A SOMATICALLY MUTATED HUMAN ANTIGANGLIOSIDE IGM ANTIBODY THAT INDUCESEXPERIMENTAL NEUROPATHY IN MICE IS ENCODED BY THE VARIABLE REGION HEAVY-CHAIN GENE, V1-18

IgM paraproteins associated with autoimmune peripheral neuropathy and anti-Pr cold agglutinins react with sialic acid epitopes present on di sialylated gangliosides including GD1b, GT1b, GQ1b, and GD3. A causal relationship between the paraprotein and the neuropathy has never been proven experimentally, From peripheral blood B cells of an affected p atient, we have cloned a human hybridoma secreting an antidisialosyl I gM mAb, termed Hal, that shows identical structural and functional cha racteristics to its serum counterpart. Variable region analysis shows Hal is encoded by the same V(H)1 family heavy chain gene, V1-18, as th e only other known anti-Pr antibody sequence and is somatically mutate d, suggesting that is arose in vivo in response to antigenic stimulati on, In the rodent peripheral nervous system, Hal immunolocalizes to do rsal root ganglia, motor nerve terminals, muscle spindles, myelinated axons, and nodes of Ranvier, After intraperitoneal injection of affini ty-purified antibody into mice for 10 d, electrophysiological recordin gs from the phrenic nerve-hemidiaphragm preparation demonstrated impai rment of nerve excitability and a reduction in quantal release of neur otransmitter, These data unequivocally establish that an antidisialosy l antibody can exert pathophysiological effects on the peripheral nerv ous system and strongly support the view that the antibody contributes to the associated human disease.