Interferon Beta-1a Modulates the Innate Immune-response-mediated Regulation of Adaptive Immunity in Early Multiple Sclerosis (131.15)

Abstract

Abstract We performed Affymetrix gene arrays (HU133, ~38,500 genes) using RNA from the in vitro activated PBMCs from patients with clinically isolated syndrome suggestive of multiple sclerosis (CIS) (n=15) and matched healthy controls (HC) (n=8). Results were confirmed and further supported by RT-PCR and RayBio Cytokine Arrays. Affymetrix data revealed that IFNB-1a induced significant (p<0.05) up-regulation of 711, and down-regulation of 587 genes in CIS patients, and 446 and 543 in HC, respectively. CXCL11 and CXCL10, the ligands of CXCR3 were significantly increased in CIS patients and HC, whereas proinflammatory chemokines CXCL2, CXCL3 and CXCL5 were decreased in CIS patients. CCL18 and CCL19 were increased in CIS, while CCL22 and CCL17 were decreased in CIS and HC. Those chemokine gene changes reflect the complex effects of IFNB-1a that likely affect differentiation/ maturation and chemotaxis of DCs and other cells bridging the innate and adaptive immune response. The anti-inflammatory cytokine IL-10 was increased in CIS, consistent with the previous findings in multiple sclerosis, while IL1A, IL1R1 and IL-16 were decreased in CIS and HC. IL-1 is an acute inflammatory phase cytokine whose inhibition may decrease differentiation of IL-17 secreting T-cells that is critical in the development of autoimmune response. SOCS7 and SCOS5 were decreased in CIS and HC that may result in impaired Th1 responses. TLR7 and its signal adapter MYD88 were increased in CIS and HC. IRAK4 and TRAF6, the components of MYD88-dependent pathway were also increased in CIS. IRF2 and IRF7 that may be involved in MYD88-independent TLR signaling pathway were increased in CIS and HC. Such effects on TLRs signaling pathways may inhibit DCs maturation and alter the innate immune response mediated regulation of adaptive immunity.