Vitamin B12 is a vital nutrient for the production of red blood cells and the formation of myelin. A deficiency can result in hematologic impairment including megaloblastic anaemia or neurological deficits, including loss of coordination, memory loss, and psychosis. Nevertheless, diagnosis is contingent upon the measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain.
By employing programmable phage immunoprecipitation sequencing, Pluvinage et al. (2024) were able to identify an autoantibody that targeted the transcobalamin receptor (CD320) in a patient presenting with progressive bilateral lower extremity pain, scanning speech, ataxia, and tremor. The anti-CD320 antibody was observed to impair the cellular uptake of cobalamin (B12) in vitro by depleting cell-surface receptor availability. Despite a normal serum concentration, vitamin B12 was found to be extremely low in the cerebrospinal fluid (CSF). The administration of immunosuppressive treatment in conjunction with high-dose systemic vitamin B12 supplementation was associated with an increase in vitamin B12 concentration in the cerebrospinal fluid (CSF) despite a persistently low CSF-to-serum ratio and a concomitant improvement in mood and cognitive function. Using an optofluidic system authors isolated a patient-derived monoclonal antibody binding to full-length CD320 that impaired B12 transport across an in vitro model of the BBB.
Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurological deficits of unknown aetiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus.
In 132 paired serum and CSF samples, the presence of anti-CD320 in the serum was found to be a reliable indicator of B12 deficiency in the brain. However, these individuals did not display any haematological manifestations of B12 deficiency, indicating the existence of alternative B12 uptake pathways in the blood cells. A genome-wide CRISPR screen was performed and revealed that the LDLR functions as an alternative B12 uptake pathway outside the CNS indicating an alternate pathway for B12 uptake when CD320 is impaired.
This study suggests that the measurement of vitamin B12 metabolites in CSF should be considered for patients with unexplained neurologic deficits who are anti-CD320 seropositive. These findings elucidate the tissue specificity of B12 transport and indicate the potential for immunomodulatory treatment and nutritional supplementation in an autoimmune neurological condition.
Key Points:
- The identification of anti-CD320 autoantibodies targeting the transcobalamin receptor is a reliable indicator of B12 deficiency in the brain.
- The anti-CD320 antibody impairs the transport of B12 across the blood-brain barrier (BBB), resulting in autoimmune B12 central deficiency with a various neurological manifestations of the central nervous system (CNS), sparing the peripheral manifestations of B12 deficiency.
- The administration of immunosuppressive treatment in conjunction with high-dose systemic vitamin B12 supplementation is associated with an increase of the vitamin B12 concentration in the cerebrospinal fluid (CSF) and a concomitant improvement in mood and cognitive function.
- The low-density lipoprotein receptor (LDLR) functions as an alternative B12 uptake pathway outside the CNS indicating an alternate pathway for B12 uptake when CD320 is impaired.
- The measurement of vitamin B12 metabolites in CSF should be considered for patients with unexplained neurologic deficits who are anti-CD320 seropositive.
Reference:
Pluvinage JV, Ngo T, Fouassier C, McDonagh M, Holmes BB, Bartley CM, Kondapavulur S, Hurabielle C, Bodansky A, Pai V, Hinman S, Aslanpour A, Alvarenga BD, Zorn KC, Zamecnik C, McCann A, Asencor AI, Huynh T, Browne W, Tubati A, Haney MS, Douglas VC, Louine M, Cree BAC, Hauser SL, Seeley W, Baranzini SE, Wells JA, Spudich S, Farhadian S, Ramachandran PS, Gillum L, Hales CM, Zikherman J, Anderson MS, Yazdany J, Smith B, Nath A, Suh G, Flanagan EP, Green AJ, Green R, Gelfand JM, DeRisi JL, Pleasure SJ, Wilson MR. Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency. Sci Transl Med. 2024 Jun 26;16(753):eadl3758. https://doi:10.1126/scitranslmed.adl3758
Co-author:
Matteo Gastaldi, Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
Publish on behalf of the Scientific Panel on Neuroimmunology