Identification of Fibrinogen C Domain-containing Protein 1 as a Novel Neuronal Autoantigen in Autoimmune Encephalitis
Claudia Papi1, Chiara Milano2, Laura Marmolejo Alcaide3, Esther Aguilar3, Mercedes Alba3, Jesus Planaguma3, Pietro Businaro4, Ana Beatriz Serafim3, Mar Guasp3, Eugenia Martinez-Hernandez3, LAURA NARANJO5, Raquel Ruiz García6, Matteo Gastaldi4, Thais Armangue7, Francesc Graus3, Lidia Sabater3, Josep Dalmau8, Marianna Spatola3
1Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona and Caixa Research Institute (CRI), Barcelona, Spain; Università Cattolica del Sacro Cuore, Rome, Italy, 2Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona and Caixa Research Institute (CRI), Barcelona, Spain; University of Pisa, Pisa, Italy, 3Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona and Caixa Research Institute (CRI), Barcelona, Spain, 4University of Pavia and Neuroimmunology research unit, IRCCS Mondino Foundation, Pavia, Italy, 5Immunology Service, Biomedical Diagnostic Center, Hospital Clínic, Barcelona, Spain, 6Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona and Caixa Research Institute (CRI), Barcelona, Spain; Immunology Service, Biomedical Diagnostic Center, Hospital Clínic, Barcelona, Spain, 7Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona and Caixa Research Institute (CRI), Barcelona, Spain; Pediatric Neuroimmunology Unit, Neurology Service, Sant Joan de Déu (SJD) Children's Hospital, University of Barcelona, Barcelona, Spain, 8Neuroimmunology Program, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomédiques August Pi i Sunyer (FRCB-IDIBAPS), University of Barcelona and Caixa Research Institute (CRI), Barcelona, Spain; Service of Neurology, University of Pennsylvania, Philadelphia, USA
Objective:
To report a novel autoimmune encephalitis associated with neuronal antibodies targeting Fibrinogen C domain-containing protein 1 (FIBCD1).
Background:
Autoimmune encephalitides represent a growing group of immune-mediated neurological disorders. Despite the identification of novel antibodies, a subset of patients remains antibody-negative after extensive testing.
Design/Methods:
We identified from our retrospective database at IDIBAPS/Barcelona six patients with encephalitis and the same characteristic cerebrospinal fluid (CSF) reactivity on rat brain immunohistochemistry. The target antigen was identified by immunoprecipitation from live hippocampal neurons and hippocampal tissue, followed by mass spectrometry. A cell-based assay (CBA) using HEK293 cells expressing the novel antigen served to assess the antigen specificity, including testing of healthy subjects and disease controls. Western blot analysis and immunoabsorption were employed as additional validation methods.
Results:
We identified a new antibody target, FIBCD1 (a transmembrane protein involved in innate immunity and neuronal function), in all six patients. All patients (median age 55.5 years, range 50-76; four female) had seizures and cognitive symptoms, associated in 4/6 with psycho-behavioral and/or mood disturbances. None had an underlying tumor. Brain MRI was abnormal in 4/6 patients (two with inflammatory lesions in temporal lobes, two with atrophy) and CSF was unremarkable except for CSF-restricted oligoclonal bands in 2/6. Four patients received immunotherapy (one first-line only, and three both first- and second-line), showing a partial response. At last follow-up (median 32 months, range 24-96), 4/6 patients had persistent seizures and/or cognitive impairment. FIBCD1 antibodies were found by CBA in all paired serum/CSF of patients, but in none of the 282 controls (60 healthy subjects, 222 with other neurological diseases).
Conclusions:
FIBCD1 antibodies associate with a newly recognized subtype of autoimmune encephalitis characterized by seizures and neuropsychiatric manifestations, partially responsive to immunotherapy.
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