Abstract Details

Title FcyRIIB Signaling Balances Natalizumab Induced Transcriptional Activation of B-Cells in Multiple Sclerosis

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 162

Objective

Background BACKGROUND: Natalizumab, a selective alpha-4-integrin inhibitor, is an approved RRMS treatment leading to significant reduction of brain inflammation. However, Natalizumab induced blood transcriptional changes and their functional role in MS are not fully understood.

Design/Methods DESIGN/METHODS: Blood samples were obtained from 20 JCV-negative RRMS patients, age 36.7±2.7 years, 16 females, EDSS 3.8±0.4, disease duration 12.2±1.8 years, at baseline and after 1 year of Natalizumab treatment and subjected for gene-expression analysis using HG-U133A-2 arrays (Affymetrix). Data was analyzed using Partek software. The most informative genes (MIGs) with p<0.01 by paired T-test after False Discovery Rate correction were applied for functional analysis by Ingenuity software.

Results RESULTS: One year Natalizumab treatment induced transcriptional changes of 406 MIGs, 265 over-expressed and 141 down-expressed. This signature was characterized by enrichment of over-expressed genes associated with variable mechanisms of B cells activation. The most significant B-cell related pathways were PI3K signaling in B-lymphocytes (p=5.2*10-9), B-cell development (p=3.2*10-8), B-cell receptor signaling (4.2*10-6) including over-expression of BCR, CD79A(B), CD19, BLK and IL7 genes and their transcription factors OU2AF1, PAX5 and SPI1. This B-cells activation was balanced by over-expression of FcyRIIB, BLNK and Ras genes related to activation of FcyRIIB signaling in B-cells (1.1*10-3). Co-aggregation of FcgRIIB with BCR is known to inhibit B-cells receptor signaling, block B-cells activation, proliferation and antibody production. These findings can be explained by relatively higher expression of integrin molecules on B-cells than on other PBMC components.

Conclusions CONCLUSIONS: Natalizumab treatment in RRMS induces B-cells transcription activation that is negatively regulated by activation of FcyRIIB inhibitory mechanism.

Authors/Disclosures
Michael Gurevich (Sheba Medical Center) PRESENTER	No disclosure on file
Alexander U. Brandt, MD (Charite - Universitatsmedizin Berlin)	No disclosure on file
	No disclosure on file
	No disclosure on file
Erez Hanael	No disclosure on file
	No disclosure on file
Anat Achiron, MD, PhD, FAAN (Sheba Medical Center, Tel-Hashomer)	Dr. Achiron has nothing to disclose.

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