Molecular mechanisms and timing of cortical immune activation in schizophrenia.

Abstract

The role of the immune system in psychiatric disorders has been garnering increased attention (1). In the absence of established classic immune-mediated neuropathology such as that seen in autoimmune or infectious disorders, the interpretations of these findings have evoked considerable controversy and debate. Previously, members of the Lewis teamattheUniversityofPittsburghreportedimmunesystem activation including higher mRNA levels of interferoninduced transmembrane protein (IFITM) in the dorsolateral prefrontal cortex from schizophrenia cases (2). In their follow-up studyin thisissue,Volketal.(3) explore a basis for this increased gene expression and seek to evaluate whether a prenatal immune-related insult, as opposed to a postnatal exposure to infectious agents, causes the observed immune gene expression increase in the prefrontal cortex of adults diagnosed with schizophrenia. The authors identify several genes that are significantly overexpressed in dorsolateral prefrontal cortex gray matter ofschizophreniasubjectsincomparisontomatchedcontrols. Specifically, they report significant increases in mRNA levels for interleukin-6 (IL-6) and interferon-b, both of which induce the expression of IFITM. Interestingly, Schnurri-2 mRNA is significantly lowered, which decreases IFITM levels by inhibiting NF-kB, a well-known transcription regulator of the immune gene network. The authors’ findings collectively amount to a significant increase in IFITM in dorsolateral prefrontal cortex gray matter of subjects diagnosed with schizophrenia. Of note, it is well known that IFITM and other immune genes reported here constitute an immune response to a host of viral infections, including influenza A, dengue, and West Nile virus (4). This raises questions as to the clinical, etiological, and/or functional relevance of IFITM expression in schizophrenia. The increasedexpressionofinterferon-bandNF-kBmakesmatters more complicated, since these are master regulators of many genes. One of the basic functions of components of the immune system is to protect the host against pathogens. However, they may also play a separate role distinct from immunologicalresponses.Ofparticularinterestisareporton