Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency
John V. Pluvinage,, Thomas Ngo,, Camille Fouassier,, Maura McDonagh,, Brandon B. Holmes,, Christopher M. Bartley,†, Sravani Kondapavulur,, Charlotte Hurabielle, Aaron Bodansky, Vincent Pai, Sam Hinman, Ava Aslanpour, Bonny D. Alvarenga,, Kelsey C. Zorn, Colin Zamecnik,, Adrian McCann, Andoni I. Asencor,, Trung Huynh,, Weston Browne,, Asritha Tubati,, Michael S. Haney, Vanja C. Douglas,, Martineau Louine,, Bruce A.C. Cree,, Stephen L. Hauser,, William Seeley,, Sergio E. Baranzini,, James A. Wells, Serena Spudich, Shelli Farhadian, Prashanth S. Ramachandran,, Leslie Gillum, Chadwick M. Hales, Julie Zikherman, Mark S. Anderson,, Jinoos Yazdany, Bryan Smith, Avindra Nath, Gina Suh, Eoin P. Flanagan, Ari J. Green,, Ralph Green, Jeffrey M. Gelfand,, Joseph L. DeRisi,, Samuel J. Pleasure,, Michael R. Wilson

Sci Tran Med 2024

Abstract: Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an au- toantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scan- ning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Im- munosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal anti- body that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies target- ing the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6 percent of healthy controls, and 21.4 percent of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.