The article by Pluvinage et al (published in Sci. Transl. Med. 2024; 16:eadl3758) explores a novel autoimmune cause of vitamin B12 deficiency in the central nervous system (CNS), termed “Autoimmune B12 Central Deficiency” (ABCD). Researchers from San Francisco discovered autoantibodies targeting the transcobalamin receptor (CD320), a key protein in vitamin B12 transport, impairing B12 uptake into the brain despite normal serum B12 levels.
The authors have used phage display technology, and demonstrated the presence of a specific autoantibody against the CD320 receptor in a patient with poorly understood progressive neurological symptoms (e.g., tremor, ataxia, speech issues). It was observed that the autoantibody blocks B12 uptake into the brain, causing B12 deficiency in nervous tissue and leading to a variety of neurological symptoms.
CD320 antibodies were also found in other patients with unexplained neurological deficits, neuropsychiatric lupus (21.4% prevalence), and some healthy controls (6% prevalence). A genome-wide CRISPR screen revealed that an alternate pathway via LDL receptors compensates for CD320 loss in hematopoietic cells but not in the CNS, explaining the tissue-specific effects.
In the index patient, high-dose systemic vitamin B12 supplementation and immunosuppressive therapy showed improvements in CSF B12 levels and clinical symptoms. Larger studies are needed to explore the prevalence and long-term effects of these autoantibodies in people with symptoms suggestive of B12 deficiency, and the therapeutic role of B12 in neuropsychiatric disorders.
Actually, I have a few additions. This paper is a magnificent description how auto-antibody discovery with phage display has been instrumental in finding anti-CD320 antibodies, how these auto-antibodies alter the kinetics of uptake of B12 into the brain, how at least 4 cases had intracerebral B12 concentrations which was considerably lower, and MMA which is considerably higher than in the serum. Striking in case 1 is that the T2 hyperintensity of the cerebellar peduncles on MRI closely resembles the appearance of subacute degeneration of the spine in systemic B12 deficiency.
These investigations really show how doctors have to be open minded to complex syndromes which they do not understand, and how complex the uptake of B12 into nervous tissue like the brain really is. The high prevalence of such auto-antibodies in lupus patients with neuropsychiatric sympstoms is stunning. Doctors should never ever again state that B12 deficiency is a simple disease which can easily be recognized based on serum measurements. Based on the dissociation between neurological and cognitive symptoms of B12 deficiency vs. the much rarer haematological changes one wonders how much of the former can be explained by low levels of anti-CD320 auto-antibodies, or other modifications to the CD320 receptor which impair B12 uptake into the brain.
Even so, a survey in the UK showed that many people with B12 deficiency need a frequency of B12 injections once weekly or even more frequently, in order to control their symptoms. It has to be determined in future studies whether anti-CD320 antibodies play a role in this. The paper sheds also some new light on the pro’s and con’s of using animal models of CD320 knock-out.
