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’ 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.

Increased percentage of HLA-DR T cells in untreated juvenile dermatomyositis

“…For example, MSAs are detectable in more than half of JDM patients, and each MSA is associated with distinct clinical phenotypes [ 2 ]. Furthermore, approximately two-thirds of treatment-naïve patients show an increased B cell percentage [ 30 ], with a subset of these B cells being positive for otoferlin [ 31 ]. These otoferlin-positive B cells are particularly abundant in treatment-naïve JDM patients and can infiltrate muscle tissue [ 31 ].…”

“…Furthermore, approximately two-thirds of treatment-naïve patients show an increased B cell percentage [ 30 ], with a subset of these B cells being positive for otoferlin [ 31 ]. These otoferlin-positive B cells are particularly abundant in treatment-naïve JDM patients and can infiltrate muscle tissue [ 31 ]. The expansion of B cells is likely driven by elevated levels of serum BAFF (B-cell activating factor) [ 30 , 32 ], which is secreted from myeloid cells.…”