Antibody-driven psychosis

Psychotic episodes in lupus patients can be triggered by an antibody attack on brain cells, according to Matus et al. (page 3221). The psychosis that occurs in a small subset of lupus patients is associated with an antibody that recognizes a trio of ribosomal phosphoproteins. It was assumed that this antibody binds to the cell surface version of one of the phosphoproteins and somehow penetrates cells to cause damage. But how the interaction between the antibody and its targets leads to a breakdown in neuronal function was a mystery. Matus et al. now find that the antibody also recognizes a novel, nonribo-somal protein on the surface of neurons. In rat brains, this protein was concentrated in regions that control cognition and emotion—the functions that go awry during lupus-related psychosis. Treating cultured neurons with the antibody or injecting it directly into rat brains caused increased intracellular calcium levels, thereby causing neuronal death. The kind of ion channel opened by antibody binding and the mechanism involved is still unknown. The team also found these antibodies in lupus patients who showed no signs of psychosis. Antibodies that attack neurons can only cause damage if they are allowed to sneak through a breach in the blood–brain barrier. The authors therefore suspect that only patients who for some reason have such a breach experience the psychosis. The function of the neuronal surface protein is unknown. Its associations with clathrin and protein domains that are characteristic of ubiquitin ligases suggest that this protein may regulate the trafficking and degradation of surface receptors in neurons. HB Antibodies, hold the light chain Antibodies don't always need light chains to function, according to Zou et al. (page 3271). In mammalian antibodies, two heavy chains link together to form a Y-shaped complex, with each arm of the Y linked to a light chain. In mice and humans, lone heavy chains are usually prevented from being secreted by a chaperone that associates with the heavy chain's constant region—the same region that links to the light chain. But the new report shows that an unusual set of fully functional heavy chain–only antibodies do get secreted. The anomalous antibodies escaped to the cell surface because they lacked the chaperone-binding region. The secretion of these antibodies was discovered in mutant mice that lack light chain genes, but the authors also found that smaller amounts were produced in the spleen of normal mice, probably as …