rash,
human disease ILD‡, cancer
Autoantigen in Myosin None Skeletal C protein Jo-1 TIF1c SRP¶, HMGCR§
murine model
Features in a Myositis Myositis Myositis Myositis, ILD‡ Myositis Myositis
murine model
Pathogenesis in a CD4þ T cell Endoplasmic CD8þ T cell Innate immunity CD8þ T cells Antibody
murine model reticulum stress
TIF1c: transcriptional intermediary factor 1c; ¶SRP: signal recognition particle; §HMGCR: 3-hydroxy-3-methylglutaryl coenzyme A reductase; †ARS:
aminoacyl transfer RNA synthetases; ‡ILD: interstitial lung disease.

against aminoacyl transfer RNA synthetases (ARS), 2. Murine models of myositis

accompanied by clinical features such as chronic
ILD, myositis, arthralgia, fever, and mechanic’s
hands [11]. Anti-ARS antibodies include autoanti-
bodies against histidyl (Jo-1), threonyl (PL-7), alanyl
(PL-12), glycyl (EJ), isoleucyl (OJ), asparaginyl (KS),
tyrosyl (Ha), and phenylalanyl (Zo); among these,
anti-Jo-1 antibody is most commonly detected [12].
IMNM is categorized into three groups: anti-3-
hydroxy-3-methylglutaryl coenzyme A reductase
(HMGCR) antibody-positive IMNM, anti-signal rec-
ognition particle (SRP) antibody-positive IMNM,
and seronegative IMNM [13]. Anti-SRP antibodies
are substantially associated with severe neurological
symptoms when compared with anti-HMGCR anti-
bodies [3]. Seronegative IMNM has been associated
with cancer [14]. IBM is also characterized by myo-
pathology; however, no specific MSA has
been identified.
Although MSAs are useful for diagnosing and
prognostic estimation of IIMs, their pathogenic role
remains unknown, and it remains to be determined
whether autoantibodies are simple disease bio-
markers or true pathogenic effectors.
To comprehensively clarify the pathogenesis of
IIMs and develop novel therapeutic strategies,
numerous animal models of IIMs have been estab-
lished, including infectious, genetic, and antigen-
induced models [15]. Although previously estab-
lished murine models of experimental autoimmune
myositis depend on immune responses against
muscle tissue-specific antigens [16,17], we recently
established a murine model of myositis by immun-
ization with TIF1c, an autoantigen for a DM-spe-
cific MSA [18]. Herein, we review the history and
evolution of murine models of myositis and sum-
marize these models in Table 1.
2.1. Experimental autoimmune myositis (EAM)
The classical murine model of autoimmune myositis
is known as EAM [16,19]. Using SJL/J mice, EAM
can be induced by repeated immunization with
muscle homogenate or partially purified myosin of
the skeletal muscle with complete Freund’s adjuvant
(CFA) containing mycobacteria on four occasions,
performed at weekly intervals. Myositis is induced
in the quadriceps femoris muscles of immunized
mice, in which CD4þ T cells predominantly infil-
trate the muscle tissue [20]. Immunoblot analysis of
immunoglobulin G (IgG) from EAM mice revealed
the presence of antibodies against a wide variety of
muscle proteins. The transfer of T cells or IgGs col-
lected from EAM mice was shown to cause myositis
in naïve mice [16].
However, SJL/J mice exhibit a defect in the dys-
ferlin gene and develop spontaneous muscle fiber
degeneration and inflammatory cell infiltration inde-
pendent of EAM immunization [21]. Another subse-
quent study has shown that severe EAM can be
induced also in BALB/c mice by a twice immuniza-
tion with increased administration doses of rat
myosin and pertussis toxin (PT) [22].
2.2. Genetically modified mice with upregulation
of major histocompatibility complex (MHC) classI
in the skeletal muscles develop myositis
In the human IIMs, upregulation of MHC class I on
the surface of muscle cells is observed in an early
phase. Nagaraju et al. [23] have reported that trans-
genic mice with conditional upregulation of MHC
class I expression in the skeletal muscles develop
clinically muscle weakness depending on muscle cell

damage and muscle inflammation. The mice often
produce autoantibodies including anti-histidyl-tRNA
synthetase antibodies. The mechanism of the myo-
sitis has been described to be depending on activa-
tion of the endoplasmic reticulum stress response
[24]. Even though the transgenic mice are not
widely available, this murine model well reflects
human IIMs.
