Disruption of HLA-DR raft, deregulations of Lck-ZAP-70-Cbl-b cross-talk and miR181a towards T cell hyporesponsiveness in leprosy.
Leprosy, a chronic human disease, results from infection of Mycobacterium leprae. Defective CMI and T cell hyporesponsiveness are the major hallmark of M. leprae pathogenesis. The present study demonstrates immunological-deregulations that eventually lead to T cell anergy/hyporesponsiveness in M. lepare infection. We firstly, evaluated the membrane fluidity and antigen-presenting-lipid-raft (HLA-DR) ... on macrophages of leprosy patients using fluorescence anisotropy and confocal microscopy, respectively. Increased membrane fluidity and raft-out localizations of over-expressed HLA-DR towards BL/LL pole are pinpointed as major defects, may be leading to defective antigen presentation in leprosy. Furthermore, altered expression and localization of Lck, ZAP-70, etc. and their deregulated cross talks with negative regulators (CD45, Cbl-b and SHP2) turned out to be the major putative reason(s) leading to T cell hyporesponsiveness in leprosy. Deregulations of Lck-ZAP-70 cross-talk in T cells were found to be associated with cholesterol-dependent-dismantling of HLA-DR rafts in macrophages in leprosy progression. Increased molecular interactions between Cbl-b and Lck/ZAP-70 and their subsequent degradation via ubiquitinization pathway, as result of high expression of Cbl-b, were turned out to be one of the principal underlying reason leading to T cell anergy in leprosy patients. Interestingly, overexpression of SHP2 due to gradual losses of miR181a and subsequent dephosphorylation of imperative T cell signaling molecules were emerged out as another important reason associated with prevailing T cell hyporesponsiveness during leprosy progression. Thus, this study for the first time pinpointed overexpression of Cbl-b and expressional losses of miR-181 as important hallmarks of progression of leprosy.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Adolescent, Adult, Antigens, CD45, Cholesterol, Clonal Anergy, Disease Progression, Female, HLA-DR Antigens, Histocompatibility Antigens Class II, Humans, Leprosy, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Macrophages, Male, Membrane Fluidity, Membrane Microdomains, MicroRNAs, Middle Aged, Mycobacterium leprae, Protein Isoforms, Proto-Oncogene Proteins c-cbl, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, ZAP-70 Protein-Tyrosine Kinase
Adaptor Proteins, Signal Transducing, Adolescent, Adult, Antigens, CD45, Cholesterol, Clonal Anergy, Disease Progression, Female, HLA-DR Antigens, Histocompatibility Antigens Class II, Humans, Leprosy, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Macrophages, Male, Membrane Fluidity, Membrane Microdomains, MicroRNAs, Middle Aged, Mycobacterium leprae, Protein Isoforms, Proto-Oncogene Proteins c-cbl, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, ZAP-70 Protein-Tyrosine Kinase
Mol. Immunol.
Date: May. 01, 2011
PubMed ID: 21453975
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