Background/Purpose: Juvenile Dermatomyositis (JDM) is a rare inflammatory myopathy in which the immunoregulatory control is not well understood.  Collaboration with A.R.  French, MD/PhD, documented   the hypophosphorylation of phophplipaseCγ2 in Natural Killer (NK-CD3-CD16/56+) cells from untreated JDM (JCI Insight 123236, 2018). This investigation evaluates JDM skin, muscle and blood for the presence of Otoferlin.  Otoferlin is a member of the dysferlin family, and has strong Ca⁺² binding ability in its C2 domain.  Among other potential targets, NK cells utilize calcium flux to discharge their granules which create pores and inflict cellular damage. The goal of this study was to validate the increased Otoferlin levels in JDM tissues and determine the possible association between levels of Otoferlin and NK cells in blood drawn from untreated JDM.

Methods: Methods:  After obtaining age-appropriate informed consent  (IRB# 2008-13457), the JDM child’s clinical variables, including age, gender, duration of untreated disease (DUD) and Disease Activity Scores ( DAS  skin, muscle total),  were entered into REDCap.  The study had 2 phases:  1) discovery by RNASeq of increased tissue based Otoferlin in untreated JDM skin, muscle   and blood compared to healthy controls.  The RNASeq study also compared healthy children’s peripheral blood mononuclear cells (PBMCs) with those from active, untreated JDM  (n=11) and 7 samples when the same child was clinically quiescent.  Otoferlin levels  were determined at both time points by  qRT-PCR;   2) validation, by qRT-PCR  of the increased Otoferlin  in a larger cohort of 23 untreated JDM  PBMCs (2 had no NK values); definite/probable  JDM,  mean age7.33 (±4.16), 90.5% female, 90.5% white compared with  sera   from 15 age-gender -matched healthy controls. The data were analyzed by Pearson correlation and student’s  T test. 

Results: Results:  These studies confirmed that the  21 untreated  active JDM had decreased  circulating  NKs  in  71.4%.   NK cell # was inversely associated with increased serum concentrations of Otoferin , p=0.008;  Pearson’s correlation coefficient=-0.556. The serum levels of Otoferlin were not associated with the age, gender or DUD of the children with JDM, but were highly associated with the DAS-muscle, p=0.0036, but not skin (p=0.94); or total (p=0.10). Otoferlin was increased in PBMCs from untreated active, but not treated inactive JDM, p=0.00056.

Conclusion: Conclusion:  We have documented a new component in the pathophysiology of untreated JDM—Otoferlin–which is increased in JDM muscle > PBMCs > controls, and appears to be associated with decreased NKs. Speculation:   Otoferlin, perhaps by virtue of its Ca+2 binding capacity and interaction with lipid membranes, may contribute to both NK dysfunction and distribution in untreated children with active JDM.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/otoferlin-is-increased-in-muscle-and-pbmcs-from-untreated-children-with-juvenile-dermatomyositis-possible-association-with-decreased-circulating-natural-killer-cells/