Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency,Science Translational Medicine

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Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency
Science Translational Medicine ( IF 15.8 ) Pub Date : 2024-06-26 , DOI: 10.1126/scitranslmed.adl3758
John V Pluvinage _{1,

2} , Thomas Ngo _{1,

2} , Camille Fouassier _{1,

2} , Maura McDonagh _{1,

2} , Brandon B Holmes _{1,

2} , Christopher M Bartley _{2,

3} , Sravani Kondapavulur _{2,

4} , Charlotte Hurabielle ₅ , Aaron Bodansky ₆ , Vincent Pai ₇ , Sam Hinman ₇ , Ava Aslanpour ₇ , Bonny D Alvarenga _{1,

2} , Kelsey C Zorn ₈ , Colin Zamecnik _{1,

2} , Adrian McCann ₉ , Andoni I Asencor _{1,

2} , Trung Huynh _{1,

2} , Weston Browne _{1,

2} , Asritha Tubati _{1,

2} , Michael S Haney ₁₀ , Vanja C Douglas _{1,

2} , Martineau Louine _{1,

2} , Bruce A C Cree _{1,

2} , Stephen L Hauser _{1,

2} , William Seeley _{1,

2} , Sergio E Baranzini _{1,

2} , James A Wells ₁₁ , Serena Spudich ₁₂ , Shelli Farhadian ₁₃ , Prashanth S Ramachandran _{1,

2} , Leslie Gillum ₁₄ , Chadwick M Hales ₁₅ , Julie Zikherman ₅ , Mark S Anderson _{16,

17} , Jinoos Yazdany ₄ , Bryan Smith ₁₈ , Avindra Nath ₁₈ , Gina Suh ₁₉ , Eoin P Flanagan ₂₀ , Ari J Green _{1,

2} , Ralph Green ₂₁ , Jeffrey M Gelfand _{1,

2} , Joseph L DeRisi _{7,

22} , Samuel J Pleasure _{1,

2} , Michael R Wilson _{1,

2}

Affiliation

Department of Neurology, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.
Weill Institute for Neurosciences, UCSF, San Francisco, CA 94158, USA.
Department of Psychiatry and Behavioral Sciences, UCSF, San Francisco, CA 94158, USA.
Department of Neurological Surgery, UCSF, San Francisco, CA 94158, USA.
Department of Medicine, Division of Rheumatology, UCSF, San Francisco, CA, 94158, USA.
Department of Pediatrics, Division of Critical Care, UCSF, San Francisco, CA 94158, USA.
Bruker Cellular Analysis, Emeryville, CA, 94608, USA.
Department of Biochemistry and Biophysics, UCSF, San Francisco, CA 94158, USA.
Bevital, Bergen 5068, Norway.
Department of Neurology, Stanford University, Stanford, CA 94304, USA.
Department of Pharmaceutical Chemistry, UCSF, San Francisco, CA 94158, USA.
Department of Neurology, Yale School of Medicine, New Haven, CT 06520, USA.
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520, USA.
Bass Medical Group, Pleasant Hill, CA 94523, USA.
Department of Neurology, Emory University, Atlanta, GA 30322, USA.
Diabetes Center, UCSF, San Francisco, CA 94143, USA.
Department of Medicine, Division of Endocrinology, UCSF, San Francisco, CA 94158, USA.
Division of Neuroimmunology and Neurovirology, National Institute of Neurologic Disorders and Stroke, Bethesda, MD 20824, USA.
Department of Medicine, Division of Infectious Disease, Mayo Clinic, Rochester, MN 55905, USA.
Department of Neurology and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Department of Pathology and Laboratory Medicine, University of California, Davis, CA 95616, USA.
Chan Zuckerberg Biohub San Francisco, San Francisco, CA 94158, USA.

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 autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning 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). Immunosuppressive 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 antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% 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.

中文翻译：

自身免疫性维生素 B12 中枢缺乏症中的转钴胺受体抗体

维生素 B12 对于造血和髓鞘形成至关重要。缺乏会导致神经系统缺陷，包括协调性丧失和认知能力下降。然而，诊断依赖于血液中维生素 B12 的测量，这可能无法准确反映大脑中的浓度。使用可编程噬菌体展示，我们在患有进行性震颤、共济失调和扫描言语的患者中鉴定出一种针对转钴胺受体（CD320）的自身抗体。抗 CD320 通过耗尽细胞表面的靶标，在体外损害细胞对钴胺素 (B12) 的摄取。尽管血清浓度正常，但在她的脑脊液 (CSF) 中几乎检测不到 B12。免疫抑制治疗和大剂量全身维生素 B12 补充与脑脊液中维生素 B12 的增加和临床改善相关。光流控筛选能够分离出一种患者来源的单克隆抗体，该抗体会损害 B12 穿过血脑屏障 (BBB) 体外模型的运输。在其他 7 名不明原因神经功能缺损患者、6% 的健康对照者和 21.4% 的神经精神性狼疮患者中，发现了针对 CD320 相同表位的自身抗体。在 132 份配对的血清和脑脊液样本中，检测到血液中的抗 CD320 可以预测大脑中存在维生素 B12 缺乏症。然而，尽管全身 CD320 受损，这些人并未表现出任何 B12 缺乏的血液学症状。通过全基因组 CRISPR 筛选，我们发现低密度脂蛋白受体可作为造血细胞中 B12 摄取的替代途径。这些发现剖析了 B12 转运的组织特异性，并阐明了可能适合免疫调节治疗和营养补充的自身免疫性神经系统疾病。

更新日期：2024-06-26

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