MLC1 antibody identified as a possible trigger of a rare neurological autoimmune disorder

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease of the central nervous system in which the immune system attacks structures in the brain, spinal cord and optic nerve. It mostly affects astrocytes, glial cells that have important support and supply functions in nerve tissue. As early as 2005, the majority of patients with NMOSD were shown to have an antibody in their serum that attacks the astrocyte protein aquaporin-4.

"This fundamental discovery indicated that astrocytes are a key target of the autoimmune attack," says Dr. Simone Mader, head of Translational Immunology at Uniklinikum Erlangen. Initially, the discovery helped distinguish NMOSD from multiple sclerosis (MS) and other related diseases with similar symptoms.

However, AQP4 antibodies cannot be found in all patients with NMOSD or symptoms similar to NMOSD. This raises the question of whether further antibodies are involved in triggering these diseases. "Particularly in these seronegative cases, it has remained largely unclear which molecular mechanisms are behind the disease," Mader explains.

MLC1 autoantibodies may trigger NMOSD-like disease

In an international research collaboration, a team led by Mader identified an autoantibody that also attacks astrocytes and could trigger NMOSD-like diseases. "The starting point was a characteristic antibody staining pattern that we observed when examining brain tissue sections with the serum of a patient," Mader says.

Through a targeted search for the underlying target protein, MLC1 was identified as the autoantigen, a membrane protein that regulates fluid and electrolyte homeostasis as well as cell volume in the brain and spinal cord.

Building on this, the researchers developed a cell-based test to detect autoantibodies against MLC1. The test is based on a principle that has already proven effective in detecting autoantibodies against other membrane proteins such as aquaporin-4.

The findings have been published in the journal Science Translational Medicine.

Evidence from patients and lab tests

Among patients with inflammatory diseases of the central nervous system, the researchers identified four individuals with MLC1 autoantibodies. None tested positive for aquaporin-4 antibodies.

Further laboratory investigations showed that MLC1 antibodies bind to astrocytes, damaging or even destroying them completely. Mader says, "The findings suggest that the studied autoantibodies are not merely an accompanying phenomenon but are involved in the processes that cause the disease."

The joint study also involved the research groups of Dr. Edgar Meinl and Dr. Naoto Kawakami, as well as the neuroimmunology outpatient clinic headed by Dr. Tania Kümpfel at LMU University Hospital Munich, the research group of Dr. Monika Bradl at the Medical University of Vienna, and numerous other research partners.

Sharper diagnosis, longer-term therapy hopes

The findings expand the understanding of NMOSD and NMOSD-like autoimmune diseases. They show that even in patients in whom the known AQP4 antibodies are not detectable, an antibody-mediated immune response against astrocytes may be present.

In further studies, MLC1 antibodies will now be examined in larger patient groups. "Identifying additional disease-relevant autoantibodies could help more precisely distinguish between the different forms of neurological autoimmune diseases," Mader says. "In the long term, such insights could also provide starting points for more targeted therapies."

This article was originally published on MedicalXpress Breaking News-and-Events.