Ca_Vα2δ Autoimmune Encephalitis: A Novel Antibody and its Characteristics

Abstract

Objective Discovery of a novel antibody would enable diagnosis and early treatment of autoimmune encephalitis. The aim was to discover a novel antibody targeting a synaptic receptor and characterize the pathogenic mechanism. Method We screened for unknown antibodies in serum and cerebrospinal fluid samples from autoimmune encephalitis patients. Samples with reactivity to rat brain sections and no reactivity to conventional antibody tests underwent further processing for antibody discovery, using immunoprecipitation to primary neuronal cells, mass‐spectrometry analysis, an antigen‐binding assay on an antigen‐overexpressing cell line, and an electrophysiological assay with cultured hippocampal neurons. Results Two patients had a novel antibody against CaVα2δ (voltage‐gated calcium channel alpha‐2/delta subunit). The patient samples stained neuropils of the hippocampus, basal ganglia, and cortex in rat brain sections and bound to a CaVα2δ‐overexpressing cell line. Knockdown of CaVα2δ expression in cultured neurons turned off the immunoreactivity of the antibody from the patients to the neurons. The patients were associated with preceding meningitis or neuroendocrine carcinoma and responded to immunotherapy. In cultured neurons, the antibody reduced neurotransmitter release from presynaptic nerve terminals by interfering with tight coupling of calcium channels and exocytosis. Interpretation Here, we discovered a novel autoimmune encephalitis associated with anti‐CaVα2δ antibody. Further analysis of the antibody in autoimmune encephalitis might promote early diagnosis and treatment. ANN NEUROL 2021;89:740–752

Pediatric anti-CaVα2δ Autoimmune Encephalitis: a case report and literature review

“…Conversely, the adult patient succumbed to septic shock during postoperative management. The authors revealed that anti-CaVα2δ antibodies interfere with the tight coupling of calcium channels and sensors, leading to reduced neurotransmitter release from the presynaptic nerve terminals and decreased excitatory postsynaptic currents and inhibitory postsynaptic currents [5]. This supports the role of CaVα2δ subunits of VGCCs as autoantigens in AE.…”

“…Lee et al [5] was the rst to report on the pathogenicity of anti-CaVα2δ AE in 2021, which included two patients (one adult and one paediatric case) exhibiting typical AE features, such as memory loss, psychiatric symptoms, and seizures. The adult case was diagnosed with paraneoplastic syndrome due to neuroendocrine carcinoma, while the paediatric case was diagnosed with prior meningitis.…”

“…Antibodies against LGI1, Caspr2, and DPPX, which target adjacent proteins or regulatory subunits of the voltage-gated potassium channel complex, have been linked to AE. Notably, the rst case of anti-voltage-gated calcium channel alpha-2/delta subunit (anti-CaVα2δ) AE was identi ed in 2021 [5]. To the best of our knowledge, no other cases of anti-CaVα2δ AE has been reported since then.…”

Pathophysiological Effects of Autoantibodies in Autoimmune Encephalitides

“…In 2021 autoantibodies of the IgG2 subclass targeting an auxiliary subunit of presynaptic voltage-gated calcium channel (VGCC or Ca V ), α-2/δ subunit (Ca V α2δ) were found in two patients by screening serum- and CSF samples from seronegative AE patients [ 89 ]. The two patients presented with subacute cognitive decline, altered behavior, seizures and decreased consciousness.…”

“…In cultured rat hippocampal neurons, binding of autoantibodies to the Ca V α2δ subunit of VGCC weakened the coupling of VGCCs and exocytosis, suggesting that the autoantibodies inhibit neurotransmitter release. Whole cell-recording of cultured rat hippocampal neurons showed that autoantibodies impaired neuronal excitatory and inhibitory postsynaptic current frequencies, potentially by interfering with the tight coupling of Ca 2+ channels and Ca 2+ sensors [ 89 ]. These findings needs to be validated, and warrant further research to evaluate the pathogenicity of IgG2 autoantibodies against Ca V α2δ.…”