Leptin Deficiency May Influence the Divergence of Cell-Mediated Immunity Between Lepromatous and Tuberculoid Leprosy Patients

References

• Eichelmann K, González SG, Salas-Alanis JC, Ocampo-Candiani J. Leprosy. An update: definition, pathogenesis, classification, diagnosis, and treatment. Actas Dermo-Sifiliográficas. 2013;104(7):554–563. doi:10.1016/j.ad.2012.03.003
   PubMedGoogle Scholar
• Macedo CS, Lara FA, Pinheiro RO, et al. New insights into the pathogenesis of leprosy: contribution of subversion of host cell metabolism to bacterial persistence, disease progression, and transmission. F1000Research. 2020;9:70. doi:10.12688/f1000research.21383.1
   Google Scholar
• Pinheiro RO, de Souza Salles J, Sarno EN, Sampaio EP. Mycobacterium leprae–host-cell interactions and genetic determinants in leprosy: an overview. Future Microbiol. 2011;6(2):217–230. doi:10.2217/fmb.10.173
   PubMed Web of Science ®Google Scholar
• Ridley DS, Jopling WH. Classification of leprosy according to immunity: a five- group system. Int J Lepr. 1966;34:255–273.
   Google Scholar
• World Health Organization. Chemotherapy of Leprosy for Control Programmes. Technical Report Series 675. Geneva: World Health Organization; 1983.
   Google Scholar
• Van Voorhis WC, Kaplan G, Sarno EN, et al. The cutaneous infiltrates of leprosy: cellular characteristics and the predominant T-cell phenotypes. N Engl J Med. 1982;307:1593–1597. doi:10.1056/NEJM198212233072601
   PubMed Web of Science ®Google Scholar
• Fonseca AB, Simon MD, Cazzaniga RA, et al. The influence of innate and adaptative immune responses on the differential clinical outcomes of leprosy. Infect Dis Poverty. 2017;6(1):1–8. doi:10.1186/s40249-016-0229-3
   PubMed Web of Science ®Google Scholar
• Modlin RL, Hofman FM, Taylor CR, Rea TH. T lymphocyte subsets in the skin lesions of patients with leprosy. J Am Acad Dermatol. 1983;8:182–189. doi:10.1016/S0190-9622(83)70021-6
   PubMed Web of Science ®Google Scholar
• Sridevi K, Khanna N, Chattree V, Pal PC, Haq W, Rao DN. Reversal of T cell anergy in leprosy patients: in vitro presentation with Mycobacterium leprae antigens using murabutide and Trat peptide in liposomal delivery. Int Immunopharmacol. 2003;3(12):1589–1600. doi:10.1016/S1567-5769(03)00181-4
   PubMed Web of Science ®Google Scholar
• Nath I. Immunopathogenesis of leprosy: a model for T cell anergy. EMJ Dermatol. 2016;4:95–101. doi:10.33590/emjdermatol/10312914
   Google Scholar
• Maurya R, Bhattacharya P, Dey R, Nakhasi HL. Leptin functions in infectious diseases. Front Immunol. 2018;2018:2741.
   Web of Science ®Google Scholar
• Conde J, Scotece M, Gómez R, Gómez-Reino JJ, Lago F, Gualillo O. At the crossroad between immunity and metabolism: focus on leptin. Expert Rev Clin Immunol. 2010;6(5):801–808. doi:10.1586/eci.10.48
   PubMed Web of Science ®Google Scholar
• Mackey-Lawrence NM, Petri WA. Leptin and mucosal immunity. Mucosal Immunol. 2012;5(5):472–479. doi:10.1038/mi.2012.40
   PubMed Web of Science ®Google Scholar
• Iikuni N, Kwan Lam QL, Lu L, Matarese G, Cava AL. Leptin and inflammation. Curr Immunol Rev. 2008;4(2):70–79. doi:10.2174/157339508784325046
   PubMedGoogle Scholar
• Matarese G. Leptin and the immune system: how nutritional status influences the immune response. Eur Cytokine Netw. 2000;11(1):7–14.
