title: Disruption of HLA-DR raft, deregulations of Lck-ZAP-70-Cbl-b cross-talk and miR181a towards T cell hyporesponsiveness in leprosy.
abstract: 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.
authors: Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
authors: Sudhir
authors: S
authors: Kumar
authors: Raza Ali
authors: RA
authors: Naqvi
authors: Neena
authors: N
authors: Khanna
authors: D N
authors: DN
authors: Rao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D002784:Cholesterol / Q000378:metabolism; D017635:Clonal Anergy / Q000276:immunology; D018450:Disease Progression; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007918:Leprosy / Q000276:immunology* / Q000382:microbiology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008264:Macrophages / Q000382:microbiology / Q000473:pathology; D008297:Male; D008560:Membrane Fluidity / Q000276:immunology; D021962:Membrane Microdomains / Q000276:immunology; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009166:Mycobacterium leprae / Q000276:immunology; D020033:Protein Isoforms / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell; D002784:Cholesterol; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human