Abstract
Leprosy is a chronic human disease; primarily affecting skin, peripheral nerves, eyes, testis etc. Comprehensive-expressional-profiling of Th1-Th2-Th3 associated markers (84 genes) using qRT-PCR array, negated the previously prevailing notion, Th2 bias towards multibacillary stage of leprosy. High production TGF-β further supported the dearth of any immune response(s) in leprosy progression. Over expression of Cbl-b, could emerge as plausible reason for contributing T cell hyporesponsiveness, possibly by degradation of T cells signaling molecules. Anti-TGF-β treatments further confirm the TGF-β-dependent-Cbl-b overexpression in multibacillary patients. Diminished Cbl-b expression in CTLA-4 knockout studies using siRNA, provided other evidence towards T cell hyporesponsiveness. Further, high T cell proliferation and IL-2 production in PBMC cultures treated with anti-TGF-β and siRNA offers here a strategy to revert T cell hyporesponsiveness by downregulating Cbl-b expression in leprosy. Thus, this study negates Th2 bias and substantiates molecular cross-talk amongst TGF-β-CTLA-4-Cbl-b eventually leads to M. leprae persistence.
Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / biosynthesis
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology*
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Amino Acid Sequence
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Antibodies, Monoclonal / pharmacology
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Antigens, Bacterial / immunology
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CTLA-4 Antigen / antagonists & inhibitors
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CTLA-4 Antigen / genetics
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CTLA-4 Antigen / immunology*
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Cell Lineage
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Cell Wall / immunology
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Cells, Cultured
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Cytokines / metabolism
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Disease Progression
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Gene Expression Profiling*
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Gene Expression Regulation
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Humans
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Immune Tolerance
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Immunity, Cellular
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Leprosy, Multibacillary / genetics
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Leprosy, Multibacillary / immunology*
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Leprosy, Paucibacillary / genetics
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Leprosy, Paucibacillary / immunology*
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Molecular Sequence Data
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Mycobacterium leprae / immunology*
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Proto-Oncogene Proteins c-cbl / biosynthesis
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / immunology*
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RNA, Small Interfering / pharmacology
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T-Lymphocytes, Regulatory / immunology*
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Th1 Cells / immunology
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Th2 Cells / immunology
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / biosynthesis
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / immunology*
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Monoclonal
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Antigens, Bacterial
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CTLA-4 Antigen
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Cytokines
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RNA, Small Interfering
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Transforming Growth Factor beta
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CBLB protein, human
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Proto-Oncogene Proteins c-cbl