Evidence for Cytokine Dysregulation in Multiple Sclerosis: Peripheral Blood Mononuclear Cell Production of Pro-inflammatory and Anti-inflammatory Cytokines During Relapse and Remission

We investigated circulating anti-inflammatory and pro-inflammatory cytokines, and their ex vivo PBMC production in the absence or presence of the neuroantigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) and T cell mitogen (PHA) in MS patients in relapse and remission, patients with other neurological disorders (OND) and normal healthy controls. MS patients in relapse exhibited significantly increased PBMC production of TNF-α spontaneously compared with MS remission and healthy controls and with MBP compared with MS remission. Patients in relapse had significantly increased spontaneous, PHA- and MBP-induced PBMC IL-1β production compared with remission MS, and was increased compared (PHA only) with OND and healthy controls. In relapse there was also significantly increased PBMC IFN-γ production (PHA only) compared with remission and a significantly lower production of biologically active TGF-β1 (PHA only) compared with remission MS and OND. In contrast, MS patients in remission produced significantly less spontaneous and MBP-induced TNF-α, spontaneous, PHA- and MBP-induced IL-1β and PHA-induced IFN-γ together with increased production of biologically active TGF-β1. MOG non-specifically increased PBMC TNF-α and IL-1β production in all groups. Pro-inflammatory cytokines in corresponding plasma samples were undetectable whilst the concentration of biologically active TGF-β1 was the reverse of ex vivo PBMC findings. The increase in biologically active TGF-β1 production ex vivo in OND patients, despite active disease, compared with the low level in the MS relapse may indicate a regulatory defect in MS. We conclude that the balance between biologically active TGF-β1 and the pro-inflammatory TNF-α, IL-1β and IFN-γ is dysregulated during MS relapse-remission and that normal counter-regulatory mechanisms during the relapse phase are defective.