Objective:

To characterize the presence of neutralizing antibodies against interferon-omega (IFN-ω) in cerebrospinal fluid (CSF) and serum from patients with NMDA receptor (NMDAR) encephalitis as an approach to establish disease mechanisms. 

Background:

The presence of neutralizing antibodies against type-I interferons has been demonstrated in serum in cases of encephalitis caused by West Nile virus (WNV). Anti-IFN-α2 and/or anti-IFN-ω neutralizing autoantibodies are present in ~40% of cases of WNV encephalitis CSF and serum/plasma. Their pathogenic potential and their presence in other causes of encephalitis have not been studied. 

Design/Methods:

Molecular Indexing of Proteins by Self-Assembly (MIPSA), a magnetic bead-based multiplex assay that generates DNA-barcoded libraries of human proteins, was used to screen for antibodies against type-I IFNs in paired CSF and serum samples. Samples were obtained from patients diagnosed with encephalitis in the Neuroinfections Emerging in the Americas Study (NEAS) in Colombia, and Johns Hopkins Hospital in the USA, and classified into three groups: infection-associated, autoimmune, and unknown cause encephalitis. 

Results:

Fifty CSF-serum pairs from subjects diagnosed with encephalitis were included: 21 infection-associated, 14 autoimmune, and 15 of unknown cause. The MIPSA assay’s library for human conformational epitopes identified 18 cases (36%) with anti-IFN antibodies. The frequency of such antibodies was higher in the autoimmune (57%) and unknown cause (40%) groups than in the infectious group (19%). Anti-IFN-ω antibodies were exclusively detected in the CSF of anti-NMDAR encephalitis (n=3/8, 38%). An ELISA is in development to quantify the concentration of anti-IFN-ω antibodies in the CSF and serum of patients with NMDAR encephalitis. 

Conclusions:

The identification of anti-IFN-ω antibodies through the MIPSA assay can provide insight into the pathogenesis of NMDAR encephalitis and be a potential predictor of outcome. Further confirmation of the titer of these antibodies through ELISA, and an eventual assessment of their functionality by a neutralization assay, can improve the understanding of disease mechanisms.