Increased Otoferlin Expression in B Cells Is Associated with Muscle Weakness in Untreated Juvenile Dermatomyositis: A Pilot Study

Ameera Bukhari; Amer Khojah; Wilfredo Marin; Andrey Khramtsov; Galina Khramtsova; Christopher Costin; Gabrielle Morgan; Prathyaya Ramesh; Marisa S. Klein-Gitelman; I. Caroline Le Poole; Lauren M. Pachman

doi:10.3390/ijms241310553

Increased Otoferlin Expression in B Cells Is Associated with Muscle Weakness in Untreated Juvenile Dermatomyositis: A Pilot Study

Ameera Bukhari, Amer Khojah, Wilfredo Marin, Andrey Khramtsov, Galina Khramtsova, Christopher Costin, Gabrielle Morgan, Prathyaya Ramesh, Marisa S. Klein-Gitelman, I. Caroline Le Poole, Lauren M. Pachman^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Otoferlin mRNA expression is increased in JDM patients’ PBMCs and muscle compared to healthy controls. This study aims to evaluate the role of otoferlin in JDM disease pathophysiology and its association with disease activity in untreated children with JDM. A total of 26 untreated JDM (88.5% female, 92.3% white, non-Hispanic) and 15 healthy controls were included in this study. Otoferlin mRNA expression was determined by qRT-PCR before and a few months after therapy. Detailed flow cytometry of various cell surface markers and cytoplasmic otoferlin was performed to identify cells expressing otoferlin. In addition, muscle otoferlin expression was evaluated in situ in six untreated JDM patients and three healthy controls. There was a significant increase in otoferlin expression in JDM children compared to controls (Median 67.5 vs. 2.1; p = 0.001). There was a positive correlation between mRNA otoferlin expression and the following disease activity markers: disease activity scores (DAS)-total (r_s = 0.62, p < 0.001); childhood myositis assessment scale (CMAS) (r_s = −0.61, p = 0.002); neopterin (r_s = 0.57, p = 0.004) and von Willebrand factor antigen (vWF: Ag) (r_s = 0.60, p = 0.004). Most of the otoferlin-positive cells were unswitched B cells (63–99.4%), with 65–75% of them expressing plasmablast markers (CD19⁺, IgM⁺, CD38^hi, CD24⁻). The findings of this pilot study suggest that otoferlin expression is associated with muscle weakness, making it a possible biomarker of disease activity. Additionally, B cells and plasmablasts were the primary cells expressing otoferlin.

Original language	English (US)
Article number	10553
Journal	International journal of molecular sciences
Volume	24
Issue number	13
DOIs	https://doi.org/10.3390/ijms241310553
State	Published - Jul 2023

Funding

Supported in part by The Vivian Allison and Daniel J. Pachman Fund, The DenUyl Family Fund, The Cure JM Foundation, and other much-appreciated donors. The REDCap database is supported by NUCATS and funded in part by a Clinical and Translational Science Award (CTSA) grant from the National Institutes of Health (NIH) [UL1TR001422]. Amer Khojah would like to thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code (23UQU4300201DSR07). This research was supported in part by resources provided by the Northwestern University Skin Biology and Diseases Resource-based Center (P30AR075049), Chicago, IL, with support from the NIH/NIAMS. Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the Northwestern University Skin Biology and Diseases Resource-based Center or the NIH/NIAMS. Ameera Bukhari would like to acknowledge the Deanship of Scientific Research, Taif University, for funding her work.

Keywords

B cell
disease activity scores
juvenile dermatomyositis
muscle weakness
otoferlin

ASJC Scopus subject areas

Catalysis
Molecular Biology
Spectroscopy
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry

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10.3390/ijms241310553

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Bukhari, A., Khojah, A., Marin, W., Khramtsov, A., Khramtsova, G., Costin, C., Morgan, G., Ramesh, P., Klein-Gitelman, M. S., Le Poole, I. C., & Pachman, L. M. (2023). Increased Otoferlin Expression in B Cells Is Associated with Muscle Weakness in Untreated Juvenile Dermatomyositis: A Pilot Study. International journal of molecular sciences, 24(13), Article 10553. https://doi.org/10.3390/ijms241310553

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title = "Increased Otoferlin Expression in B Cells Is Associated with Muscle Weakness in Untreated Juvenile Dermatomyositis: A Pilot Study",

abstract = "Otoferlin mRNA expression is increased in JDM patients{\textquoteright} PBMCs and muscle compared to healthy controls. This study aims to evaluate the role of otoferlin in JDM disease pathophysiology and its association with disease activity in untreated children with JDM. A total of 26 untreated JDM (88.5\% female, 92.3\% white, non-Hispanic) and 15 healthy controls were included in this study. Otoferlin mRNA expression was determined by qRT-PCR before and a few months after therapy. Detailed flow cytometry of various cell surface markers and cytoplasmic otoferlin was performed to identify cells expressing otoferlin. In addition, muscle otoferlin expression was evaluated in situ in six untreated JDM patients and three healthy controls. There was a significant increase in otoferlin expression in JDM children compared to controls (Median 67.5 vs. 2.1; p = 0.001). There was a positive correlation between mRNA otoferlin expression and the following disease activity markers: disease activity scores (DAS)-total (rs = 0.62, p < 0.001); childhood myositis assessment scale (CMAS) (rs = −0.61, p = 0.002); neopterin (rs = 0.57, p = 0.004) and von Willebrand factor antigen (vWF: Ag) (rs = 0.60, p = 0.004). Most of the otoferlin-positive cells were unswitched B cells (63–99.4\%), with 65–75\% of them expressing plasmablast markers (CD19+, IgM+, CD38hi, CD24−). The findings of this pilot study suggest that otoferlin expression is associated with muscle weakness, making it a possible biomarker of disease activity. Additionally, B cells and plasmablasts were the primary cells expressing otoferlin.",

