Medical research

"A ticking time bomb"

Healthy individuals have potentially dangerous autoantibodies

16. 10. 2013 | In ten percent of all tested individuals, scientists of the Max Planck Institute of Experimental Medicine and of the Göttingen-based research centre CNMPB find autoantibodies which can cause neuropsychiatric dysfunctions when the blood-brain barrier becomes more permeable.
"Anti-NMDA receptor encephalitis" is the name of an acute brain disease, presumed causes and treatments have been described in a number of recent publications. On the molecular level, this acute form of encephalitis is accompanied by a reduced function of glutamate receptors (NMDAR), which is again caused by autoantibodies against these receptors. Symptoms can be acute psychosis, movement disorders, epileptic seizures or cognitive deterioration. However, as most studies are based on a small number of patients, they neither cast a light on the relevance of NMDAR autoantibodies in the bloodstream for the pathogenesis of the disease, nor do they yield data about their prevalence in healthy individuals.

Prof. Hannelore Ehrenreich
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Prof. Hannelore Ehrenreich
New findings are provided in a study by Prof. Hannelore Ehrenreich and her team in cooperation with the Göttingen DFG Research Center and Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB). This study demonstrates that NMDAR autoantibodies can be found in the serum of more than 10 percent of almost 3,000 tested individuals, regardless of whether they are healthy individuals or patients. Surprisingly, comparable autoantibody titers, antibody classes and functionalities were detected in healthy subjects as well as in patients with a neuropsychiatric disease. This insight led the authors to the following central question: If these autoantibodies play some pathological role, how is it that healthy carriers stay healthy?

In a series of animal experiments, the scientists could demonstrate that the prerequisite for a triggering of symptoms by these autoantibodies, and thus for pathogenesis, is a dysfunction of the blood-brain barrier. In healthy organisms, this physiological barrier isolates the central nervous system like a filter from the general bloodstream, thus protecting it from circulating pathogenic agents and toxins. A disruption of its natural barrier function enables the NMDAR autoantibodies circulating in the blood to enter the brain. This is how they reach the NMDA receptors located in the brain and can cause impairments, resulting in psychosis-like symptoms, epileptic seizures or cognitive dysfunctions.

"In other words, more than 10 percent of all individuals carry a 'ticking time bomb', the disease relevance of which is only suppressed by an intact blood-brain barrier", remarks Prof. Ehrenreich. Damages to the blood-brain barrier can be caused by a stroke, a brain trauma or by a viral infection, among other causes. Next, the scientists performed an additional retrospective evaluation based on a large cohort of patients. They could show an increase in the severity of neurological symptoms in subjects with a temporary or persisting blood-brain barrier dysfunction who also carry NMDAR autoantibodies.

But how is the generation of NMDAR autoantibodies triggered in the first place? The scientists involved in this study found an association with past influenza A or B infections. They also identified a genetic risk factor related to NMDAR biology, by means of a genome-wide association study. Christian Hammer, lead author of the study, and his colleagues conclude that this finding yields considerable insight into a pathophysiological mechanism that is of crucial importance for neuropsychiatry, as well as for other clinical disciplines.
Hence the scientists recommend that "patients with acute or chronic impairment of the blood-brain barrier, e.g. after a brain injury, a stroke, any kind of encephalitis, epilepsy and also multiple sclerosis should be screened for the presence of NMDAR autoantibodies". This might contribute to improve the patient's prognosis by therapeutic methods and prevent long-term complications.   (© Max Planck Institute for Experimental Medicine, CNMPB, AcademiaNet)
Dr. Heike Benecke

More information

Source

  • Hammer C, Stepniak B, Schneider A, Papiol S, Tantra M, Begemann M, Sirén AL, Pardo LA, Sperling S, Mohd Jofrry S, Gurvich A, Jensen N, Ostmeier K, Lühder F, Probst C, Martens H, Gillis M, Saher G, Assogna F, Spalletta G, Stöcker W, Schulz TF, Nave KA, Ehrenreich H.: Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity, Molecular Psychiatry, 2013 Sep 3, doi: 10.1038/mp.2013.110

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