Ion channelopathies of the immune system.

Ion channels and transporters move ions across membrane barriers and are essential for a host of cell functions in many organs. They conduct K+, Na+ and Cl-, which are essential for regulating the membrane potential, H+ to control intracellular and extracellular pH and divalent cations such as Ca2+, Mg2+ and Zn2+, which function as second messengers and cofactors for many proteins. Inherited channelopathies due to mutations in ion channels or their accessory proteins cause a variety of diseases in the nervous, cardiovascular and other tissues, but channelopathies that affect immune function are not as well studied. Mutations in ORAI1 and STIM1 genes that encode the Ca2+ release-activated Ca2+ (CRAC) channel in immune cells, the Mg2+ transporter MAGT1 and the Cl- channel LRRC8A all cause immunodeficiency with increased susceptibility to infection. Mutations in the Zn2+ transporters SLC39A4 (ZIP4) and SLC30A2 (ZnT2) result in nutritional Zn2+ deficiency and immune dysfunction. These channels, however, only represent a fraction of ion channels that regulate immunity as demonstrated by immune dysregulation in channel knockout mice. The immune system itself can cause acquired channelopathies that are associated with a variety of diseases of nervous, cardiovascular and endocrine systems resulting from autoantibodies binding to ion channels. These autoantibodies highlight the therapeutic potential of functional anti-ion channel antibodies that are being developed for the treatment of autoimmune, inflammatory and other diseases.