   PubMed Web of Science ®Google Scholar
• Kerr-Pontes LR, Barreto ML, Evangelista CM, Rodrigues LC, Heukelbach J, Feldmeier H. Socioeconomic, environmental, and behavioural risk factors for leprosy in North-east Brazil: results of a case–control study. Int J Epidemiol. 2006;35(4):994–1000. doi:10.1093/ije/dyl072
   PubMed Web of Science ®Google Scholar
• Feenstra SG, Nahar Q, Pahan D, Oskam L, Richardus JH. Recent food shortage is associated with leprosy disease in Bangladesh: a case-control study. PLoS Negl Trop Dis. 2011;5(5):e1029. doi:10.1371/journal.pntd.0001029
   PubMed Web of Science ®Google Scholar
• Anantharam P, Emerson LE, Bilcha KD, Fairley JK, Tesfaye AB. Undernutrition, food insecurity, and leprosy in North Gondar Zone, Ethiopia: a case-control study to identify infection risk factors associated with poverty. PLoS Negl Trop Dis. 2021;15(6):e0009456. doi:10.1371/journal.pntd.0009456
   PubMed Web of Science ®Google Scholar
• Dwivedi VP, Banerjee A, Das I, et al. Diet and nutrition: an important risk factor in leprosy. Microb Pathog. 2019;137:103714. doi:10.1016/j.micpath.2019.103714
   PubMed Web of Science ®Google Scholar
• De Rosa V, Procaccini C, Calì G, et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity. 2007;26(2):241–255. doi:10.1016/j.immuni.2007.01.011
   PubMed Web of Science ®Google Scholar
• Palermo ML, Pagliari C, Trindade MA, et al. Increased expression of regulatory T cells and down-regulatory molecules in lepromatous leprosy. Am J Trop Med Hyg. 2012;86(5):878. doi:10.4269/ajtmh.2012.12-0088
   PubMed Web of Science ®Google Scholar
• Mattioli B, Straface E, Quaranta MG, Giordani L, Viora M. Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming. J Immunol. 2005;174(11):6820–6828. doi:10.4049/jimmunol.174.11.6820
   PubMed Web of Science ®Google Scholar
• Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol. 2012;12(5):325–338. doi:10.1038/nri3198
   PubMed Web of Science ®Google Scholar
• Dabi YT, Degechisa ST, Bobosha K, Wassie L. Changes in plasma level of endocrine hormones in lepromatous leprosy patients. IJID Regions. 2022.
   Google Scholar
• Ye M, Bian LF. Association of serum leptin levels and pulmonary tuberculosis: a meta-analysis. J Thorac Dis. 2018;10(2):1027. doi:10.21037/jtd.2018.01.70
   PubMed Web of Science ®Google Scholar
• Tsegaye Y, Admassu W, Edao A, et al. Alteration of endocrine hormones and antibody responses in different spectrum of tuberculosis disease. Front Immunol. 2022;25:731.
   Google Scholar
• Skinsnes LK, Higa LH. The role of protein malnutrition in the pathogenesis of ulcerative “Lazarine” leprosy. Int J Lepr Other Mycobact Dis. 1976;44:346–358.
   PubMedGoogle Scholar
• Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature. 1998;394(6696):897–901. doi:10.1038/29795
   PubMed Web of Science ®Google Scholar
• Matarese G, Di Giacomo A, Sanna V, et al. Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol. 2001;166(10):5909–5916. doi:10.4049/jimmunol.166.10.5909
   PubMed Web of Science ®Google Scholar
• Chandra RK. Cell-mediated immunity in genetically obese (C57BL/6J ob/ob) mice. Am J Clin Nutr. 1980;33(1):13–16. doi:10.1093/ajcn/33.1.13
   PubMed Web of Science ®Google Scholar
• Mandel MA, Mahmoud AA. Impairment of cell-mediated immunity in mutation diabetic mice (db/db). J Immunol. 1978;120(4):1375–1377.
