Haploinsufficiency of immune checkpoint receptor CTLA4 induces a distinct neuroinflammatory disorder

• Published in: The Journal of clinical investigation Vol. 130; no. 10; pp. 5551 - 5561
• Main Authors: Schindler, Matthew K, Pittaluga, Stefania, Enose-Akahata, Yoshimi, Su, Helen C, Rao, V Koneti, Rump, Amy, Jacobson, Steven, Cortese, Irene, Reich, Daniel S, Uzel, Gulbu
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.10.2020
• Subjects: Adolescent; Adult; Antigens; Biomedical research; Biopsy; Brain - diagnostic imaging; Brain - pathology; Brain damage; Brain research; Central Nervous System Diseases - etiology; Central Nervous System Diseases - genetics; Central Nervous System Diseases - immunology; Cerebrospinal fluid; Child; Child, Preschool; Clinical Medicine; Cohort Studies; Convulsions & seizures; CTLA-4 Antigen - deficiency; CTLA-4 Antigen - genetics; CTLA-4 Antigen - immunology; CTLA-4 protein; Cytotoxicity; Demyelination; Female; Gene mutation; Genetic aspects; Haploinsufficiency; Headache; Headaches; Homeostasis; Humans; Immune checkpoint; Immunology; Inflammation; Ipilimumab; Longitudinal Studies; Lymphocytes; Lymphocytes T; Magnetic Resonance Imaging; Male; Medical imaging; Medical research; Middle Aged; Multiple sclerosis; Mutation; Nervous system; Neuritis - etiology; Neuritis - genetics; Neuritis - immunology; Neuroimaging; Neuroimmunomodulation; Parenchyma; Patients; Spinal cord; Spinal Cord - diagnostic imaging; Spinal Cord - pathology; T cells; Young Adult; Neuroimaging; Neuroscience; Inflammation; Autoimmune diseases; Genetic diseases
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI135947

BACKGROUNDCytotoxic T lymphocyte antigen 4 (CTLA4) is essential for immune homeostasis. Genetic mutations causing haploinsufficiency (CTLA4h) lead to a phenotypically heterogenous, immune-mediated disease that can include neuroinflammation. The neurological manifestations of CTLA4h are poorly characterized.METHODSWe performed an observational natural history study of 50 patients with CTLA4h who were followed at the NIH. We analyzed clinical, radiological, immunological, and histopathological data.RESULTSEvidence for neuroinflammation was observed in 32% (n = 16 of 50) of patients in this cohort by magnetic resonance imaging (MRI) and/or by cerebrospinal fluid analysis. Clinical symptoms were commonly absent or mild in severity, with headaches as the leading complaint (n = 13 of 16). The most striking findings were relapsing, large, contrast-enhancing focal lesions in the brain and spinal cord observed on MRI. We detected inflammation in the cerebrospinal fluid and leptomeninges before the parenchyma. Brain biopsies of inflammatory lesions from 10 patients showed perivascular and intraparenchymal mixed cellular infiltrates with little accompanying demyelination or neuronal injury.CONCLUSIONSNeuroinflammation due to CTLA4h is mediated primarily by an infiltrative process with a distinct and striking dissociation between clinical symptoms and radiological findings in the majority of patients.FUNDINGNIAID, NIH, Division of Intramural Research, NINDS, NIH, Division of Intramural Research, and the National Multiple Sclerosis Society-American Brain Foundation.TRIAL REGISTRATIONClinicalTrials.gov NCT00001355.