03179nas a2200481   4500000000100000008004100001260001300042653004100055653001500096653001000111653001600121653001800137653002400155653001100179653002000190653004100210653001100251653001200262653003000274653005700304653001600361653000900377653002200386653002600408653001400434653001600448653002500464653002100489653003400510653003100544653002400575653001800599653003500617100001200652700001300664700001300677700001200690245013400702300001200836490000700848520182800855022001402683       2011                            d  c2011 May10aAdaptor Proteins, Signal Transducing10aAdolescent10aAdult10aCholesterol10aClonal Anergy10aDisease Progression10aFemale10aHLA-DR Antigens10aHistocompatibility Antigens Class II10aHumans10aleprosy10aLeukocyte Common Antigens10aLymphocyte Specific Protein Tyrosine Kinase p56(lck)10aMacrophages10aMale10aMembrane Fluidity10aMembrane Microdomains10aMicroRNAs10aMiddle Aged10aMycobacterium leprae10aProtein Isoforms10aProto-Oncogene Proteins c-cbl10aReceptors, Antigen, T-Cell10aSignal Transduction10aT-Lymphocytes10aZAP-70 Protein-Tyrosine Kinase1 aKumar S1 aNaqvi RA1 aKhanna N1 aRao D N00aDisruption of HLA-DR raft, deregulations of Lck-ZAP-70-Cbl-b cross-talk and miR181a towards T cell hyporesponsiveness in leprosy.  a1178-900 v483 a<p>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.</p>  a1872-9142