To develop an easy blood assay detecting IgG aggregates as biomarkers for diagnosing multiple sclerosis (MS) and for predicting secondary progressive MS (SPMS) from other subtypes.

Intrathecal immunoglobulin G (IgG) and oligoclonal bands (OCB) are seminal features of MS. However, contradictory studies have been reported regarding levels of IgG antibodies in the peripheral blood. We recently reported that MS plasma IgG antibodies form large aggregates (>100 nm), inducing complement-dependent neuronal apoptosis (Zhou et al., 2023).

Using samples from two cohorts totaling 190 MS and 160 controls (other central nervous system disorders and healthy donors), we enriched the IgG aggregates from MS plasma and controls. We detected IgG1, IgG3, and total IgG in the aggregates using capture ELISA.

We demonstrated the presence of significantly higher levels of IgG1, IgG3, and total IgG antibodies in MS plasma IgG aggregates (p<0.0001), which can be used as biomarkers, with Area Under the Receiver Operating Characteristic (ROC) curve (AUC) greater than 90%. Furthermore, plasma IgG1 can be used as a disease activity biomarker diagnosing SPMS from both relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) (AUC=91%). Significantly, we provided a biological rationale for MS plasma IgG biomarkers by demonstrating the strong correlation between higher IgG antibodies and elevated levels of IgG-induced neuronal cytotoxicity.