1. Department of Neurology and Neurological Sciences, Stanford University
2. Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California 94305, USA
3. GRECC and,
4. Laboratory Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA
5. Department of Biosciences, TNO Quality of Life, 2301 CE Leiden, The Netherlands
6. National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
7. Center for Neurologic Disease, Harvard Medical School, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA

Correspondence to: Lawrence Steinman¹ Correspondence and requests for materials should be addressed to L.S. (Email: steinman@stanford.edu).

B-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-apoptotic^{2, 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 brain^{9, 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.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.