Neuronal Intermediate Filament Autoimmunity

Objective: To describe a novel autoimmune neurological entity with neuronal intermediate filament (NIF)-IgGs as biomarkers, specifically diagnosable by a 2-step diagnostic algorithm. Background: Neurofilament antibodies have been previously reported, though with limited clinical specificity (by ELISA or Western blot alone). In contrast, we have previously demonstrated autoimmune GFAP astrocytopathy as a specific entity (tissue-based indirect immunofluorescence assay [IFA] followed by human recombinant antigen-specific HEK293 cell based assay [CBA]). Design/Methods: Forty adults had archived serum or CSF yielding neuronal filamentous staining patterns by IFA. Autoantigens were identified by western blot and mass spectrometry. NIF specificity was confirmed by dual IF staining on tissue sections and NIF-specific CBAs. Results: NIF autoimmunity required positivity by IFA and u003e/= 1 of 5 CBAs. Patients IgG profiles (u003e1 IgG in 75%) consisted of: alpha internexin, 25; neurofilament light (NF-L) chain, 15; neurofilament medium chain, 29; neurofilament heavy chain, 26, and peripherin, 13. Neurological symptom onset (available in 38) was subacute in all. Patients had ≥1 of encephalopathy, cerebellar ataxia or neuropathy in 36/38 (95%); disorders were multifocal in 14 (37%). Syndromes included: encephalopathy, 19; peripheral neuropathy, 11; cerebellar ataxia, 9; myelopathy, 6; optic neuropathies, 2; other, 5. NF-L-IgG ( P = 0.027) and peripherin-IgG ( P = 0.032) were independent predictors of neuroendocrine-lineage carcinomas (Merkel cell, small cell). Merkel cell carcinoma, from a patient with ataxia accompanying NIF autoimmunity, had immunoreactivity for 4/5 NIFs. Of 11 immunotherapy-treated patients, 9 improved. Two patients recovered spontaneously; neither had cancer, nor NF-L-IgG, nor peripherin-IgG. Three patients died; all had cancer, and NF-L-IgG and peripherin-IgG. Occasional neurological controls (5%) had reactivity by CBA only (never IFA). Two small cell carcinoma controls had reactivity by CBA and IFA. Conclusions: NIF-specific IgGs represent novel autoimmune neurological biomarkers. Certain NIF-IgG profiles predict neuroendocrine-lineage carcinoma. A 2-step diagnostic algorithm (IFA to screen, recombinant human cDNA-transfected CBA to confirm) is required. Study Supported by: The Mayo Clinic Center for Individualized Medicine Disclosure: Dr. Basal has nothing to disclose. Dr. Kryzer has nothing to disclose. Dr. Dubey has nothing to disclose. Dr. Guo has nothing to disclose. Dr. Hinson has nothing to disclose. Dr. Majed has nothing to disclose. Dr. Benarroch has nothing to disclose. Dr. Lucchinetti has nothing to disclose. Dr. Pittock has nothing to disclose. Dr. Lennon has received royalty, license fees, or contractual rights payments from RSR, royalties from sale kits for AQP4 IgG detetction and from clinical service assays performed outside Mayo clinic. Dr. McKeon has received research support from Medimmune, Euroimmun, Grifols and Alexion.