Autoimmune glial fibrillary acidic protein astrocytopathy resembling isolated central nervous system lymphomatoid granulomatosis

Kimura, Akio; Takekoshi, Akira; Yagi, Nobuaki; Yanagida, Narufumi; Kitaguchi, Hiroshi; Akiyama, Daisuke; Shimizu, Hiroshi; Kakita, Akiyoshi; Shimohata, Takayoshi

doi:10.1016/j.jneuroim.2021.577748

Cited by 9 publications

(14 citation statements)

References 25 publications

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“…These results revealed that the pathogenesis of GFAP‐A is predominantly Th1 + Tfh/B‐cell and that Th2/Treg is involved in the pathogenesis. This cascade is consistent with the hypothesis that the antibody is not pathogenic because GFAP is present in astrocytic glial cells and that GFAP‐specific CD8 + T lymphocytes are activated to produce an inflammatory state 14–16,27,29–31 . Although the significance of anti‐GFAP antibodies on the Th1‐dominant chemokine production observed in GFAP‐A is still unknown, a T‐cell‐mediated inflammatory pathology may be involved 14–16,27,29–35 .…”

Section: Discussionsupporting

confidence: 85%

“…Given the lack of guidelines for GFAP-A diagnosis, the measurement of CSF anti-GFAP antibodies is essential, but they could represent only an immunologic epiphenomenon rather than the nature of the disease, and the pathogenesis is not fully understood. [14][15][16]27,[29][30][31][32][33] The chemokine profile of GFAP-A provides insight into the pathogenesis of the disease. In this study, CSF levels of CXCL9 and CXCL10 were elevated, indicating a Th1-predominant cascade.…”

Section: Discussionmentioning

confidence: 99%

“…This cascade is consistent with the hypothesis that the antibody is not pathogenic because GFAP is present in astrocytic glial cells and that GFAP-specific CD8 + T lymphocytes are activated to produce an inflammatory state. [14][15][16]27,[29][30][31] Although the significance of anti-GFAP antibodies on the Th1-dominant chemokine production observed in GFAP-A is still unknown, a T-cell-mediated inflammatory pathology may be involved. [14][15][16]27,[29][30][31][32][33][34][35] The chemokine profiles in this study suggest that CXCR3 ligand interactions may be important in the pathophysiology of GFAP-A.…”

Section: Discussionmentioning

confidence: 99%

“…GFAP‐A is difficult to diagnose, even with pathologic findings. Given the lack of guidelines for GFAP‐A diagnosis, the measurement of CSF anti‐GFAP antibodies is essential, but they could represent only an immunologic epiphenomenon rather than the nature of the disease, and the pathogenesis is not fully understood 14–16,27,29–33 . The chemokine profile of GFAP‐A provides insight into the pathogenesis of the disease.…”

Section: Discussionmentioning

confidence: 99%

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Level of CSF CXCL10 is highly elevated and decreased after steroid therapy in patients with autoimmune glial fibrillary acidic protein astrocytopathy

Kikuchi

Takao

Sato

et al. 2022

Clinical & Exp Neuroim

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Objectives: To examine the chemokine profile in the cerebrospinal fluid (CSF) of patients with glial fibrillary acidic protein astrocytopathy (GFAP-A), central nervous system immune-related adverse event (CNS-irAE), neurosarcoidosis (NS), neuromyelitis optica spectrum disorders (NMOSD), multiple sclerosis (MS), and human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy (HAM). Methods:The study included 38 patients presenting to St. Marianna University Hospital between May 2013 and November 2021 with GFAP-A, CNS-irAE, NMOSD, MS, NS, HAM and noninflammatory neurological diseases (NIND). We recorded the age, sex, duration of disease, brain/spinal lesions on magnetic resonance imaging (MRI), blood data, and measured chemokines (CXCL9, À10, À13, CCL3, À4, À17, À20, À22) in CSF. In patients with GFAP-A, clinical symptoms, and CSF CXCL10 levels were compared before and after steroid treatment.Results: Patients with GFAP-A had higher CSF levels of CXCL10, CXCL13, and CCL22 (10736.1 [8786.7-149079.0] pg/ml (p < .05), 378.4 [239.9-412.2] pg/ml (p < .01) and 159.9 [130.5-413.9] pg/ml (p < .01), respectively). The CSF levels of CXCL10 improved from 10736.1 [8786.7-149079.0] pg/ml to 1879.0 [783.9-4360.0] pg/ml in patients with GFAP-A by steroid therapy.Conclusion: CSF CXCL10 levels were particularly high in GFAP-A, and changes in levels after treatment correlated with clinical improvements, suggesting CXCL10 involvement in GFAP-A pathogenesis.autoimmune encephalopathy, autoimmune glial fibrillary acidic protein astrocytopathy, C-X-C motif chemokine ligand 10, Luminex Naoki Takao equaly contributed first author.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Level of CSF CXCL10 is highly elevated and decreased after steroid therapy in patients with autoimmune glial fibrillary acidic protein astrocytopathy

