When the immune system attacks brain cells
When the immune system fights the body's own structures, consequences can be devastating. Especially in those cases where the brain's nerve cells are being attacked. Researchers from Bochum and Göttingen now revealed that such autoimmune reactions against a certain receptor of nerve cells in the brain are much more complex than previously thought. In addition, it became clear that the mere presence of such autoantibodies in the bloodstream does not necessarily mean you will get sick. The project was spearheaded by RUB biochemist Prof. Dr. Michael Hollmann and medical scientist Prof. Dr. Hannelore Ehrenreich of the Max Planck Institute for Experimental Medicine in Göttingen. The researchers reported in the journal "Molecular Psychiatry".
Severe symptoms are possible
In the brains of humans and other mammals glutamate receptors are responsible for the majority of excitatory signal transduction between nerve cells. Just like other structures of the body these receptors can erroneously become the target of the immune system - causing a so-called autoimmune disease. In this process autoantibodies are generated that attack the glutamate receptor, thereby causing severe symptoms such as epileptic seizures, movement disorders, psychoses, and cognitive deficiencies.
Antibodies against different structures
The NMDA receptor in particular, a glutamate receptor subtype that is essential for learning and memory formation, can become the target of autoantibodies: a so-called anti-NMDA receptor encephalitis develops. In the present study the group of Michael Hollmann showed that, contrary to current doctrine, autoantibodies can be generated against a multitude of different structural elements of NMDA receptors, known as epitopes. Until now it had been assumed that a single, specific epitope of the receptor located on the outside of the cell induces autoantibody formation, and that all autoantibodies are of the same type, namely the immunoglobulin type G (IgG).
Target structures even inside the cell
"The target structures of this normally cell membrane-residing receptor can be on the outside as well as within the membrane or even the inside of the cell", explains Michael Hollmann. Moreover, it turned out that the epitopes recognized by the autoantibodies are independent of the disease pattern. They occur in patients with vastly varying neurological conditions and even show up in healthy controls. These autoantibodies can be of any immunoglobulin type: Besides IgG antibodies, IgM and IgA types have been observed as well.
Compromised signal transduction
The causal event for the often grave symptoms caused by NMDA receptor autoantibodies is, in all likelihood, a disturbed signal transduction in the brain. "This occurs because autoantibodies trigger the removal of NMDA receptors from the cell membrane", explains Michael Hollmann. "Thus, nerve cells lack active receptors, so that they will produce only limited or no responses to the messenger molecule glutamate, and consequently cannot pick up signals from neighboring cells."
Autoantibodies alone won't make you sick
The researchers were surprised to find that all blood samples containing autoantibodies have the same effect on nerve cells -- no matter whether they originated with patients or normal controls. This means that autoantibodies against NMDA receptors, while always capable of triggering a severe neurological disease, quite often don't do that. In the blood of elderly people in particular, it is common to find autoantibodies directed against NMDA receptors in more than 20% of all cases, but only a small percentage of these people ever develop any neurological symptoms.
The blood-brain barrier can prevent neurological diseases
"For a neurological disease to manifest itself, the blood-brain barrier, which normally prevents antibodies from reaching the brain, very likely has to be compromised", Michael Hollmann concludes. As a consequence of these findings, a blood test positive for NMDA receptor autoantibodies alone is no proof of a neurological disease and does not warrant immunosuppressive treatment.
The group of Michael Hollmann at the Dept. of Biochemistry I - Receptor Biochemistry in the Faculty of Chemistry and Biochemistry of the RUB closely collaborated with the group of Prof. Dr. Hannelore Ehrenreich at the MPI for Experimental Medicine in Göttingen as well as colleagues at the Charité in Berlin, the University of Magdeburg, and the company HiQscreen in Geneva.
Esther Castillo-Gómez et. al.: All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class. In: Molecular Psychiatry, in press. Advanced online publication, 9. August 2016, doi:10.1038/mp.2016.125