Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy: A Novel Meningoencephalomyelitis.
OBJECTIVE
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.


METHODS
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).


METHODS
Frequency and definition of novel autoantibody, the autoantigen's immunochemical identification, clinical and magnetic resonance imaging correlations of the autoantibody, and immunotherapy responsiveness.


RESULTS
Of 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
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.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Boyan
B
Fang
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota2Department of Neurology, Mayo Clinic, Rochester, Minnesota.
Andrew
A
McKeon
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Shannon R
SR
Hinson
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Thomas J
TJ
Kryzer
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota2Department of Neurology, Mayo Clinic, Rochester, Minnesota.
Sean J
SJ
Pittock
Department of Neurology, Mayo Clinic, Rochester, Minnesota.
Allen J
AJ
Aksamit
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota2Department of Neurology, Mayo Clinic, Rochester, Minnesota3Department of Immunology, Mayo Clinic, Rochester, Minnesota.
Vanda A
VA
Lennon
D000328:Adult; D000368:Aged; D001253:Astrocytes / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood* / Q000134:cerebrospinal fluid; D020274:Autoimmune Diseases of the Nervous System / Q000097:blood* / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G; D008297:Male; D008590:Meningoencephalitis / Q000097:blood* / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D008875:Middle Aged; D009187:Myelitis / Q000097:blood* / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D020361:Paraneoplastic Syndromes, Nervous System / Q000097:blood* / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D012008:Recurrence; D012189:Retrospective Studies; D055815:Young Adult
D001323:Autoantibodies; D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D007074:Immunoglobulin G