Plasma Complement 3 and Complement 4 Are Promising Biomarkers for Distinguishing NMOSD From MOGAD and Are Associated With the Blood-Brain-Barrier Disruption in NMOSD

Abstract

Background and ObjectiveNeuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody (MOG-IgG) associated disease (MOGAD) are autoimmune inflammatory demyelinating diseases of the central nervous system (CNS). As the clinical features of NMOSD are similar to MOGAD, diagnostic confusion exists between the two diseases. To better discriminate NMOSD from MOGAD, we investigated whether the plasma levels of complement 3 (C3) and complement 4 (C4) are different in NMOSD and MOGAD during the acute attacks of the diseases. We sought to determine whether C3 or C4 has an influence on the features of NMOSD.MethodsIn this observational study, data from 73 aquaporin-4 antibodies (AQP4-IgG) positive NMOSD patients and 22 MOG-IgG positive MOGAD patients were collected retrospectively. Demographics, clinical characteristics, plasma parameters, and cerebrospinal fluid (CSF) findings will be analyzed for comparability between the two groups. Immunoglobulin-G (IgG) and albumin were measured in both plasma and CSF. Plasma levels of C3 and C4 were measured and compared between the NMOSD, MOGAD, and 42 healthy controls (HC). The correlations between plasma C3, C4, and NMOSD clinical parameters were analyzed.ResultsThe ages of onset were later in the AQP4-IgG positive NMOSD group and females predominated, which differed from the MOGAD group, whose ages were younger and with a slight male preponderance. The AQP4-IgG positive NMOSD patients presented with the clinical symptoms of optic neuritis (ON) and transverse myelitis (TM), whereas encephalitis symptoms were more prevalent in MOGAD patients. CSF analysis shows that slight but not significantly higher white cell count (WCC) and protein were observed in the MOGAD group than in the AQP4-IgG positive NMOSD group. The plasma levels of IgG in MOGAD patients are significantly lower (p = 0.027) than in NMOSD patients. On the contrary, the plasma levels of albumin in MOGAD were higher than in NMOSD, which reached statistical significance (p = 0.039). Both the plasma C3 and C4 levels in the NMOSD group were significantly lower than in MOGAD and HC. The receiver operating characteristic (ROC) curve of the prediction model comprises C3 and C4 to distinguish NMOSD from MOGAD [area under the curve (AUC): 0.731, 0.645], which are considered to have discriminatory values. The results of Spearman’s analysis revealed that there was a significant positive correlation between the plasma C3 and the CSF WCC (r = 0.383, p = 0.040). There was an inverse correlation between plasma C4 and plasma IgG (r = -0.244, p = 0.038). Plasma C3 or C4 was significantly positively correlated with CSF albumin and Q-Alb, which is considered a measure of blood-brain barrier (BBB) disruption.ConclusionDuring the acute phase of NMOSD and MOGAD, plasma C3 and C4 may become potential biomarkers for distinguishing the two diseases and reflecting the NMOSD BBB damage.

Systemic inflammation response index is a useful indicator in distinguishing MOGAD from AQP4-IgG-positive NMOSD

“…Liu et al. found that C3 levels in the blood plasma were positively correlated with CSF WCC ( 23 ). In the MOGAD group, C3 consumption was lower, while CSF WCC were higher ( 23 ).…”

“…found that C3 levels in the blood plasma were positively correlated with CSF WCC ( 23 ). In the MOGAD group, C3 consumption was lower, while CSF WCC were higher ( 23 ). This indirectly supports the earlier idea that the majority of MOG-IgG detected in the CSF is synthesized intrathecally by plasmablasts inside the CSF, whereas most of the AQP4-IgG in the CSF originated from extrathecal sources and passively entered the CSF through the blood-brain barrier ( 24 ).…”

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

“…Recent evidence, for example, supports a complement and coagulation protein pathway mechanism by which omega-3 polyunsaturated fatty acids might contribute to cognitive and symptom improvements in individuals with early psychosis [41]. A role for C4 in neuroinflammation is based on positive, negative, and mixed associations of C4 levels with markers of white matter integrity, CSF biochemistry, cortical thinning, and patterns of expression with postmortem brain structures and functions [31,32,42,51,52,54,[90][91][92][93][94][95][96][97].…”

Association of plasma sPD‐1 and sPD‐L1 with disease status and future relapse in AQP4‐IgG (+) NMOSD

“…The pathogenic effects of AQP4‐IgG binding to astrocytes are primarily thought to activate complement‐dependent cytotoxicity via the classical pathway by binding to C1q, which is followed by C3 convertase enzymes converting C3 into C3a and C3b 30,31 . This process will cause subtle consumption of C3, and multiple studies have found that an obvious declined serum/plasma level of C3 in patients with NMOSD, especially AQP4‐IgG (+) NMOSD than healthy controls 32,33 . In the attack phase, AQP4‐IgG initiates a more severe attack on astrocytes, leading to the activation of the complement system and a massive depletion of C3, which may explain why patients in the acute phase have significantly lower levels of C3 compared to the remission phase.…”

“… 30 , 31 This process will cause subtle consumption of C3, and multiple studies have found that an obvious declined serum/plasma level of C3 in patients with NMOSD, especially AQP4‐IgG (+) NMOSD than healthy controls. 32 , 33 In the attack phase, AQP4‐IgG initiates a more severe attack on astrocytes, leading to the activation of the complement system and a massive depletion of C3, which may explain why patients in the acute phase have significantly lower levels of C3 compared to the remission phase. However, plasma C4 levels did not differ significantly between patients in the attack and remission phases in this study, similar to the results of a related study in SLE, which showed that C3 level was associated with disease activity and lupus nephritis, but C4 level was not.…”