Investigation of Complement Activation and Cytokine Signatures in AQP4+ NMOSD, MOGAD, and MS

Aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder (AQP4+ NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and multiple sclerosis (MS) are pathophysiologically distinct neuroinflammatory disorders. Complement activation is a major mechanism of injury in AQP4+ NMOSD, whereas its role in MS is complex and in MOGAD controversial. We aimed to compare complement components and cytokines between AQP4+ NMOSD, MOGAD, and MS.

CSF complement components, CSF and plasma cytokines, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were measured in people with AQP4+ NMOSD (CSF: n = 19; plasma: n = 18), MOGAD (CSF: n = 29; plasma: n = 35) and MS (CSF: n = 36; plasma: n = 58) with recent disease activity. Controls included subjects with non-inflammatory conditions (CSF: n = 51) and healthy controls (plasma: n = 29).

CSF IL-10 and TNF-a were elevated across all neuroinflammatory disease groups relative to controls. CSF IL-6 was elevated only in AQP4+ NMOSD and MOGAD. There were no significant differences in plasma cytokines between groups. Most complement components were elevated in AQP4+ NMOSD and MOGAD; only specific activation products (C2b, C3d, C4a, C5a) were elevated in MS. CSF GFAP and NfL correlated with several CSF cytokines and complement components in AQP4+ NMOSD and MOGAD. Expanded Disability Status Scale at nadir during attacks correlated with CSF BAFF, GFAP, free C1q, C1s, C1s-C1inh, C4a in AQP4+ NMOSD, and CSF IL-10, TNF-a, free C1q, C1inh, C4a in MOGAD.

Our findings suggest distinct CSF cytokine profiles in AQP4+ NMOSD, MOGAD, and MS, and widespread activation of complement pathways in AQP4+ NMOSD and MOGAD. CSF complement and cytokine profiling may help characterize neuroinflammatory disease mechanisms, although further validation of these findings in larger cohorts is needed.