Immune-Inflammatory and Metabolic Processes in Multiple Sclerosis

Cytokines are proteins that participate in intercellular communications that regulate the immune and inflammatory systems. A complex cytokine network is involved in normal immune function, and this network is comprised of positive and negative feedback loops that enhance or suppress a response. Many immune-mediated diseases, e.g., rheumatoid arthritis (RA) and multiple sclerosis (MS), involve dysregulated inflammatory molecules such as the cytokines. This can be manifested either by defective production of suppressive factors or by overproduction of  pro-inflammatory factors such as the major pro-inflammatory cytokines.

In MS patients there is a much higher number of brain-(neuro)-antigen, e.g., myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG), auto-reactive T-cells which are in an increased state of activation compared with healthy controls, and which increase during exacerbation (relapse). Cytokines from these activated T cells (and macrophages) have been strongly implicated in the pathogenesis of MS. For example, the up-regulation of adhesion molecules on endothelial cells and the subsequent infiltration of activated T cells into the CNS are immunopathogenic events controlled by pro-inflammatory cytokines such as tumour necrosis factor-ɑ (TNF-ɑ), interleukin-1β (IL-1β) and interferon-ɣ (IFN-ɣ).

Furthermore, studies have shown that these cytokines exert direct myelinotoxicity properties and prolong the disease process in experimental animal models of MS (experimental autoimmune encephalomyelitis). TNF-ɑ, IL-1β and IFN-ɣ have all been shown to be present in CNS active lesions in MS and elevated concentrations of these cytokines are secreted from MS peripheral blood mononuclear cells (PBMC). Many studies have also shown that an increase in these inflammatory cytokines coincides with the clinical relapse phase of the disease. Furthermore, some studies have shown that transforming growth factor-beta1 (TGF-β1), a potent anti-inflammatory and immunosuppressive cytokine, is reduced during the MS relapse phase and increases as the patient enters remission.

The balance between biologically active TGF-β1 and pro-inflammatory TNF-ɑ, IL-1β, IFN-ɣ is therefore dysregulated during MS relapse-remission (Fig 1). The actual processes of axonal damage e.g. chronic inflammation, demyelination and astrogliosis in MS is complex but white matter inflammation and demyelination are considered by scientists and clinicians to determine disease severity.

In addition, some studies suggest that axonal damage in MS begins in the early stages of the disease and contributes to disability. Furthermore, some scientists have also considered metabolic disturbances, in some MS patients, to be behind the primary oligodendrocyte damage with immune-inflammatory processes having a secondary but important involvement in the pathogenesis of MS.

Fig 1. Immune-inflammatory Mechanisms in Multiple Sclerosis