Oklahoma Medical Research Foundation Oklahoma City, OK, United States
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Biji T Kurien1, Rebecca Wood2, Gavin Pharaoh3, Joshua Cavett1, Valerie Lewis1, Bhaskaran Shylesh1, Lida radfar1, Astrid Rasmussen1, Christopher Lessard1, A. Darise Farris1, Kathy Sivils4, Kristi Koelsch1, Holly Van Remmen1 and R Hal Scofield5, 1Oklahoma Medical Research Foundation, Oklahoma City, OK, 2University of Oklahoma Health Sciences Center, Edmond, OK, 3University of Washington, Seattle, WA, 4Janssen Research & Development, LLC, Edmond, OK, 5Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK
Background/Purpose: Sjögren's disease (SjD) is a chronic, autoimmune condition with diminished lacrimal and salivary gland secretion leading to keratoconjunctivitis sicca and xerostomia, respectively. In addition, subjects with SjD experience significant fatigue. We hypothesized that SjD subjects have mitochondrial dysfunction and that fatigue will be associated with mitochondrial dysfunction in a subset of subjects with SjD.
Methods: Seventeen SjD subjects and eight age-matched subjects underwent a fasting blood draw and completed fatigue questionnaires (Bowman's SjD, Fatigue Impact Scale, Multidimensional assessment of fatigue, Centers for Epidemiological Studies-Depression Scale, Fatigue Severity Scale, The Rheumatology Attitudes Index or Helplessness Score, Modified Health Assessment, Validation of the Functioning in Chronic Illness Scale, SLEEP 1, and SLEEP 2). T cells were purified through negative selection using Miltenyi Biotech B and T cell isolation kit and analyzed for mitochondrial oxygen consumption rate and extracellular acidification rate (glycolysis) using the Seahorse XF24 assay. Mitochondrial macrostructure of PBMC's isolated from SjD or control subjects was analyzed using transmission electron microscopy.
Results: There was no significant difference in the ages of the controls and the SjD subjects (52.25 years ± 3.21 vs 59.88 years ± 3.17 respectively, p=0.17) and there were no age-related changes in the oxygen consumption rate. However, we observed significantly decreased basal, ATP-linked, and maximal respiration as well as reserve capacity in the T cells of SjD subjects compared to controls. We found that scores from the Bowman fatigue questionnaire correlated the best with basal oxygen consumption (r2=0.34, p=0.014), ATP-linked respiration (r2=0.36, p=0.011), maximal respiration (r2=0.491, p=0.0017), and reserve capacity (r2=0.486, p=0.0019) in SjD. Scores from the general fatigue category (pain/discomfort) related to the question "the worst problem with pains, the worst discomfort I've experienced in 2 weeks" provided most of the power for these associations. Scores from Bowman mental fatigue questionnaire showed a trend towards correlating with ATP-linked respiration (r2=0.22, p=0.0588). Fatigue Severity Scale scores correlated only with mitochondrial reserve capacity in SjD (r2=0.244, p=0.044). Transmission electron microscopy studies clearly show swollen mitochondria in the lymphocytes from SjD, with the cristae appearing to be prominently disorganized compared to mitochondria from the control.
Conclusion: Mitochondrial dysfunction, associated with fatigue, appears to be a significant problem in SjD.
B. Kurien: None; R. Wood: None; G. Pharaoh: None; J. Cavett: None; V. Lewis: None; B. Shylesh: None; L. radfar: None; A. Rasmussen: None; C. Lessard: Janssen, 5; A. Farris: Janssen Research and Development, LLC, 5; K. Sivils: Janssen, 3; K. Koelsch: None; H. Van Remmen: None; R. Scofield: None.
