Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy

Abstract

IMPORTANCE A novel astrocytic autoantibody has been identified as a biomarker of a relapsing autoimmune meningoencephalomyelitis that is immunotherapy responsive. Seropositivity distinguishes autoimmune glial fibrillary acidic protein (GFAP) meningoencephalomyelitis from disorders commonly considered in the differential diagnosis.OBJECTIVE To describe a novel IgG autoantibody found in serum or cerebrospinal fluid that is specific for a cytosolic intermediate filament protein of astrocytes.DESIGN, SETTING, AND PARTICIPANTS Retrospective review of the medical records of seropositive patients identified in the Mayo Clinic Neuroimmunology Laboratory from October 15, 1998, to April 1, 2016, in blinded comprehensive serologic evaluation for autoantibody profiles to aid the diagnosis of neurologic autoimmunity (and predict cancer likelihood). MAIN OUTCOMES AND MEASURESFrequency and definition of novel autoantibody, the autoantigen's immunochemical identification, clinical and magnetic resonance imaging correlations of the autoantibody, and immunotherapy responsiveness. RESULTSOf 103 patients whose medical records were available for review, the 16 initial patients identified as seropositive were the subject of this study. Median age at neurologic symptom onset was 42 years (range, 21-73 years); there was no sex predominance. The novel neural autoantibody, which we discovered to be GFAP-specific, is disease spectrum restricted but not rare (frequency equivalent to Purkinje cell antibody type 1 [anti-Yo]). Its filamentous pial, subventricular, and perivascular immunostaining pattern on mouse tissue resembles the characteristic magnetic resonance imaging findings of linear perivascular enhancement in patients. Prominent clinical manifestations are headache, subacute encephalopathy, optic papillitis, inflammatory myelitis, postural tremor, and cerebellar ataxia. Cerebrospinal fluid was inflammatory in 13 of 14 patients (93%) with data available. Neoplasia was diagnosed within 3 years of neurologic onset in 6 of 16 patients (38%): prostate and gastroesophageal adenocarcinomas, myeloma, melanoma, colonic carcinoid, parotid pleomorphic adenoma, and teratoma. Neurologic improvement followed treatment with high-dose corticosteroids, with a tendency of patients to relapse without long-term immunosuppression.CONCLUSIONS AND RELEVANCE Glial fibrillary acidic protein-specific IgG identifies a distinctive, corticosteroid-responsive, sometimes paraneoplastic autoimmune meningoencephalomyelitis. It has a lethal canine equivalent: necrotizing meningoencephalitis. Expression of GFAP has been reported in some of the tumor types identified in paraneoplastic cases. Glial fibrillary acidic protein peptide-specific cytotoxic CD8 + T cells are implicated as effectors in a transgenic mouse model of autoimmune GFAP meningoencephalitis.

Brain Immunohistopathology in a Patient with Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy

“…Despite the limited response to immunomodulatory treatments, the age, the gender, the clinical presentation, the CSF results, and the MRI changes in this patient were consistent with the novel autoimmune disorder autoimmune GFAP astrocytopathy [1-5]. …”

“…Furthermore, our results showed that there was no pathological alteration of astrocytes (no loss of GFAP in the patient brain). This autoimmune astrocytopathy is probably mediated by antigen-specific cytotoxic T cells [1, 4]. Cytotoxic T cells specific for GFAP-derived peptides were shown to be pathogenic in a mouse model of autoimmune GFAP meningoencephalomyelitis where GFAP-specific CD8 + cytotoxic T cells caused various forms of central nervous system inflammation [9].…”

“…Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a novel autoimmune meningoencephalomyelitis first reported by Fang et al [1] in 2016 and noted to affect the meninges, brain, spinal cord, and optic nerve. GFAP antibodies targeted to astrocytes have been reported to be a specific biomarker of this disease [1-5].…”

“…GFAP antibodies targeted to astrocytes have been reported to be a specific biomarker of this disease [1-5]. However, the pathogenesis of this central nervous system syndrome is unknown.…”

Treatment of Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy: Follow-Up in 7 Cases

“…in animals or humans with this disease [1][2][3][4] . A human study at the Mayo Clinic showed that 13 patients responded well to initial intravenous high-dose steroid treatment, but 7 patients experienced relapse during dose tapering.…”