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, nonribosomal 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.