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  • Review Article
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A molecular trio in relapse and remission in multiple sclerosis

Nature Reviews Immunology volume 9, pages 440–447 (2009)Cite this article

Key Points

  • Three molecules have a key role in the remissions and relapses seen in around two thirds of patients with multiple sclerosis — α4β1 integrin, osteopontin and αB crystallin.

  • The key integrin in lymphocyte homing to the brain in multiple sclerosis is α4β1 integrin. Blockade of this integrin with a humanized monoclonal antibody, natalizumab, reduces the relapse rate by two thirds. It is the most potent approved drug for the treatment of multiple sclerosis.

  • Osteopontin is a binding partner of α4β1 integrin. It is a pro-survival molecule and inhibits apoptosis through its actions on the transcription factors forkhead box O3A (FOXO3A) and nuclear factor-κB (NF-κB).

  • Administration of osteopontin into mice with experimental autoimmune encephalomyelitis (EAE) triggers relapse of the disease. The relapses are a result of the inhibition of apoptosis and the increased production of T helper 1 (TH1)- and TH17-type cytokines from autoreactive T cells.

  • Remission in multiple sclerosis is driven by a small heat shock protein, αB crystallin. αB crystallin decreases the production of TH1- and TH17-type cytokines from autoreactive T cells.

  • Infusion of αB crystallin in animal models of multiple sclerosis resolves progressive disease and terminates relapse.

  • αB crystallin is produced in copious amounts at the sites of inflammation in the brains of patients with multiple sclerosis.

Abstract

Two thirds of patients with multiple sclerosis have the relapsing-remitting form, which often progresses to more debilitating disease. Striking clinical recovery, termed remission, often follows these periodic neurological defects, termed relapses. Recent work has revealed the role of three key molecules in relapse and remission: α4β1 integrin (also known as VLA4) is an adhesion molecule that mediates T cell migration from the blood into the brain; osteopontin binds to α4β1 integrin, stimulating the production of pro-inflammatory cytokines and inhibiting apoptosis; and αB crystallin inhibits inflammation in the brain. This Review discusses how this molecular trio interacts to initiate relapses (in the case of osteopontin and α4β1 integrin) and then to terminate them as remissions in multiple sclerosis (in the case of αB crystallin).

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Figure 1: Pathogenesis of multiple sclerosis.
Figure 2: Induction of relapses by osteopontin.
Figure 3: Mechanism of remission induced by αB crystallin.

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Acknowledgements

L. Steinman acknowledges the fruitful collaboration with D.T. Denhardt over the past decade.

Author information

Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Interdepartmental Program in Immunology, Beckman Center for Molecular Medicine, Stanford University School of Medicine, Stanford, 94305, California, USA

    Lawrence Steinman

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Correspondence to Lawrence Steinman.

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Competing interests

L. Steinman has patent applications and issued patents on therapeutic uses of osteopontin and αB crystallin. He consults for Bayhill Therapeutics and Cardinal, which own interests in these patents. L. Steinman founded both companies and serves on their board of directors.

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FURTHER INFORMATION

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Glossary

Gadolinium-enhanced lesion

A lesion that is visualized with magnetic resonance imaging and that is enhanced with the element gadolinium, which has a magnetic spin. These lesions correlate with areas of inflammation in the brains of patients with multiple sclerosis.

Perivascular cuff

An area surrounding an inflamed blood vessel, containing inflammatory lymphocytes, and delimited by endothelium on one side and basement membrane on the other side.

Myelin oligodendrocyte glycoprotein

One of the myelin proteins and a member of the immunoglobulin superfamily.

TH1 cell

An inflammatory cell, the signature cytokine of which is interferon-γ.

TH17 cell

An inflammatory cell, the signature cytokine of which is interleukin-17.

Reactive astrocyte

A type of glial cell within the brain that has many properties of macrophages.

Microglial cell

A type of macrophage-like glial cell that is derived from bone marrow and resides in the central nervous system.

Coagulation cascade

A biochemical sequence of reactions that regulates coagulation by a series of proteases acting on substrates such as fibrinogen and fibrin.

Laser capture microdissection

A technique in which tissues are dissected with a laser and then subjected to biochemical analysis. The pathological stage of the specimen can be correlated with biochemistry.

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Steinman, L. A molecular trio in relapse and remission in multiple sclerosis. Nat Rev Immunol 9, 440–447 (2009). https://doi.org/10.1038/nri2548

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