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  • Review Article
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New concepts in the immunopathogenesis of multiple sclerosis

Nature Reviews Neuroscience volume 3, pages 291–301 (2002)Cite this article

Key Points

  • Multiple sclerosis (MS), a demyelinating neurological disorder, has been thought of as an autoimmune disease that involves the response of CD4+ T cells to myelin antigens. However, there is substantial evidence that the disorder is more complex, as other immune cells seem to participate in the pathogenesis of MS.

  • The original concepts about the involvement of CD4+ cells in MS emanated from work on an animal model of the disease — experimental autoimmune encephalomyelitis (EAE). The insights from EAE were tested in MS, and some similarities were observed. In fact, most of the available therapies for MS target CD4+ responses. But the use of new techniques has made it possible to test more stringently the CD4+ model, showing that some of its predictions are not borne out, and providing evidence for the involvement of other immune cells, such as CD8+ cells and B lymphocytes.

  • As the CD4+ model has its limitations, alternative ideas have been put forward to account for the pathogenesis of MS. Among them, the possibility of an immune reaction against a brain pathogen has received some attention. Similarly, the idea that MS is primarily a neurodegenerative disorder that is subsequently accompanied by an immune reaction has been entertained.

  • A model for the pathogenesis of MS argues that cross-reactive antigens, a brain-resident pathogen or brain proteins after primary degeneration are released into the periphery, setting off an immune response that involves the priming of T and B cells. Primed cells will accumulate in the brain where they encounter their target antigens, initiating their effector functions and recruiting inflammatory cells, such as macrophages. In parallel to this immune response, repair mechanisms will be initiated, resulting in remyelination.

  • The development of new therapies for MS will depend on a deeper understanding of its molecular mechanisms. More importantly, the limitations of the CD4+ model compel us to look beyond the idea that MS is strictly an autoimmune disorder, and to pursue the development of treatments that are focused on other pathogenic causes.

Abstract

Multiple sclerosis (MS) is a commonly occurring inflammatory and demyelinating neurological disease. It has been considered to be an autoimmune disorder mediated by CD4+ type 1 T helper cells, but recent studies have challenged this idea by indicating a role for other immune cells. So, T- and B-cell responses in the brain of patients with MS involve the clonal expansion of lymphocytes and the antigen-driven maturation of the B-cell receptors, indicating that the immune response in MS engages a broad range of immune cells that target a limited number of brain antigens. At variance with the classical view, axons are not spared during the inflammatory process. Indeed, axonal damage determines clinical outcome to a large extent. Studies of the mechanisms of axonal damage and neurodegeneration in MS are in their infancy. Here, we summarize recent advances in our understanding of the pathogenesis of MS, and conclude with an outlook on how to capitalize on this knowledge to develop new therapeutic approaches.

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Figure 1: Possible target antigens in the white matter.
Figure 2: Possible mechanisms leading to neuroinflammation.
Figure 3: Immune responses in multiple sclerosis.
Figure 4: Molecular interactions in central nervous system inflammation and repair.

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Acknowledgements

Bernhard Hemmer is a Heisenberg Fellow of the Deutsche Forschungsgemeinschaft (DFG). We thank S. Cepok for comments on the manuscript. The Gemeinnützige Hertiestiftung and the DFG have continuously supported the research of the authors.

Author information

Authors and Affiliations

  1. Department of Neurology, Philipps-Universität, Marburg, 35033, Germany

    Bernhard Hemmer

  2. Department of Neurology, Karl-Franzens-Universität, Graz, A-8036, Austria

    Juan J. Archelos

  3. Department of Neurology, Heinrich-Heine-Universität, Düsseldorf, D-40225, Germany

    Hans-Peter Hartung

Authors
  1. Bernhard Hemmer
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  2. Juan J. Archelos
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  3. Hans-Peter Hartung
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Corresponding author

Correspondence to Hans-Peter Hartung.

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DATABASES

LocusLink

brain-derived neurotrophic factor

CD4

CD8

HLA-DRB1

HLA-DQB1

IFN-β

IFN-γ

IgG1

IgG3

IgM

IL-2

IL-4

IL-5

IL-10

IL-13

insulin-like growth factor

MAG

MBP

MOG

neurotrophin 3

platelet-derived growth factor

PLP

TNF-α

TNF-β

OMIM

multiple sclerosis

subacute sclerosing panencephalitis

FURTHER INFORMATION

Encyclopedia of Life Sciences

microglia

nervous and immune system interactions

neuroimmunology

Glossary

FREUND'S ADJUVANT

An oil emulsion that contains an immunogen, an emulsifying agent and mycobacteria, which enhance the immune response to the immunogen.

ADOPTIVE TRANSFER

An immune response involving the transfer of immunocompetent cells from a primed donor to a non-immune recipient.

