Complement Dysregulation in Stiff Person Syndrome: Pathophysiological Insights
Amanda Piquet1, Brendan Freitas2, Jackson Tumas French2, Sean Selva1, Jadyn Zook1, Sadie Eggmann1, Xiaoli Yu2
1Neurology, 2Neurosurgery, University of Colorado
Objective:
To investigate complement activation in the cerebrospinal fluid (CSF) and plasma of Stiff Person Syndrome (SPS) patients to inform on the immune profile.
Background:
SPS is a rare autoimmune neurologic disorder characterized by progressive muscle stiffness and painful muscle spasms. The underlying pathophysiology is elusive, and while autoantibodies are commonly implicated, the role of complement activation in SPS remains poorly understood.
Design/Methods:
We analyzed complement components in the plasma of patients with SPS (n=32), healthy controls (n=14), and patients with other central nervous system (CNS) disorders including multiple sclerosis (n=15). We also compared paired CSF and plasma samples in SPS (n = 5) and controls (n = 8). Quantified markers included C3, C3b, C4b, Factor D, C5, Factor H, and Properdin. Statistical comparisons were performed using ANOVA and ROC curve analysis.
Results:
SPS patients exhibited distinct complement activation patterns between CSF and plasma. In CSF, levels of C3, C3b/iC3b, C4b, and Factor D were elevated, while C5, Factor H, and Properdin were significantly lower compared to plasma. Plasma levels of C3 and C4 were markedly decreased in SPS versus healthy controls (p< 0.0001). When comparing SPS to both healthy and other neurological disorder (OND) groups, Factor B, Factor H, and Factor I levels were significantly reduced (p< 0.0001). ROC analysis identified Factor I as a robust biomarker for SPS, with an AUC of 0.863, indicating strong discriminatory power. A combined panel of C4, C5, and C9 demonstrated a strong biomarker potential for SPS (AUC = 0.88 vs. healthy; AUC = 0.9583 vs. OND).
Conclusions:
Our findings reveal abnormal complement activation in SPS, with differential expression across CSF and plasma compartments. C4, C5, C9, and Factor I emerge as promising biomarkers for distinguishing SPS from healthy and other neurological controls, offering potential for improved diagnostic precision and therapeutic targets.
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