title: Th3 immune responses in the progression of leprosy via molecular cross-talks of TGF-β, CTLA-4 and Cbl-b.
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.
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kumar
authors.forename: Raza A
authors.initials: RA
authors.lastname: Naqvi
authors.forename: Neena
authors.initials: N
authors.lastname: Khanna
authors.forename: Pankaj
authors.initials: P
authors.lastname: Pathak
authors.forename: D N
authors.initials: DN
authors.lastname: Rao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage; D002473:Cell Wall / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D056006:Leprosy, Multibacillary / Q000235:genetics / Q000276:immunology*; D056005:Leprosy, Paucibacillary / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D009166:Mycobacterium leprae / Q000276:immunology*; D050721:Proto-Oncogene Proteins c-cbl / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D060908:CTLA-4 Antigen; D016207:Cytokines; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl