Autoantibodies detected to expressed K⁺ channels are implicated in neuromyotonia

Abstract

Antibody-mediated autoimmunity underlies a diverse range of disorders, particularly in the nervous system where the extracellular domains of ion channels and receptors are especially vulnerable targets. We present here a novel means of detecting autoantibodies where the genes of the suspected target proteins are known, and use it to detect specific autoantibodies in acquired neuromyotonia (Isaacs' syndrome), a disorder characterized by hyperexcitable motor nerves and sometimes by central abnormalities. We expressed different human brain voltage-gated potassium channels in Xenopus oocytes by injecting the relevant alpha-subunit complementary RNA, and detected antibody binding by immunohistochemistry on frozen sections. Antibodies were detected to one or more human brain voltage-gated potassium channel in 12 of 12 neuromyotonia patients and none of 18 control subjects. The results establish neuromyotonia as a new antibody-mediated channelopathy and indicate the investigative potential of this molecular immunohistochemical assay.

Autoimmune disorders of the neuromuscular junction

“…The antibodies are currently measured by radioimmunoprecipitation of VGKC Kv1.1, 1.2 and 1.6 that are conveniently identified by binding of the snake toxin, dendrotoxin. [84] Kv1.1 and 1.2 are highly expressed in the peripheral nervous system, particularly in the juxtaparanodal region of the nodes of Ranvier [85] and this is the most likely target for the antibodies, but they may also be expressed at the motor nerve terminal.…”

“…[84,86] The precise specificity of the antibodies is difficult to determine as the VGKCs are tetrameric proteins made up of different combinations of different Kv subunits. There are several reports that the antibodies, or IgG fractions, reduce potassium currents in cells transfected with the Kv1.2 subtype [87] and that this does not require complement.…”

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

“…This screening assay utilises cultured mammalian cells that have been transiently transfected to express the target autoantigen of interest (Hart et al 1997). Sera from patients suspected to contain autoantibodies are incubated with transfected cells and any binding revealed using a fluorescently conjugated anti-human secondary antibody.…”

Síndrome de Isaacs: relato de três casos

“…A alteração do estado de excitabilidade dos neurônios dos nervos periféricos ocorre pela presença de anticorpos anti-CKVD, localizados na membrana dos axônios dos nervos motores, que impede o efluxo normal de potássio durante a fase de repolarização [12][13][14][15][16][17][18] . O bloqueio dos CKVD ocasiona aumento do potencial de repouso a valores próximos ao potencial de gatilho, tornando-os suscetíveis a geração de potenciais de ação espontâneos [12][13][14][15][16][17][18] .…”

“…Descargas espontâneas de potenciais de unidade motora (PUM) são os principais achados da eletromiografia (EMG) de agulha, observados como descargas mioquímicas ou neuromiotônicas generalizadas [6][7][8][9][10][11] . As descargas dos PUM ocorrem por alterações do estado de excitabilidade das porções terminais dos axônios motores, devido a ação de anticorpos, contra canais de potássio voltagem dependente (CKVD) [12][13][14][15][16] . Pela raridade desta doença relatamos os achados clínicos, laboratoriais, eletroneurofisioló-gicos de três casos de síndrome de Isaacs, afim de contribuir para a melhor compreensão dos fenômenos fisiológicos.…”