ABSTRACT
Pediatric and adult autoimmune encephalitis (AE) are often associated with Abs to the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Very little is known regarding the cerebrospinal fluid humoral immune profile and Ab genetics associated with pediatric anti-NMDAR-AE. Using a combination of cellular, molecular, and immunogenetics tools, we collected cerebrospinal fluid from pediatric subjects and generated 1) flow cytometry data to calculate the frequency of B cell subtypes in the cerebrospinal fluid of pediatric subjects with anti-NMDAR-AE and controls, 2) a panel of recombinant human Abs from a pediatric case of anti-NMDAR-AE that was refractory to treatment, and 3) a detailed analysis of the Ab genes that bound the NR1 subunit of the NMDAR. Ag-experienced B cells including memory cells, plasmablasts, and Ab-secreting cells were expanded in the pediatric anti-NMDAR-AE cohort, but not in the controls. These Ag-experienced B cells in the cerebrospinal fluid of a pediatric case of NMDAR-AE that was refractory to treatment had expanded use of variable H chain family 2 (VH2) genes with high somatic hypermutation that all bound to the NR1 subunit of the NMDAR. A CDR3 motif was identified in this refractory case that likely drove early stage activation and expansion of naive B cells to Ab-secreting cells, facilitating autoimmunity associated with pediatric anti-NMDAR-AE through the production of Abs that bind NR1. These features of humoral immune responses in the cerebrospinal fluid of pediatric anti-NMDAR-AE patients may be relevant for clinical diagnosis and treatment.
Subject(s)
Anti-N-Methyl-D-Aspartate Receptor Encephalitis , Hashimoto Disease , Adult , Humans , Child , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/cerebrospinal fluid , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/diagnosis , B-Lymphocytes , Receptors, N-Methyl-D-Aspartate , AutoantibodiesABSTRACT
The nicotinic acetylcholine receptor (nAChR) antibody directly contributes to the autonomic dysfunction in Autoimmune Autonomic Ganglionopathy (AAG). The pathological mechanism leading to autonomic dysfunction in seronegative AAG is unclear. We evaluated patients with presumed antibody negative AAG (n=49) to determine whether there was an association with other autoantibodies. Three patients met the clinical criteria and were positive for N-type calcium channel antibodies. All patients had severe autonomic dysfunction characterized by orthostatic hypotension and gastrointestinal involvement. Autonomic testing revealed severe impairment of sudomotor, cardiovagal, and adrenergic domains. These findings raise the possibility that other autoantibodies may contribute to the pathogenesis of AAG.