Life science
Medicine, Drug discovery

Pathogenesis of dermatomyositis
Department of Dermatology, Graduate School of Medicine
Professor Manabu Fujimoto
Researchmap https://researchmap.jp/read0122743

Life science

Abstract
Dermatomyositis is a prototypic connective tissue disease, ofwhich the pathogenesis is autoimmunity. Autoantibodies against
transcriptional intermediary factor 1-γ (TIF1-γ) are positive in approximately 20% of patients. increase. In this study, we establisheda novel mouse myositis model that was induced by the immunization with human TIF1-γ protein. This new animal model is considered to mimic the pathophysiology of human dermatomyositis, andis expected to serve as a useful tool for development and screening of new therapeutic agents.

▍ Background & Results
Connective tissue diseases are classified as systemic autoimmune diseases. They are life-threatening intractable diseases, andtherapy based on specific pathogenesis has yet been developed,
except for rheumatoid arthritis. Dermatomyositis presents with muscle weakness due to muscle inflammation and characteristic skinlesions. The elucidation of the pathogenesis has been delayed,
mainly because there have been no animal disease model relevantwith human disease.
In recent years, a number of myositis-specific autoantibodies
have been discovered in dermatomyositis. Since they correlate
closely with clinical manifestations, they are not only useful biomarkers for predicting complications and treatment responsiveness, but also for studying molecular mechanisms of how thedisease develops. One of the major dermatomyositis-specific antibodies is the anti-TIF1-γ antibody. In this study, we established amouse model that develops myositis by immunization with TIF1-γ
protein.
A human TIF1γ full-length protein with post-translational modification similar to that of mammals was prepared and purified using
a synthetic system using baculovirus, and repeatedly subcutaneously administered to mice together with adjuvant. As a result, wefound that myositis developed in the thigh muscles. Histopathological findings included the infiltration of inflammatory cells, mainly
CD8+ T cells surrounding the muscle fibers as well as perifascicular atrophy, a typical finding of human dermatomyositis. Furthermore, the transfer of CD8+ T cells from mice in which myositis has
been induced to naive mice was able to induce myositis. Thus,
CD8+ T cells have an essential role in this myositis model.
Type I interferon is considered to be strongly involved in the development of human dermatomyositis. In this study, mice deficientfor type I interferon receptor were shown to exhibit milder muscle
disease. In addition, administration of a Janus kinase (JAK) inhibitor, which blocks cytokine signals such as type I interferon, suppressed the development of myositis.

▍Significance of the research and Future perspective

This myositis mouse model can be induced by immunization ofself-antigens that have been present in human diseases. Therefore,

this model will be useful for the development as well as evaluationof therapeutic agents.
Anti-TIF1-γ antibody-positive dermatitis is known to be associated with malignancy. It is postulated that mutation in the TIF1-γ
gene, which acts as a tumor suppressor gene, in malignant tumors
induces an autoimmune response. Then, as was demonstrated inthis study, the immune response to TIF1-γ actually causes myositis. In this way, we can comprehensively explain the whole processes of a prototypic connective tissue disease. Therefore, this novel
mouse model of myositis is considered to have great significancefor elucidating the molecular mechanism of how this disease develops.

Various manifestations in dermatomyositis and polymyositis

Dysphagia

Interstitial lung disease

Carditis
Rash
Raynaud’s phenomenon

Myositis

Malignancy

Mouse myositis model induced by TIF1γ immunization
Mouse myositis model induced by TIF1γ immunization

B6
mouse
B6mouseevaluation
Day 0

Day 7

Day 14

Day 21

Day 0Day 7

Day 14

Day 21

evaluation

Back (s.c) +pertussis toxin (i.p)

Back (s.c)

Back (s.c)

Back/footpad (s.c.)recombinantBackprotein
Back (s.c) + Human TIF1g
Back (s.c)(s.c)and adjuvant
Back/footpad (s.c.)pertussis toxin (i.p)
Human TIF1g recombinant protein and adjuvant

P a t e n t
Tr e a t i s e

Okiyama, N; Ichimura, Y; Shobo, M; Tanaka, R et al. Immune response to dermatomyositis-specific autoantigen, transcriptional intermediary factor 1γ canresult in experimental myositis. Ann Rheum Dis. 2021 Sep; 80(9): 1201-1208. doi: 10.1136/annrheumdis-2020-218661.

URL
K e y w o r d connective tissue disease, dermatomyositis, autoimmunity