Multiple Sclerosis: Etiological Mechanisms and Future Directions

Abstract

Multiple sclerosis (MS) is a complex human autoimmune-type disease with a predominantly unknown etiology. Immunologic destruction of myelin basic protein (MBP) throughout the nervous system is the major pathology of multiple sclerosis. This review will attempt to update new information about basic mechanisms and therapeutic management of the disease. The significance of the structure of MBP is discussed with respect to the contribution of such structures to the disease process. A number of MBP peptides that serve as the immunodominant antigens in MS patients have been identified. These peptides have been studied in animal models for their antigenic characteristics and ability to induce disease. Evidence for genetic contributions is reviewed with multigenerational twin studies providing the best evidence for susceptible haplotypes. The role of microorganisms/viruses and environmental agents are discussed as potential etiological factors but are now thought to be of minor importance to the primary causal development of the disease. Of major consideration are immunological mechanisms that contribute to the development of autoimmunity. In particular, antigen expression, cytokine and leukocyte interactions, and regulatory T-cells are discussed. Particular attention is given to regulatory T-cells (Treg), which help balance/modulate other T-cells such as Th1 and Th2 cells, and how such Treg regulate autoimmunity is addressed. The importance of the role of Tregs is exemplified by the demonstration that administration of oral antigens can induce specific Tregs that counteract experimental autoimmune encephalomyelitis in animal models. The significance of animal studies to human multiple sclerosis is discussed. A potential role for natural antibodies and innate immune mechanisms to help provide resistance to disease development is also reviewed. Finally, a variety of therapeutic agents that have been and continue to be utilized for multiple sclerosis is reviewed. Trials with oral antigens, such as glatirmer acetate (copolymer 1) especially in combination with interferon-beta, have shown promise. Antibody therapy and bone marrow transplantation are also briefly discussed.

G protein-coupled receptors as therapeutic targets for multiple sclerosis

“…They experience remission of MS and have fewer relapses during their pregnancy. However, these women exhibit a marked increase in relapse rate 3 months after delivery, when endogenous opioid levels are decreased [142,143]. These findings suggest that one or more of the elevated opioids are acting with relevant receptors to attenuate the pathogenesis of MS.…”

Peptidylarginine deiminase 2 (PAD2) overexpression in transgenic mice leads to myelin loss in the central nervous system

“…Although the cause of MS still remains elusive, the available evidence suggests a complex multi-factorial (genetic, immune and environmental) etiology (Lutton et al, 2004). The triggers that lead to the development of lesions in the 'normalappearing white matter' (NAWM) have been hypothesized by us to provide some new pathogenic clues Moscarello et al, 2007).…”

Epidural blood patch in a patient with multiple sclerosis: is it safe?

“…This causes action potentials to travel at reduced velocity, and conduction may become partially or completely blocked. [1][2][3] It is well established that conduction of action potentials in healthy axons can be blocked by pressure, and the threshold for this effect is inversely related to the duration of applied pressure. In in vivo and in vitro animal studies, propagation of evoked compound action potentials may be blocked by pressures as low as 30 mmHg when applied for hours, and much more rapid block is observed with pressures exceeding 200 mmHg.…”

“…[1][2][3] Cerebral spinal fluid samples obtained by lumbar puncture may be performed to help support the diagnosis of MS. 4 A well-described complication of lumbar puncture is the postdural puncture headache (PDPH), but the classic treatment of this complication -epidural blood patch (EBP) -may be of theoretical concern in this unique type of patient. There is extensive literature showing that pressure can interfere with axonal conduction of nervous impulses, [5][6][7][8] and it is unknown whether affected axons of the MS patient are particularly vulnerable to the increase in epidural pressure that can occur as a consequence of the blood patch.…”