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Original Investigation |

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy A Novel Meningoencephalomyelitis ONLINE FIRST

Boyan Fang, MD, PhD1; Andrew McKeon, MD1,2; Shannon R. Hinson, PhD1; Thomas J. Kryzer, AA1; Sean J. Pittock, MD1,2; Allen J. Aksamit, MD2; Vanda A. Lennon, MD, PhD1,2,3
[+] Author Affiliations
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
2Department of Neurology, Mayo Clinic, Rochester, Minnesota
3Department of Immunology, Mayo Clinic, Rochester, Minnesota
JAMA Neurol. Published online September 12, 2016. doi:10.1001/jamaneurol.2016.2549
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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 Measures  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 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.

Figures in this Article


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Figure 1.
Immunofluorescence Pattern of Patient IgG Bound to Rodent Central Nervous System Tissues in Part Resembles Brain and Spinal Cord Magnetic Resonance Imaging Patterns of Patients With Autoimmune Glial Fibrillary Acidic Protein Meningoencephalomyelitis

A, Distribution of patient IgG (green) in mouse pia or subpia and midbrain parenchyma is consistent with astrocytes (original magnification ×20). B, Periventricular region (original magnification ×20). C, Gastric smooth muscle contains immunoreactive ganglia (yellow arrowheads) and nerve bundles and segments, some (white arrowheads) penetrating the mucosa (original magnification ×40). D, Filamentous staining of rat hemispinal cord is prominent around the central canal (CC) (arrowhead) (original magnification ×20). E and F, Brain image of patient 7 reveals a prominent radial pattern of periventricular postgadolinium enhancement (T1, sagittal). G-J, Spinal cord of patient 10. T2 signal abnormalities are hazy (sagittal, G; axial, I and J), longitudinally extensive (G), and most prominent centrally (I). Gadolinium enhancement of the central spinal cord is prominent and longitudinally extensive in the sagittal (T1) image (H, arrowheads). GM indicates ventral gray matter; WM, white matter.

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Figure 2.
Dual Immunostaining of Mouse Tissues With Commercial IgGs Specific for Glial Fibrillary Acidic Protein (GFAP) Intermediate Filament Isoforms and Patient IgG

A, GFAP-α and patient IgGs largely colocalize in astrocytes of pia and subpia (original magnification ×20). B, Unlike GFAP-α–specific IgG, patient IgG is largely nonreactive with radial processes of cerebellar cortical Bergmann glia (original magnification ×20). C, Both IgGs completely colocalize in myenteric plexus glia (original magnification ×20). D-F, GFAP-δ–specific IgG and patient IgG colocalize extensively in the pia and subpia (D), cerebellum (E) (note that neither GFAP-δ–specific IgG nor patient IgG binds to Bergmann glial processes), and myenteric plexus (F). Colocalized IgGs appear yellow in merged panels, and DNA is blue (4′,6-diamidino-2-phenylindole staining) (D). ε is human GFAP isoform nomenclature; δ is rodent GFAP nomenclature.

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Figure 3.
Autoantigen Identification

A, Western blot of proteins isolated from rat spinal cord probed with IgG from 4 individual patients and 2 healthy controls. Patient IgG binds to an approximately 50-kDa band. B, Immunostaining of mouse periventricular region with IgG in original patient serum and with neutralized IgG acid eluted from a nonstained replica of transblotted immunoreactive band. C, Cytoplasm of glioblastoma multiforme (GBM) xenograft cells binds patient IgG, commercial glial fibrillary acidic protein (GFAP)–specific IgGs, pan-reactive, and ε-isoform–specific (green) but not control human IgG. DNA is stained blue with 4′,6-diamidino-2-phenylindole. Scale bar indicates 50 µm. D, Western blot of GBM tumor xenograft lysate (8000g insoluble fraction) probed with commercial GFAP-specific IgGs and healthy control or 2 patient IgGs. E, GBM lysate proteins separated by 2-dimensional (2-D) electrophoresis and probed with IgG from 2 patients. Red outline defines the protein identified as GFAP by mass spectrometry analysis. ε is human GFAP isoform nomenclature; δ is rodent GFAP nomenclature.

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Figure 4.
IgG Binding to HEK293 Cells Transfected With Expression Plasmids Encoding Green Fluorescent Protein–Tagged Human Glial Fibrillary Acidic Protein α or ε Isoform

Analysis by immunofluorescence (fixed, permeabilized cells) and by Western blot (postnuclear cell lysates; actin immunoreactivity confirmed equivalent protein loading). A, Pan-GFAP–reactive control IgG bound to both the α and ε isoforms of GFAP. Control IgGs monospecific for GFAP-α (B) or GFAP-ε (C) isoforms bound selectively to the anticipated protein product. D, Healthy human control IgG did not bind to nontransfected GFAP-α or GFAP-ε transfected cells or lysates. Examples of patient IgGs binding to GFAP-α only (E) or both GFAP-α and GFAP-ε (F). ε, human GFAP isoform nomenclature, corresponds to δ GFAP isoform in rodents.

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