Impaired expression of peripheral blood apoptotic-related gene transcripts in acute multiple sclerosis relapse

Anat Achiron, Anna Feldman, Mathilda Mandel, Michael Gurevich

Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

Abstract

Differential expression of apoptotic genes may influence the susceptibility of activated lymphocytes to expand and induce acute relapse and persistent inflammation in patients with relapsing-remitting multiple sclerosis (RRMS). The exact relationship between alterations in apoptotic-related gene expression and clinical disease activity has not been broadly evaluated. In this study we studied peripheral blood mononuclear cells (PBMCs) expression of pro- and antiapoptotic genes in RRMS patients during acute relapse in comparison to patients in remission. Using cDNA Affymetrix microarrays platform (U133A2 microarrays) we analyzed the gene expression profile of PBMC derived from 22 RRMS patients in acute relapse (15 females, mean age 34.6 ± 1.8 years, disease duration 5.6 ± 0.8 years) in comparison to 20 sex- and age-matched RRMS patients in remission. One thousand five hundred seventy-eight gene transcripts significantly differentiated acute multiple sclerosis (MS) relapse from remission. This characteristic gene expression signature was enriched by an apoptotic-related pathway. The 1578 gene transcripts that significantly differentiated acute relapse from remission were enriched by 55 apoptotic-related genes in that reflected different operating pathways during the acute phase of the disease. These genes mainly involved the caspase-dependent pathway and included overexpression of the negative regulator of FAS-induced apoptosis (TOSO) and the BCL2 antiapoptotic family members (BCL2, BCL2 AA) as well as downexpression of proapoptotic genes like BAX, apoptotic protease-activating factor 1 (APAF1) and caspases 1, 2, 8, 9. and 10. An additional group of antiapoptotic genes related to T cell receptor-mediated apoptosis was also found to be overexpressed in acute relapse and included TCR-binding CD3E antigen, antiapoptotic serine threonin kinase (AKT), and NFκB-associated genes like reticuloendotheliosis viral oncogene homologA(RELA) and human T cell leukemia virus type I-binding protein (Tax1BP) known to inhibit tumor necrosis factor (TNF)-induced apoptosis. Our findings demonstrate impaired apoptotic mechanisms in peripheral lymphocytes from RRMS patients during acute relapse. This suggests that the inflammatory process in active disease is targeted by inhibition of proapoptotic and repression of antiapoptotic genes that allow prolonged abnormal immune responses.

Original languageEnglish
Title of host publicationAutoimmunity, Part C The Mosaic of Autoimmunity
PublisherBlackwell Publishing Inc.
Pages155-167
Number of pages13
ISBN (Print)1573316628, 9781573316620
DOIs
StatePublished - Jun 2007

Publication series

NameAnnals of the New York Academy of Sciences
Volume1107
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Acute relapse
  • Apoptosis
  • Gene expression
  • Multiple sclerosis

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