CD4+ T CELLS

A subset of T lymphocytes that carry the CD4 receptor and are essential for turning on antibody production, activating cytotoxic T cells and initiating other immune responses.

CYTOKINES

In general terms, cytokines are proteins made by cells that affect the behaviour of other cells. They are produced mainly by the immune system.

TH1 CELLS

A subset of T cells that secrete inflammatory cytokines.

CD8+ T CELLS

A subset of T lymphocytes that carry the CD8 receptor, such as cytotoxic T cells. The CD8 protein is the co-receptor for class I molecules of the major histocompatibility complex.

INNATE IMMUNITY

The early response of a host to infection. One of its main features is the pro-inflammatory response induced by antigen-presenting cells — macrophages, dendritic cells and, in the brain, microglial cells. This response is followed by an adaptive response that is mediated by clonal selection of lymphocytes, which leads to long-term immune protection.

SUBACUTE SCLEROSING PANENCEPHALITIS

A form of encephalitis that develops after the reactivation of a latent measles virus. It is characterized by progressive motor and mental deterioration, accompanied by myoclonus.

HTLV-I-ASSOCIATED MYELOPATHY

Also known as tropical spastic paraparesis, this progressive neurological disorder is associated with the human T lymphotropic virus type I, and is characterized by spasticity and hyperreflexia.

HUMORAL RESPONSE

An immune reaction that can be transferred with immune serum. In general, this term refers to immune resistance that results from the presence of specific antibodies.

EPSTEIN–BARR VIRUS

A herpesvirus that is the main cause of mononucleosis and is associated with several cancers, particularly lymphomas, in immunosuppressed people.

OLIGOCLONAL

Describes cells or members of a clone that share a specific feature.

INTRATHECAL

Within the meninges.

HEAVY CHAIN

All immunoglobulins have two types of chain — heavy (50–70 kDa) and light (25 kDa). The basic immunoglobulin unit consists of two heavy and two light chains.

CLONAL EXPANSION

The proliferation of antigen-specific lymphocytes from a single cell in response to antigenic stimulation. This expansion precedes their differentiation into effector cells.

COMPLEMENT CASCADE

The complement system is a set of plasma proteins that attack extracellular pathogens. The pathogen becomes coated with complement proteins that facilitate pathogen removal by phagocytes. Complement components are also involved in inflammation and tissue destruction.

ANTIGEN-PRESENTING CELLS

Specialized cells that present specific antigens to T cells. Macrophages and dendritic cells are the main antigen-presenting cells, but in the CNS the microglia have this role.

DENDRITIC CELLS

Also known as interdigitating reticular cells because of their branched morphology, dendritic cells are the most potent stimulators of T-cell responses.

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). There are two classes of MHC molecules. MHC class I molecules are present at the surface of most cells and present proteins generated in the cytosol to T lymphocytes. MHC class II molecules are expressed only at the surface of activated antigen-presenting cells, and they present peptides degraded in cellular vesicles to T cells.

FAS

A transmembrane protein that mediates apoptosis and might be involved in the negative selection of autoreactive T cells in the thymus.

EXPRESSION LIBRARY

A gene library that allows the cloning of genes on the basis of the transfection of a large number of cells with cDNA in an expression vector and subsequent screening for a functional property.

PHAGE DISPLAY LIBRARY

A gene library that encodes fusion proteins of a foreign sequence and a coat protein of a phage. When cloned, the phage is said to display the foreign protein.

COMBINATORIAL PEPTIDE LIBRARY

A collection of large numbers of peptides that is a very useful in the fields of drug discovery and structural biology.

MICROARRAY

A device that is used to interrogate complex nucleic acid samples by hybridization. It makes i t possible to count the number of different RNA or cDNA molecules that are present in a sample as a preparative stage for their subsequent characterization.

GLATIRAMER ACETATE

A synthetic protein that simulates myelin basic protein, a component of myelin. Through a mechanism that is not completely understood, this drug seems to block T cells by acting as a myelin decoy. A further mode of action seems to be stimulation of T suppressor cells that travel to the CNS and provide 'bystander suppression'.

CHEMOKINES

Small, secreted proteins that stimulate the motile behaviour of leukocytes.

LOD SCORE

Base 10 'logarithm of the odds', or 'log-odds'. A method of hypothesis testing that is defined as the logarithm of the ratio between likelihoods under the null and alternative hypotheses.

LINKAGE DISEQUILIBRIUM

A condition in which the frequency of a particular haplotype for two loci is significantly greater than that expected from the product of the observed allelic frequencies at each locus.

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Hemmer, B., Archelos, J. & Hartung, HP. New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci 3, 291–301 (2002). https://doi.org/10.1038/nrn784

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