Transcriptomics

Dataset Information

34

Sema4A, a novel serum marker of multiple sclerosis, implicates Th17 pathology and efficacy of interferon-β.


ABSTRACT: Background: Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system and the leading cause of lasting neurological disabilities in young adults. Increasing evidence suggests that early treatment prevents the development of disability. However, there have been no reliable serum markers to assist the early diagnosis. In addition, interferon (IFN)-β, which is the major treatment for MS, is not always effective. Therefore, the development of simple serological test to help the early diagnosis and predict responsiveness to IFN-β is of clinical importance. On the other hand, a transmembrane-type semaphorin, Sema4A, has been implicated in experimental autoimmune encephalomyelitis (EAE) by regulating helper T (Th) cell differentiation. Thus, we aimed to identify the implications of Sema4A in diagnosis and pathogenesis of MS. Methods: We assayed serum Sema4A in 59 patients with relapsing-remitting MS (RRMS), 22 patients with clinically isolated syndrome (CIS) and 126 patients with other neurological diseases (OND) by developing a sandwich ELISA. To identify a source of soluble Sema4A and characteristics of MS patients with high levels of Sema4A, we analyzed peripheral blood mononuclear cells (PBMCs) from MS patients and healthy controls by flow cytometry (FACS) and gene chip analysis. The effect of Sema4A was examined in vitro and in vivo using an EAE model. Findings: Sema4A was significantly increased in sera of patients with MS and CIS compared to controls. Sema4A expression was increased on the surface of DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner, affecting the Th17skewing. In addition, patients with high Sema4A levels exhibited more severe disabilities, and IFN-β treatment was not beneficial to those patients. Interpretation: Measuring Sema4A is a practical laboratory test to help diagnose MS and to predict responsiveness to IFN-β therapy. Microarray analysis showed that metalloproteinases such as ADAM 10 and MMPs 1, 3, 9, 12 and 25, which are reported to be involved in the pathogenesis of MS, were increased in PBMCs from MS patients with high Sema4A levels compared to those with low Sema4A and healthy controls. However, ADAM 17 and MMP 2 and 7 did not correlate with Sema4A levels. Taken together, these findings strongly suggest that Sema4A, abundantly expressed on monocytes and DCs in MS patients, is enzymatically cleaved and shed in a portion of the patients, which contributes to the high soluble Sema4A detected by the ELISA. Multiple sclerosis patients were classified according to Serum Sema4A levels. RNA from peripheral blood from 4 healthy controls, 3 MS patients with high serum Sema4A levels and 3 MS patients with low serum Sema4A levels was extracted and hybridized on Affymetrix microarrays. We sought to see whether there is corrlated genes with serum Sema4A levels or not, especially for genes for varions proteases.

ORGANISM(S): Homo sapiens  

SUBMITTER: Satoshi Nojima  Ayako Uto-Konomi   Tetsuya Kimura   Akiko Matsui   Misa Nakano   Tomoyuki Sugimoto   Yukinobu Nakagawa   Saburo Sakoda   Hyota Takamatsu   Masato Kubo   Yuji Nakatsuji   Atsushi Kumanogoh   Tatsusada Okuno   Makoto Kinoshita   Masayuki Moriya   Toshihiko Toyofuku   Sinobu Suzuki   Akiko Matsui-Hasumi   Kazushiro Takata   Sujin Kang    

PROVIDER: E-GEOD-26484 | ArrayExpress | 2011-06-13

SECONDARY ACCESSION(S): GSE26484PRJNA136511

REPOSITORIES: GEO, ArrayExpress

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