Insights Into the Antigenic Repertoire of Unclassified Synaptic Antibodies.

OBJECTIVE

We sought to characterize the sixth most common finding in our neuroimmunological laboratory practice (tissue assay-observed unclassified neural antibodies [UNAs]), combining protein microarray and phage immunoprecipitation sequencing (PhIP-Seq).

METHODS

Patient specimens (258; 133 serums; 125 CSF) meeting UNA criteria were profiled; October 2022-September 2023. Top-ranking candidate antigens were validated in silico, by dual-staining confocal microscopy, and ≥ 1 protein-specific assay. Clinical data were reviewed.

RESULTS

Among 21 patients, 11 autoantibodies were characterized (serum, 19; CSF, all 9 available). Autoantigens were CACNA1I, 1; CAMK2B, 2; CLIP2, 1; FMN2, 2; MAP1A, 2; MAP2, 5; NECAB1, 1; SNAP91, 3; SRCIN1, 1; SYNJ1, 1; SYT3, 2. Analytical validation was by confocal TIIFA (all), western blot (10/10 available), and cell-based assay (5/5 performed). Clinical accompaniments were: encephalitis, 6; brainstem encephalitis, 2; encephalomyelitis, 2; cerebellar ataxia, 2; longitudinally extensive transverse myelitis (LETM), 2; sensory neuronopathy, 1; peripheral neuropathy, 4, and movement disorders, 2. Inflammatory MRI abnormalities were identified in 5/16 patients (31%) with CNS disorders: T2 signal change (2), LETM (2), leptomeningeal enhancement (1). Seven of 8 (88%) had inflammatory CSF (pleocytosis, 5 [median 25.5 cells, range 7-294]; elevated IgG index/synthesis rate, 4; CSF-exclusive oligoclonal bands, 4). Six had paraneoplastic causation (lung cancer, 2; other, 4); 3 were postinfectious (1 each of COVID-19, HSV-1, and post-Group A streptococcal infection). Of 9 immunotherapy-treated patients, 5 improved.

INTERPRETATION: UNAs are partly accounted for by a repertoire of diverse mostly intracellular synaptic antigens. Their characterization is expedited by protein arrays and PhIPSeq. Further individual studies are needed to assess them as disease biomarkers.