2.3. C Protein-induced myositis (CIM)
Subsequently, biochemical studies have suggested
that skeletal C protein, a myosin-binding protein, is
the major immunogen in the myosin fraction that
can induce EAM in rats [25]. Sugihara et al. [17]
established modified and improved EAM, i.e., CIM,
in C57BL/6 (B6) mice by administering a single sub-
cutaneous injection of CFA-conjugated human or
murine C protein fragments, along with an intraper-
itoneal injection of pertussis toxin (PT), another
adjuvant. CIM is an improved murine model of
autoimmune myositis when compared with classic
EAM, given that CIM can be induced even in B6
mice, the most commonly used mouse strain for
gene modification.
The C protein-immunized mice develop myositis
2–3 weeks after immunization. Immunohistochemistry
studies revealed that CD8þ T cells localize to the
endomysial site of muscle tissues of CIM mice when
compared with perimysial and perivascular sites. In
addition, Sugihara et al. [26] found that major histo-
compatibility complex (MHC) class I knockout (KO)
mice failed to develop CIM, and perforin deficiency, a
cytolytic protein in cytotoxic CD8þ T cell granules,
inhibited muscle fiber injury in CIM. Moreover, the
adoptive transfer of CD8þ T cells collected from CIM
mice could induce more severe muscle fiber injury in
recipient B6 mice than in CD4þ T cells. Transferring
bone marrow-derived dendritic cells presenting a
CD8 epitope peptide from the C protein could induce
myositis in recipient mice [27]. These results indicate
that CIM is characterized by CD8þ T cell-mediated
muscle fiber injury.
Moreover, along with autoaggressive CD8þ T
cells, adjuvant-activated muscle tissue conditions are
essential for established CIM, like ’seeds and soil’
[28,29]. Given that innate/acquired immunity medi-
ates myositis, previous studies using the CIM model
have identified several therapeutic targets, including
interleukin (IL)-6, IL-1, tumor necrosis factor-a, L-
selectin, CXCL10, CD80/86, IL-23, and high mobil-
ity group box 1 (HMGB1) [30–36]. In contrast,
interferon (IFN)-c, but not IL-4, might be a sup-
pressive factor in CIM [37].
IMMUNOLOGICAL MEDICINE 11
2.4. Jo-1-induced ASS model
Another murine model of experimental myositis
was generated by immunization with purified epit-
opic peptides derived from histidyl-tRNA synthetase
(HisRS, Jo-1) with CFA [38]. Subcutaneous injec-
tions of murine HisRS induced local muscle and
lung inflammation in congenic B6 mice (B6.G7).
Histological studies of muscle tissues revealed
diverse infiltration patterns, with perimysial/epimy-
sial inflammation in a perivascular distribution,
endomysial inflammation, and muscle fiber inva-
sion/degeneration. The immunized mice showed a
HisRS-specific CD4þ T cell response and antibody
production. However, DO11.10/Rag-2-KO mice with
abrogated HisRS-specific B and T cell responses
demonstrated significant muscle inflammation after
immunization with HisRS [39]. Moreover, C3H/HeJ
(TLR4-KO) mice lacking significant anti-HisRS anti-
body levels exhibited muscle inflammation induced
by immunization with HisRS. These findings sup-
port a key role for innate immune responses, but
not HisRS-specific autoimmunity, in a HisRS-
induced model of myositis. However, analysis of
bronchoalveolar lavage fluid samples collected from
anti-Jo-1 antibody-positive patients with IIM
revealed that HisRS-specific CD4þ T cells might be
present within the lungs of patients [40].
2.5. Transfer of human IgGs from patients with
IMNM induces muscle deficiency
Anti-SRP and anti-HMGCR antibodies are often
detected as MSAs specific to IMNM. Bergua et al.
[41] found that transferring human IgGs from
patients with IMNM, comprising anti-SRP or
HMGCR antibodies, provoked muscle deficiency
and myofiber necrosis in recipient B6 wild-type or
Rag-2-KO mice. Muscle deficiency tends to be less
severe in mice receiving IgGs from anti-HMGCR
antibody-positive patients than in those receiving
IgGs from anti-SRP antibody-positive patients.
These phenomena may reflect the features of IMNM
[3]. The myopathy severity in IMNM IgG-trans-
ferred complement C3-KO mice was reduced,
whereas supplementation with human complement
could increase severity. This model suggested that
patient-derived anti-SRP and anti-HMGCR antibod-
ies are pathogenic toward muscles in vivo through a
complement-mediated mechanism. Accordingly,
anti-SRP and anti-HMGCR autoantibodies are not
only diagnostic biomarkers of IMNM but also direct
pathogenic factors.
