Background: MS is a chronic inflammatory demyelinating disease of the central nervous system. Many findings suggest that the disease has an autoimmune pathogenesis; the target of the immune response is not yet known.
Methods: These investigators screened serum IgG from MSers to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of MSers. Using a proteomic approach focusing on membrane proteins, they identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. They used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in MS and to show its potential pathogenicity in vivo.
Results: Serum levels of antibodies to KIR4.1 were higher in MSers than in persons with other neurologic diseases and healthy donors (P<0.001 for both comparisons). They replicated this finding in two independent groups of MSers or other neurologic diseases (P<0.001 for both comparisons). Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 MSers (46.9%), in 3 of 329 person with other neurologic diseases (0.9%), and in none of the 59 healthy donors. These antibodies bound to the first extracellular loop of KIR4.1. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum.
Conclusions: KIR4.1 is a target of the autoantibody response in a subgroup of MSers.
“This is a very important paper in that 47% of MSers have this autoantibody. Could this be a diagnostic test for MS? Possibly! The results will need to be reproduced. More importantly it will have to be shown to be a pathogenic antibody. More work will need to be done to show this.”
“What is KIR4.1? KIR4.1 a member of the inward rectifier-type potassium channel family that is characterized by having a greater tendency to allow potassium to flow into, rather than out of, a cell. Kir4.1, may form a heterodimer with another potassium channel protein and may be responsible for the potassium buffering action of glial cells in the brain.”