Genetic dissection of anxiety in autoimmune disease
(2003)
Journal - Human Molecular Genetics
Abstract :
Systemic lupus erythematosus (SLE), a complex multigenic disease,is characterized by hypergammaglobulinemia, autoantibody productionand immune complex-type lupus nephritis. In addition to thesesigns and symptoms in SLE, there can be symptoms of neurologicaldisorders, including anxiety. To clarify mechanisms governingthe anxiety seen in lupus, we carried out genome-wide scans,and found that the region including interferon- (IFN-) on NZBchromosome 4 is significantly linked to the anxiety-like behaviorseen in SLE-prone New Zealand Black (NZB)xNew Zealand White(NZW) F1 (B/W F1) mice. This finding was confirmed by anxiety-likeperformances of mice with heterozygous NZB/NZW alleles in thesusceptibility region onto the NZW background. In B/W F1 mice,neuronal IFN- levels were elevated, and blockade of the µ1opioid receptor or corticotropin-releasing hormone receptor1, possible downstream effectors for IFN- in the brain partiallyovercame the anxiety-like behavior seen in the B/W F1 mice.Consistently, neuronal corticotropin-releasing hormone levelswere higher in B/W F1 than NZW mice. Furthermore, pretreatmentof µ1 opioid receptor antagonist abolished anxiety-likebehaviour seen in IFN--treated NZW mice. Anxiety is shown tobe mediated by multiple mediators. Our data suggest that a geneticallydetermined endogenous excess amount of IFN- in the brain mayform one aspect of anxiety-like behavior seen in SLE-prone mice.* To whom correspondence should be addressed at: Second Departmentof Pathology, Juntendo University School of Medicine, 2-1-1,Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Tel: +81 358021039;Fax: +81 338133164; Email: sacchi{at}med.juntendo.ac.jp Emeritus Professor.