12 R. KONISHI ET AL.
Figure 1. A new murine model of dermatomyositis, transcriptional intermediary factor 1c (TIF1c)-induced myositis (TIM), can
be induced by weekly subcutaneous injections of recombinant human TIF1c protein emulsified in complete Freund’s adjuvant
(CFA), four times. Adoptive transfer of CD8þ T cells, but not CD4þ T cells and IgGs, from TIF1c-immunized mice induces myo-
sitis in recipient mice.
2.6. Tif1c-induced myositis model (TIM)
Anti-TIF1c antibody-positive DM is known to be
associated with malignancies, particularly in elderly
patients [8], and may also be associated with preg-
nancy [42]. TIF1c is frequently mutated or overex-
pressed in tumors [43,44] and is overexpressed in
the embryo and mammary epithelial cells during
pregnancy [45,46]. Therefore, it can be speculated
that cancer and pregnancy trigger autoimmunity
against TIF1c and autoimmunity to TIF1c can
induce the establishment of myositis. However, elu-
cidating the suggested mechanisms can be
challenging.
We established TIM in B6 mice by administering
weekly subcutaneous injections of recombinant
human TIF1cprotein emulsified in CFA four times,
along with an intraperitoneal injection of PT [18].
The immunized mice developed TIF1c-specific T
cells and anti-human and murine TIF1c antibodies,
resulting in myositis in the hamstrings and quadri-
ceps two weeks after the last immunization.
Histological studies revealed atrophy and necrosis of
muscle fibers, accompanied by infiltrating mono-
nuclear cells in the perifascicular and endomysial
sites of muscle tissues.
Immunohistochemistry studies showed that T
cells, particularly CD8þ T cells, predominantly infil-
trated and adhered to the muscle fibers, which upre-
gulated the expression of MHC class I and type I
interferon (IFN)-responsive molecule Mx1. Beta 2
microglobulin-KO mice lacking MHC class I expres-
sion, perforin-KO mice, and anti-CD8 depleting
antibody-treated mice rarely developed TIM.
Furthermore, the adoptive transfer of CD8þ T cells
from TIM mice could induce myositis in recipient
B6 mice, whereas the transfer of CD4þ T cells failed
to exhibit this effect. Collectively, CD8þ T cells were
identified as pathogenic in TIM. In contrast, lMT
mice, which completely lack B-cell lineages, devel-
oped myositis, and the adoptive transfer of IgGs col-
lected from TIM mice failed to induce myositis in
recipient mice. These results indicate that B cells
and autoantibodies are not essential for developing
TIM. In other words, the anti-TIF1c antibody
detected in patients with DM may be a diagnostic
biomarker but not a direct pathogenic factor, unlike
anti-SRP/HMGCR antibodies in patients with
IMNM. Accordingly, TIM, which is dependent on
autoimmunity against TIF1c, was mediated by
TIF1c-specific CD8þ T cells but not TIF1c-specific
CD4þ T cells, B cells, and autoantibodies (Figure 1).
Type I IFNs are suspected to be involved in the
pathogenesis of DM [47,48]. We have reported that
IFN-a/b receptor deficiency partially inhibited the
development of TIM. In addition, treatment with
tofacitinib, a Janus kinase (JAK) inhibitor for vari-
ous cytokine receptor signaling, including type I
IFN signaling, could treat established TIM without
suppressing TIF1c-specific T cell response and auto-
antibody production. Therefore, JAK inhibitors
could afford a good treatment strategy for DM that
does not involve acquired immunity, which is
important for protecting against pathogen-
induced infection.
While EAM and CIM completely depend on
immune responses specific to muscular antigens,
myosin, and C protein [16,17], TIM induction relies
on autoimmunity against a ubiquitous intracellular
molecule, TIF1c, an autoantigen for MSAs. This
new murine model of experimental myositis, which
closely reflects the pathological mechanisms of DM,
could be a useful tool for developing novel treat-
ment strategies against anti-TIF1c antibody-posi-
tive DM.

3. Conclusion
In recent years, murine models of myositis for each
MSA, such as TIM, have been developed (Table 1).
These models suggest that each MSA-related IIM
exhibits distinct pathogenesis; thus, the establish-
ment of myositis models for other MSAs can
be expected.
Disclosure statement
No potential conflict of interest was reported by
the author(s).
ORCID
Risa Konishi http://orcid.org/0000-0003-3681-2441
Yuki Ichimura http://orcid.org/0000-0003-0375-2243
Naoko Okiyama http://orcid.org/0000-0002-5398-0773
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