How does one attempt to find immunomodulatory proteins that are important in the autoimmune disease multiple sclerosis (MS)? In the past, investigators often proceeded from one candidate to the next and progress was slow. Now, microarray analysis, which allows investigators to examine thousands of genes at a time, has been applied to studies of MS and a striking result has been obtained. Chabas et al. [1xThe influence of the pro-inflammatory cytokine osteopontin on autoimmune demyelinating disease. Chabas, D et al. Science. 2001; 294: 1731–1735Crossref | PubMed | Scopus (632)See all References][1] have found that the proinflammatory cytokine osteopontin might play an important role in the development of progressive MS.MS is the most common neurodegenerative disease, with a global incidence of 0.1%. It is particularly prevalent in the Northern hemisphere and there is evidence of an infectious environmental etiology, although its nature is not at all clear. MS is characterized by relapsing episodes of neurological impairment, followed by remissions. In approximately one-third of patients, the disease evolves to follow a progressive course. Current treatment involves anti-inflammatory steroids and, more recently, interferon β (IFN-β). This was first used as an anti-viral agent (given the possibility of viral involvement) and then found to decrease the number of attacks and limit brain damage as assessed by magnetic-resonance imaging. However, the effects of IFN-β are only partial and not understood, and there is a pressing need for better therapies.The aim of the present study was to search for proteins that might play a role in the pathogenesis of MS. The study began with an analysis of the expression of 517 genes in the brains of rats with experimental autoimmune encephalomyelitis (EAE), a well-studied animal model of MS. Customized oligonucleotide microarrays containing these genes were used for screening, revealing that the level of transcripts for osteopontin was elevated. In parallel, high-throughput sequencing of cDNAs from MS brain lesions and control brains was carried out. This revealed that several genes are expressed highly in the MS brain, with the gene encoding osteopontin being the most prominent cytokine-encoding gene. This finding was of interest because osteopontin is a proinflammatory cytokine that promotes the activation of T helper 1 (Th1) cells by inducing the expression of cytokines, such as interleukin-12 and IFN-γ. The authors then probed MS tissues immunohistochemically for the expression of osteopontin, and again found its level to be elevated. Next, the role of osteopontin in EAE was examined using osteopontin-knockout mice. Disease severity in these mice was reduced significantly and in particular, the progression of disease was influenced, such that remission from disease was much more evident in the knockout mice. Finally, Th2 responses were much more pronounced in T cells from the osteopontin-knockout mice compared with wild-type mice with EAE.Because of the role played by osteopontin in inflammation and Th1 responses, the authors speculate that it could be important for the pathogenesis of demyelinating disease. In particular, the secretion of osteopontin by neurons might modulate inflammation and demyelination, and thereby influence the clinical severity of disease. Therefore, inhibiting the actions of osteopontin might be useful for the treatment of progressive MS.