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.
Bibliographical noteFunding Information:
The authors are thankful to ICMR and CSIR for providing financial support to carry out this work. SK and RAN are again thankful to ICMR and CSIR for their fellowships. We are also thankful to Dr. J. Sen Gupta, Department of Physiology, AIIMS for providing confocal microscopy facility and Prof. Rajeev Bhat, Dept of Biotechnology, JNU for their invaluable guidance in FA experiments. We are also thankful to Mr. Pankaj Pathak, Department of Pathology, AIIMS and Mr. Hemant Mishra, Department of Medicine, AIIMS for real time PCR analysis in this study.
- Antigen presentation
- Lipid raft
- Mycobacterium leprae
- T cell hyporesponsiveness/anergy