keywords = "B cell, disease activity scores, juvenile dermatomyositis, muscle weakness, otoferlin",

author = "Ameera Bukhari and Amer Khojah and Wilfredo Marin and Andrey Khramtsov and Galina Khramtsova and Christopher Costin and Gabrielle Morgan and Prathyaya Ramesh and Klein-Gitelman, \{Marisa S.\} and \{Le Poole\}, \{I. Caroline\} and Pachman, \{Lauren M.\}",

note = "Publisher Copyright: {\textcopyright} 2023 by the authors.",

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Bukhari, A, Khojah, A, Marin, W, Khramtsov, A, Khramtsova, G, Costin, C, Morgan, G, Ramesh, P, Klein-Gitelman, MS , Le Poole, IC & Pachman, LM 2023, 'Increased Otoferlin Expression in B Cells Is Associated with Muscle Weakness in Untreated Juvenile Dermatomyositis: A Pilot Study', International journal of molecular sciences, vol. 24, no. 13, 10553. https://doi.org/10.3390/ijms241310553

TY - JOUR

T1 - Increased Otoferlin Expression in B Cells Is Associated with Muscle Weakness in Untreated Juvenile Dermatomyositis

T2 - A Pilot Study

AU - Bukhari, Ameera

AU - Khojah, Amer

AU - Marin, Wilfredo

AU - Khramtsov, Andrey

AU - Khramtsova, Galina

AU - Costin, Christopher

AU - Morgan, Gabrielle

AU - Ramesh, Prathyaya

AU - Klein-Gitelman, Marisa S.

AU - Le Poole, I. Caroline

AU - Pachman, Lauren M.

PY - 2023/7

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N2 - Otoferlin mRNA expression is increased in JDM patients’ PBMCs and muscle compared to healthy controls. This study aims to evaluate the role of otoferlin in JDM disease pathophysiology and its association with disease activity in untreated children with JDM. A total of 26 untreated JDM (88.5% female, 92.3% white, non-Hispanic) and 15 healthy controls were included in this study. Otoferlin mRNA expression was determined by qRT-PCR before and a few months after therapy. Detailed flow cytometry of various cell surface markers and cytoplasmic otoferlin was performed to identify cells expressing otoferlin. In addition, muscle otoferlin expression was evaluated in situ in six untreated JDM patients and three healthy controls. There was a significant increase in otoferlin expression in JDM children compared to controls (Median 67.5 vs. 2.1; p = 0.001). There was a positive correlation between mRNA otoferlin expression and the following disease activity markers: disease activity scores (DAS)-total (rs = 0.62, p < 0.001); childhood myositis assessment scale (CMAS) (rs = −0.61, p = 0.002); neopterin (rs = 0.57, p = 0.004) and von Willebrand factor antigen (vWF: Ag) (rs = 0.60, p = 0.004). Most of the otoferlin-positive cells were unswitched B cells (63–99.4%), with 65–75% of them expressing plasmablast markers (CD19+, IgM+, CD38hi, CD24−). The findings of this pilot study suggest that otoferlin expression is associated with muscle weakness, making it a possible biomarker of disease activity. Additionally, B cells and plasmablasts were the primary cells expressing otoferlin.

AB - Otoferlin mRNA expression is increased in JDM patients’ PBMCs and muscle compared to healthy controls. This study aims to evaluate the role of otoferlin in JDM disease pathophysiology and its association with disease activity in untreated children with JDM. A total of 26 untreated JDM (88.5% female, 92.3% white, non-Hispanic) and 15 healthy controls were included in this study. Otoferlin mRNA expression was determined by qRT-PCR before and a few months after therapy. Detailed flow cytometry of various cell surface markers and cytoplasmic otoferlin was performed to identify cells expressing otoferlin. In addition, muscle otoferlin expression was evaluated in situ in six untreated JDM patients and three healthy controls. There was a significant increase in otoferlin expression in JDM children compared to controls (Median 67.5 vs. 2.1; p = 0.001). There was a positive correlation between mRNA otoferlin expression and the following disease activity markers: disease activity scores (DAS)-total (rs = 0.62, p < 0.001); childhood myositis assessment scale (CMAS) (rs = −0.61, p = 0.002); neopterin (rs = 0.57, p = 0.004) and von Willebrand factor antigen (vWF: Ag) (rs = 0.60, p = 0.004). Most of the otoferlin-positive cells were unswitched B cells (63–99.4%), with 65–75% of them expressing plasmablast markers (CD19+, IgM+, CD38hi, CD24−). The findings of this pilot study suggest that otoferlin expression is associated with muscle weakness, making it a possible biomarker of disease activity. Additionally, B cells and plasmablasts were the primary cells expressing otoferlin.

KW - B cell

KW - disease activity scores

KW - juvenile dermatomyositis

KW - muscle weakness

KW - otoferlin

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ER -

Increased Otoferlin Expression in B Cells Is Associated with Muscle Weakness in Untreated Juvenile Dermatomyositis: A Pilot Study

Abstract

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