Autoimmune Versus Oligodendrogliopathy: The Pathogenesis of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system (CNS); it affect millions of patients worldwide and the number of patients is on the rise. Current treatment options are fairly limited and there is a strong unmet need for disease-targeted therapies for MS. The most widely accepted hypothesis for the pathogenesis of MS is that it is a primary autoimmune disease in which myelin-specific T cells play a central role in the progression of demyelination. According to this hypothesis, a powerful immune suppression or a reconstruction of the immune system to abrogate disease-specific leukocytes early in the development of the disease is expected to halt or even reverse the disease, since remyelination is an exceptionally efficient regenerative process in the CNS. However, recent neuropathological studies have provided evidence of primary oligodendrogliopathy as a cause of demyelination, suggesting that immune reactions may be a mere secondary event in the course of MS. On the other hand, some recent clinical trial results of new immune-suppressive treatments showed a nearly complete blockade of relapses and significant, albeit incomplete, neurological improvement. Therefore, which hypothesis--autoimmunity or oligodendrogliopathy--lights the correct path to a "cure" for MS?

MicroRNAs: Novel Regulators of Oligodendrocyte Differentiation and Potential Therapeutic Targets in Demyelination-Related Diseases

“…MS is the most frequent chronic inflammatory demyelinating disease of the CNS. Oligodendrogliopathy is the primary event in MS pathogenesis and immune reactions are merely secondary phenomena [51]. Both OL recruitment and maturation defects are major causes of poor remyelination and axonal injury in MS. A differentiation block in oligodendroglial progenitors is a major determinant of remyelination failure in chronic MS lesions [52].…”

Redundancy between Cysteine Cathepsins in Murine Experimental Autoimmune Encephalomyelitis

“…The initial infiltration precedes widespread activation of macrophages and microglia in and around the CNS, in parallel with continued and extensive immune infiltration of autoreactive lymphocytes and macrophages [21–23]. Experimental autoimmune encephalomyelitis (EAE) is the most commonly-used animal model for examining the immune processes associated with MS [22]. In C57BL/6 mice, EAE is a CD4+ T cell driven autoimmune disease in response to peripheral inoculation with myelin oligodendrocyte glycoprotein (MOG) protein or peptide [24].…”

Oligodendrocyte death results in immune-mediated CNS demyelination

“…In most patients, MS initiates as a relapsing-remitting neurological disorder that over time advances to a chronic progressive disease characterized by the accumulation of neurological deficits. Although MS has long been considered an inflammatory neurodegenerative disease, its etiology is not well understood 2 . The principal ‘outside-in’ hypothesis for MS pathogenesis centers on the idea that primary dysregulation of the immune system leads to autoreactivity against myelin-sheath components 3,4 , which secondarily leads to breakdown of the blood–brain barrier.…”