Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis

Abstract

BACKGROUND Multiple sclerosis 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 We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo. RESULTS Serum levels of antibodies to KIR4.1 were higher in persons with multiple sclerosis than in persons with other neurologic diseases and healthy donors (P<0.001 for both comparisons). We replicated this finding in two independent groups of persons with multiple sclerosis 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 persons with multiple sclerosis (46.9%), in 3 of 329 persons 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 persons with multiple sclerosis. (Funded by the German Ministry for Education and Research and Deutsche Forschungsgemeinschaft.)

PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis

“…reported that serum autoantibodies recognizing the extracellular loop of the potassium channel KIR4.1 (residues 83-120) could be detected in 46.9 percent of patients with multiple sclerosis. [23] A KIR4.1 peptide spanning residues 88-123 is present in T7-Pep, but was not significantly enriched by any patients in our study.…”

Reactivity to AQP4 epitopes in relapsing–remitting multiple sclerosis

“…It is considered a T-cell orchestrated disorder, although significant evidence supports the notion that B-cell autoimmunity is an important contributor. Histopathological studies have shown the existence of B-cell mediated type II MS (Lucchinetti et al, 2000) and serological studies have described a number of autoantibodies, the most typical being the antibodies against MOG and the most recent being the antibodies against ion channel Kir4.1 (Srivastava et al, 2012). In contrast, in Neuromyelitis optica (NMO) or Devic's disease the main pathogenetic factor is the antibodies against AQP4, a water channel mainly expressed in astrocytes (Lennon et al, 2005).…”

Anoctamin 2 identified as an autoimmune target in multiple sclerosis

“…The list of the selected antigens (n = 384) was based on our previous results and was complemented with proteins associated with MS risk, such as Epstein-Barr virus nuclear antigen-1 (EBNA-1), and protein fragments representing previously proposed autoimmune targets in MS, such as the potassium channel protein KIR4.1 (KCNJ10) (6). This extended analysis confirmed increased IgG reactivity in plasma samples of MS patients against a calciumactivated chloride-channel protein called "anoctamin 2" (ANO2), also denoted as "transmembrane protein 16B" (TMEM16B).…”