Divergence of C4A and C4B in first-episode psychosis: Insights from CSF and plasma immune profiling

The complement genes C4A and C4B share high sequence similarity yet differ in biological function and disease relevance. C4A, in contrast to C4B, is implicated in synaptic pruning and increased risk for schizophrenia, however beyond this their distinct roles within the human brain remain poorly understood. We analyzed cerebrospinal fluid (CSF) levels of C4A, C4B, C1Q, along with 48 inflammation-related proteins, measured in both CSF and plasma, in 90 healthy controls and 113 patients with first-episode psychosis (FEP). In controls, C4A and C4B were positively associated with C1Q (z = 0.41, p < 0.001, and z = 0.48, p < 0.001, respectively), whereas in FEP, the CSF C1Q-C4A association was abolished (z = 0.09, p = 0.40). Across inflammatory markers, C4A levels in controls showed predominantly negative correlations in CSF, while C4B and C1Q exhibited mostly positive correlations. Using permutation tests on directional mean differences, we observed a robust positive directional shift for C4A in FEP (z = 3.81, p < 0.0001), while C4B showed a non-significant negative shift (z = -2.64, p > 0.9). The overall C4A directional shift was largely preserved in plasma, though the structure of complement-protein interactions differed markedly between the biological compartments, CSF and plasma. Together, these findings identify distinct and compartment-specific patterns of immune network interactions for C4A and C4B and suggest that C4A-inflammatory protein relationships are selectively altered in FEP.