Kikuchi

Takao

Sato

et al. 2022

Clinical & Exp Neuroim

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“…However, GFAP antibody in CSF of this patient turned negative after steroid treatment, suggesting that the two diseases may coexist, that was, this patient's GFAP astrocytopathy could be the result of a paraneoplastic syndrome. Interestingly, it's reported recently that GFAP astrocytopathy could resemble isolated central nervous system lymphomatoid granulomatosis, which is classified as a subclass of mature B-cell neoplasms (7,25). Speculatively, there may be a link between lymphomatoid granulomatosis and GFAP astrocytopathy, as well as between PCNSL and GFAP astrocytopathy.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Need for Caution in the Diagnosis of GFAP Astrocytopathy—A Case of GFAP Astrocytopathy Coexistent With Primary Central Nervous System Lymphoma

Fang

Tong

2022

Front. Neurol.

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We reported a case of primary central nervous system lymphoma (PCNSL) coexistent with glial fibrillary acidic protein (GFAP) astrocytopathy, and discussed the problems needing attention in the diagnosis and differential diagnosis of GFAP astrocytopathy. Our patient was a 51-year-old female who presented with somnolence for a month, and memory declination for 10 days. Brain magnetic resonance imaging (MRI) demonstrated multiple abnormal enhancement lesions in bilateral basal ganglia and around the third ventricle, as well as transient T2-weighted hyper-intensity lesions at the splenium of the corpus callosum during the course of the disease. The cerebrospinal fluid (CSF) was positive for anti-GFAP antibodies by antigen-transfected HEK293 cell-based assay (indirect immunofluorescence assay). She was initially diagnosed with autoimmune GFAP astrocytopathy. After treatment with corticosteroids for about 2 months, she displayed poor response and even worsened clinical manifestations when the dose of prednisone reduced to 45 mg. Stereotactic brain biopsy was adopted and the diagnosis of large B-cell lymphoma, non-germinal center type was established on pathological examination. The results of brain biopsy also showed perivascular inflammation and CD8+ T cell infiltration, which also accorded with GFAP astrocytopathy. After chemotherapy with rituximab and methotrexate, the patient showed clinical and radiological improvement significantly. Our findings suggest that positivity of GFAP antibody calls for cautious interpretation. Cancer screening appropriate for age, sex, and risk factors is recommended for GFAP antibody-positive patients, especially for patients with atypical clinical and radiologic manifestations.

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New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis

Guo,

Endmayr,

Zekeridou

et al. 2024

Acta Neuropathol

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Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease diagnosable by the presence of anti-GFAP autoantibodies in the cerebrospinal fluid and presents as meningoencephalomyelitis in the majority of patients. Only few neuropathological reports are available and little is known about the pathogenic mechanisms. We performed a histopathological study of two autopsies and nine CNS biopsies of patients with anti-GFAP autoantibodies and found predominantly a lymphocytic and in one autopsy case a granulomatous inflammatory phenotype. Inflammatory infiltrates were composed of B and T cells, including tissue-resident memory T cells. Although obvious astrocytic damage was absent in the GFAP-staining, we found cytotoxic T cell-mediated reactions reflected by the presence of CD8+/perforin+/granzyme A/B+ cells, polarized towards astrocytes. MHC-class-I was upregulated in reactive astrocytes of all biopsies and two autopsies but not in healthy controls. Importantly, we observed a prominent immunoreactivity of astrocytes with the complement factor C4d. Finally, we provided insight into an early phase of GFAP autoimmunity in an autopsy of a pug dog encephalitis that was characterized by marked meningoencephalitis with selective astrocytic damage with loss of GFAP and AQP4 in the lesions.Our histopathological findings indicate that a cytotoxic T cell-mediated immune reaction is present in GFAP autoimmunity. Complement C4d deposition on astrocytes could either represent the cause or consequence of astrocytic reactivity. Selective astrocytic damage is prominent in the early phase of GFAP autoimmunity in a canine autopsy case, but mild or absent in subacute and chronic stages in human disease, probably due to the high regeneration potential of astrocytes. The lymphocytic and granulomatous phenotypes might reflect different stages of lesion development or patient-specific modifications of the immune response. Future studies will be necessary to investigate possible implications of pathological subtypes for clinical disease course and therapeutic strategies.

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Autoimmune glial fibrillary acidic protein astrocytopathy resembling isolated central nervous system lymphomatoid granulomatosis

Cited by 9 publications

References 25 publications

Level of CSF CXCL10 is highly elevated and decreased after steroid therapy in patients with autoimmune glial fibrillary acidic protein astrocytopathy

Level of CSF CXCL10 is highly elevated and decreased after steroid therapy in patients with autoimmune glial fibrillary acidic protein astrocytopathy

Case Report: Need for Caution in the Diagnosis of GFAP Astrocytopathy—A Case of GFAP Astrocytopathy Coexistent With Primary Central Nervous System Lymphoma

New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis

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