Neurons located in baso-medial regions of the hypothalamus are implicated in the regulation of satiety and feeding behaviour (Oomura et al. 1969;Levin et al. 1999). Thus, ablation of hypothalamic centres such as the ventromedial hypothalamic nucleus (VMH) leads to overeating and obesity (Borg et al. 1994), whereas destruction of the lateral hypothalamic area (LHA) results in hypophagia and weight loss (Leibowitz, 1984). The VMH, along with the arcuate nucleus (ARC), is the major target of the satiety factor and obese (ob) gene product, leptin (Zhang et al. 1994). These hypothalamic centres contain both glucoseresponsive (GR) neurons, which respond to increases in glucose concentration with an increased firing rate, and glucose-sensitive (GS) neurons, whose electrical activity is decreased with increasing concentrations of the sugar (Levin et al. 1999), as well as glucose non-responsive neurons.The mechanisms underlying the regulation of neuronal activity by glucose are presently undefined. The ability of sulphonylureas such as tolbutamide to depolarise VMH and ARC hypothalamic neurons (Ashford et al. 1990;Spanswick et al. 1997), and the expression within the hypothalamus of the islet/liver form of glucokinase (hexokinase IV) (Jetton et al. 1994), have implicated a signalling mechanism for glucose analogous to that believed to operate in pancreatic islet b-cells Rutter, 2001). In the latter case, increases in the free cytosolic ATP concentration ([ATP] c ) (Kennedy et al. 1999), resulting from enhanced mitochondrial metabolism of glucose carbons (Panten et al. 1973), probably leads to the closure of an ATP-sensitive K + (K ATP ) channel. This, in turn, suppresses the efflux of K + ions (Boschero et al. 1988), leading to depolarisation of the plasma membrane (Henquin & Meissner, 1984), and the firing of action potentials.

IgM paraproteins associated with autoimmune peripheral neuropathy and anti-Pr cold agglutinins react with sialic acid epitopes present on disialylated 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 patient, we have cloned a human hybridoma secreting an antidisialosyl IgM mAb, termed Ha1, that shows identical structural and functional characteristics to its serum counterpart. Variable region analysis shows Ha1 is encoded by the same V H 1 family heavy chain gene, V1-18, as the only other known anti-Pr antibody sequence and is somatically mutated, suggesting that is arose in vivo in response to antigenic stimulation. In the rodent peripheral nervous system, Ha1 immunolocalizes to dorsal root ganglia, motor nerve terminals, muscle spindles, myelinated axons, and nodes of Ranvier. After intraperitoneal injection of affinity-purified antibody into mice for 10 d, electrophysiological recordings from the phrenic nerve-hemidiaphragm preparation demonstrated impairment of nerve excitability and a reduction in quantal release of neurotransmitter. These data unequivocally establish that an antidisialosyl antibody can exert pathophysiological effects on the peripheral nervous system and strongly support the view that the antibody contributes to the associated human disease. ( J. Clin. Invest. 1996. 97:1155-1164.)

The authors propose that a plasma factor(s) in SNMG patients, distinct from MuSK IgG antibodies, binds to a muscle membrane receptor and activates a second messenger pathway leading to AChR phosphorylation and reduced AChR function. Identifying the target for this factor should lead to improved diagnosis of MG in MuSK antibody-negative patients and may provide new insights into the function of the neuromuscular junction and pathophysiological mechanisms in MG.

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