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Multiple sclerosis
David A. Hafler
David A. Hafler
Published March 15, 2004
Citation Information: J Clin Invest. 2004;113(6):788-794. https://doi.org/10.1172/JCI21357.
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Science in Medicine Article has an altmetric score of 23

Multiple sclerosis

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Abstract

Multiple sclerosis is a complex genetic disease associated with inflammation in the CNS white matter thought to be mediated by autoreactive T cells. Clonal expansion of B cells, their antibody products, and T cells, hallmarks of inflammation in the CNS, are found in MS. This review discusses new methods to define the molecular pathology of human disease with high-throughput examination of germline DNA haplotypes, RNA expression, and protein structures that will allow the generation of a new series of hypotheses that can be tested to develop better understanding of and therapies for this disease.

Authors

David A. Hafler

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Figure 1

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Working hypothesis as to the cause of MS. (I) In a genetically susceptib...
Working hypothesis as to the cause of MS. (I) In a genetically susceptible host, common microbes both activate the APCs through toll receptors and contain protein sequences cross-reactive with self myelin antigens. This leads to what can be defined as the minimal requirement for inducing an autoimmune, inflammatory CNS disease in mammals. (II) Underlying immunoregulatory defects, such as decreases of regulatory T cells in the circulation of patients with MS, allow the further pathologic activation of autoreactive T cells (96). (III) Activated myelin-reactive T cells migrate into the CNS and recognize antigen presented by microglia, local APCs. Th1 cytokines are secreted and an inflammatory cascade is initiated. (IV) Regulation of autoimmune responses. Naturally occurring mechanisms may exist to regulate autoimmune responses including the induction of autoreactive Th2 (IL-4, IL-5, IL-13), Th3 (TGF-β), or Tr1 (IL-10) cytokine–secreting T cells that migrate to the CNS and downregulate (red arrow) inflammatory Th1 autoreactive T cells (green arrow). Therapies may attempt to induce Th2 (Copaxone, altered peptide ligands), Th3 (mucosal antigen), or Tr1 (β-IFNs, steroids). ThP, precursor T cell.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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