Hypothesis: Multiple Sclerosis is a Type I Interferon Deficiency Syndrome

Abstract

Multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system (CNS), is in part an immune mediated disease (1). MS is clinically associated with periods of disability (relapse) alternating with periods of recovery (remission) but often leading to progressive neurological disability (2). White matter lesions in the CNS are associated with mononuclear infiltrates that consist primarily of T cells and macrophages and resemble the lesion produced by T-lymphocyte delayed type hypersensitivity (DTH) (2–3). Alternatively, T-cell infiltration may not be the “initial hit” but T cells may be recruited secondarily by the release of chemokines from activated macrophages (4). Activated immune cells in the CNS lead to inflammation and eventually demyelination. MS has been associated with abnormalities of immunoregulation (5).

We propose a unifying hypothesis of the etiopathogenesis of MS that mirrors the relapsing-remitting character of clinical MS and defines MS as a type I interferon (IFN) immunodeficiency syndrome. At the core of our unifying theory is the interaction between the two major components of the immune system, the older innate and the newer acquired immune systems. Foreign nucleic acids, cells, and bacteria cause type I IFN secretion by the innate immune system and act as the initial nonspecific antiviral, antibacterial, and antiproliferative defense system. Type I IFN secretion activates antigen-presenting cells, allowing the transition into antigen-specific humoral and cell-mediated immunity. However the products of the innate immune system, type I IFNs, can also function as immunomodulators to balance the effects of the acquired immune system. We hypothesize that under normal circumstances there is a dynamic interaction between the innate immune system that initially generates antiforeign and secondarily immunomodulating cytokines, including IFN-α/β (type I IFNs), and the acquired immune system that generates pro-inflammatory IFN-γ (type II IFN), resulting in a physiological downmodulation of the total immune response. In MS and possibly in other autoimmune diseases, there may be a deficiency of immunomodulation of the innate immune system.