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Protective and therapeutic role for αB-crystallin in autoimmune demyelination

Nature volume 448, pages 474–479 (2007)Cite this article

Abstract

αB-crystallin (CRYAB) is the most abundant gene transcript present in early active multiple sclerosis lesions, whereas such transcripts are absent in normal brain tissue1. This crystallin has anti-apoptotic2,3,4,5,6,7 and neuroprotective8 functions. CRYAB is the major target of CD4+ T-cell immunity to the myelin sheath from multiple sclerosis brain9,10. The pathophysiological implications of this immune response were investigated here. We demonstrate that CRYAB is a potent negative regulator acting as a brake on several inflammatory pathways in both the immune system and central nervous system (CNS). Cryab-/- mice showed worse experimental autoimmune encephalomyelitis (EAE) at the acute and progressive phases, with higher Th1 and Th17 cytokine secretion from T cells and macrophages, and more intense CNS inflammation, compared with their wild-type counterparts. Furthermore, Cryab-/- astrocytes showed more cleaved caspase-3 and more TUNEL staining, indicating an anti-apoptotic function of Cryab. Antibody to CRYAB was detected in cerebrospinal fluid from multiple sclerosis patients and in sera from mice with EAE. Administration of recombinant CRYAB ameliorated EAE. Thus, the immune response against a negative regulator of inflammation, CRYAB, in multiple sclerosis, would exacerbate inflammation and demyelination. This can be countered by giving CRYAB itself for therapy of ongoing disease.

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Figure 1: Worse EAE, increased immune activation and glial apoptosis in Cryab -/- mice.
Figure 2: T cells from Cryab -/- EAE mice are hyper-responsive.
Figure 3: Macrophages deficient in Cryab are hyperactive.
Figure 4: Cryab -/- astrocytes are more susceptible to cell death and augment ERK and NF-κB signalling.
Figure 5: Myelin antigen array analysis demonstrates antibody targeting of CRYAB in RRMS patients.
Figure 6: CRYAB suppresses disease and inflammation in EAE.

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Acknowledgements

This research was supported by NIH and National Multiple Sclerosis Society (NMSS) grants to L.S. and fellowships to S.S.O. from the NMSS and Multiple Sclerosis Society of Canada (MSSC). We thank R. Tibshirani for his advice on statistical analysis.

Author Contributions S.S.O. and L.S. formulated the hypothesis and aims and designed all experiments. W.H.R. and B.H.T. did the myelin array experiment. D.A.H. and K.O’C. provided multiple sclerosis CSF for the myelin array. R.A.S. analysed and quantified the EAE and astrocyte histology. J.M.V.N. provided the CRYAB human protein construct for the myelin array and performed the western blot for CRYAB in multiple sclerosis sera and CSF. E.F.W. developed and provided the Cryab-/- mice.

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Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University,

    Shalina S. Ousman & Lawrence Steinman

  2. Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California 94305, USA,

    Beren H. Tomooka & William H. Robinson

  3. GRECC and,,

    Beren H. Tomooka & William H. Robinson

  4. Laboratory Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA,

    Raymond A. Sobel

  5. Department of Biosciences, TNO Quality of Life, 2301 CE Leiden, The Netherlands,

    Johannes M. van Noort

  6. National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA,

    Eric F. Wawrousek

  7. Center for Neurologic Disease, Harvard Medical School, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA,

    Kevin O’Conner & David A. Hafler

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  1. Shalina S. Ousman
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Correspondence to Lawrence Steinman.

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Supplementary Information

This file contains Supplementary Tables S1-S4 and Supplementary Figures S1-S7 with Legends. The document shows Supplementary i) CNS histology of WT and αBC-/- EAE animals ii) WT and αBC-/- dendritic cell responses iii) Rag2-/- adoptive transfer with WT and αBC-/- splenocytes iv) Recombinant αBC treatment in αBC-/- and SJL/J EAE mice v) Statistical analysis of western blots vi) αBC in MS CSF and sera. (PDF 18916 kb)

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Ousman, S., Tomooka, B., van Noort, J. et al. Protective and therapeutic role for αB-crystallin in autoimmune demyelination. Nature 448, 474–479 (2007). https://doi.org/10.1038/nature05935

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