Autoantibodies Against GRP78 May Underlie PCD in LEMS, Study Suggests

Autoantibodies against the GRP78 protein could explain why some Lambert-Eaton myasthenic syndrome (LEMS) patients develop paraneoplastic cerebellar degeneration (PCD), a study suggests.

The GRP78-targeting autoantibodies may disrupt the blood-brain barrier that shields the central nervous system, allowing LEMS autoantibodies to reach the brain.

The study, “GRP78 antibodies damage the blood-brain barrier and relate to cerebellar degeneration in Lambert-Eaton myasthenic syndrome,” was published in the journal Brain.

The majority of LEMS patients develop antibodies against the body’s own voltage-gated calcium channels (VGCCs) of the P/Q-type, a group of ion channels on the surface of cells. These autoantibodies bind to the nerve terminal at the neuromuscular junction and block the entry of calcium into the cells, which reduces the release of the neurotransmitter acetylcholine, causing muscle weakness.

These autoantibodies are also associated with PCD, where the autoantibodies reach the cerebellum — the part of the brain responsible for coordination — and attack neurons called Purkinje cells.

“The features of cerebellar dysfunction are observed in [less than] 10% of LEMS patients; those who suffer from both PCD and LEMS are diagnosed with PCD with LEMS (PCD-LEMS),” the authors wrote. Despite the knowledge of these autoantibodies, their precise role in the development of PCD-LEMS is still not fully understood.

The Japanese researchers reasoned that as is seen in other neurodegenerative diseases, damage to the blood brain barrier (BBB) — a highly selective membrane that shields the central nervous system with its cerebrospinal fluid from the general blood circulation — could play a role in the progression of PCD-LEMS.

They recently reported that autoantibodies against the glucose-regulated protein 78 (GRP78), located in the endothelial cells — those lining the blood vessels of the BBB — promote its dysfunction.

Now, they tested the role of GRP78 autoantibodies in PCD-LEMS. To test their hypothesis, they isolated antibodies from the blood of four PCD-LEMS and five LEMS patients, plus eight healthy controls, and tested the effects of the antibodies in an artificial BBB model created in the lab.

The results showed that antibodies from PDC-LEMS patients, but not from LEMS patients, increased the permeability of the BBB and reduced the levels of a protein, called claudin-5, which helps “glue” the blood vessels’ cells and maintain the barrier effect of the BBB.

Next, they found that the antibodies from the four PDC-LEMS samples and one LEMS patient were binding to the GRP78 protein, while no binding was seen for the remaining LEMS patients or healthy controls, suggesting that this could be triggering the dysfunction of BBB.

Researchers then tested the reactivity of additional blood antibodies against GRP78 and found that 11 of 14 PCD-LEMS patients were positive, whereas none of the 10 additional LEMS patient samples reacted against GRP78.

Overall, these findings suggest that “GRP78 autoantibodies are associated with BBB dysfunction in PCD-LEMS and that these antibodies could be involved in mediating BBB transit of pathogenic P/Q-type VGCC autoantibodies,” the study concluded.