Neuroinflammation in multiple sclerosis: Evidence for autoimmune dysregulation, not simple autoimmune reaction
Introduction
MS is a demyelinating autoimmune disease characterized by inflammation in the central nervous system (CNS) leading to damage of the myelin sheath. The myelin sheath consists of complexes containing lipids and proteins such as myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG). Autoantibodies and autoreactive T cells against these myelin antigens have been detected in MS patients [1]. The same myelin antigens have also been used to induce experimental allergic encephalomyelitis (EAE); studies of EAE, the animal model of MS, indicate that cytokines, chemokines and adhesion molecules lead to the recruitment of leukocytes from the periphery to the CNS via a disrupted blood–brain barrier, thereby creating the appropriate inflammatory environment. The inflammatory process will eventually result in myelin as well as axonal damage and consequently in variable loss of functions [2], [3]. Currently utilized immunomodulating agents in the treatment of MS, although only partially effective in terms of the clinical evolution of the disease, may exert some control over the underlying immunopathology [4].
Section snippets
Immunopathogenesis
Despite our increasing knowledge of the details of the immunological cascade of MS immunopathogenesis, it remains very complex [5], [6]. A very basic concept is that MS is a CD4+ T-helper 1 (Th1)-mediated autoimmune disease [7]. CD4 T cells may differentiate into Th1 and Th2 cells characterized by the production of different cytokines. Th1 cells produce pro-inflammatory cytokines such as IFNγ, TNFa, interleukin-2 (IL-2) and low levels of interleukin-10 (IL-10), whereas Th2 cells produce
The role of regulatory cells
To simply consider Th1 versus Th2 as the basis for the immunopathogenesis of MS is an oversimplification of the concept of induction versus protection. The balance between Th1 or Th2 activity has been shown to be important for the control and resolution of infectious disorders, but it is also involved in the autoimmune process [9]. Although EAE can be passively transferred by injecting Th1 cells from an EAE-induced animal into a naive host, the same cannot be done by transferring Th2 cells, a
The CD4+CD25+ regulatory T cells
Autoimmune diseases such as MS may result from the failure of tolerance mechanisms that prevent the expansion of pathogenic T cells. This assumption arises from the observation that activated T cells may be detected in healthy individuals. Tr cells play a major role in these tolerance mechanisms; the importance of their role is exemplified by the demonstration that administration of oral antigens can induce specific Tr cells that counteract EAE. Two major Tr populations have been described so
A key factor in the function of Tr cells: the transcriptional regulator Foxp3
The discovery of the importance of both the transcriptional regulator Foxp3 in mouse CD4 CD25 T regulatory cell function [34], [35] and of the previous observations that patients with IPEX (immune dysregulation, polyendocrinopathy, enteropathy and X-linked inheritance), a severe inflammatory disease similar to that seen in mice deficient in CD4+ CD25+ Tr cells, have mutations in Foxp3 [36], provided a direct correlation between an autoimmune animal model, mouse Tr cells and a human autoimmune
Acknowledgment
This work is part of a project supported by a Serono Hellas research grant.
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