   PubMed Web of Science ®Google Scholar
• Wieland CW, Florquin S, Chan ED, et al. Pulmonary Mycobacterium tuberculosis infection in leptin-deficient ob/ob mice. Int Immunol. 2005;17(11):1399–1408. doi:10.1093/intimm/dxh317
   PubMed Web of Science ®Google Scholar
• Hasenkrug KJ. The leptin connection: regulatory T cells and autoimmunity. Immunity. 2007;26(2):143–145. doi:10.1016/j.immuni.2007.02.002
   PubMed Web of Science ®Google Scholar
• Matarese G, La Cava A, Sanna V, et al. Balancing susceptibility to infection and autoimmunity: a role for leptin? Trends Immunol. 2002;23(4):182–187. doi:10.1016/S1471-4906(02)02188-9
   PubMed Web of Science ®Google Scholar
• Procaccini C, Jirillo E, Matarese G. Leptin as an immunomodulator. Mol Aspects Med. 2012;33(1):35–45. doi:10.1016/j.mam.2011.10.012
   PubMed Web of Science ®Google Scholar
• Cava AL, Matarese G. The weight of leptin in immunity. Nat Rev Immunol. 2004;4(5):371–379. doi:10.1038/nri1350
   PubMed Web of Science ®Google Scholar
• Alti D, Sambamurthy C, Kalangi SK. Emergence of leptin in infection and immunity: scope and challenges in vaccines formulation. Front Cell Infect Microbiol. 2018;8:147. doi:10.3389/fcimb.2018.00147
   PubMed Web of Science ®Google Scholar
• Bobosha K, Wilson L, van Meijgaarden KE, et al. T-cell regulation in lepromatous leprosy. PLoS Negl Trop Dis. 2014;8(4):e2773. doi:10.1371/journal.pntd.0002773
   PubMed Web of Science ®Google Scholar
• Cao Q, Wang L, Du F, et al. Down regulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells. Cell Res. 2007;17(7):627–637. doi:10.1038/cr.2007.46
   PubMed Web of Science ®Google Scholar
• Takahashi T, Kuniyasu Y, Toda M, et al. Immunologic self-tolerance maintained by CD25+ CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol. 1998;10(12):1969–1980. doi:10.1093/intimm/10.12.1969
   PubMed Web of Science ®Google Scholar
• Zhou X, Bailey-Bucktrout SL, Jeker LT, et al. Instability of the transcription factor FOXP3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol. 2009;10(9):1000–1007. doi:10.1038/ni.1774
   PubMed Web of Science ®Google Scholar
• Saini C, Ramesh V, Nath I. Increase in TGF-β secreting CD4+ CD25+ FOXP3+ T regulatory cells in anergic lepromatous leprosy patients. PLoS Negl Trop Dis. 2014;8(1):e2639. doi:10.1371/journal.pntd.0002639
   PubMed Web of Science ®Google Scholar
• Sadhu S, Khaitan BK, Joshi B, Sengupta U, Nautiyal AK, Mitra DK. Reciprocity between regulatory T cells and Th17 cells: relevance to polarized immunity in leprosy. PLoS Negl Trop Dis. 2016;10(1):e0004338. doi:10.1371/journal.pntd.0004338
   PubMed Web of Science ®Google Scholar
• Procaccini C, De Rosa V, Galgani M, et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity. 2010;33(6):929–941. doi:10.1016/j.immuni.2010.11.024
   PubMed Web of Science ®Google Scholar
• Parente JN, Talhari C, Schettini AP, Massone C. T regulatory cells (CD4+ CD25+ FOXP3+) distribution in the different clinical forms of leprosy and reactional states. An Bras Dermatol. 2015;90:41–47. doi:10.1590/abd1806-4841.20153311
   PubMed Web of Science ®Google Scholar
• Zeng H, Chi H. The interplay between regulatory T cells and metabolism in immune regulation. Oncoimmunology. 2013;2(11):e26586. doi:10.4161/onci.26586
   PubMed Web of Science ®Google Scholar
• Wei R, Hu Y, Dong F, Xu X, Hu A, Gao G. Hepatoma cell‐derived leptin downregulates the immunosuppressive function of regulatory T‐cells to enhance the anti‐tumor activity of CD8+ T‐cells. Immunol Cell Biol. 2016;94(4):388–399. doi:10.1038/icb.2015.110
   PubMed Web of Science ®Google Scholar
• Maya-Monteiro C, Bozza P. Leptin and mTOR: partners in metabolism and inflammation. Cell Cycle. 2008;7(12):1713–1717. doi:10.4161/cc.7.12.6157
   PubMed Web of Science ®Google Scholar
• Chen Y, Colello J, Jarjour W, Zheng SG. Cellular metabolic regulation in the differentiation and function of regulatory T cells. Cells. 2019;8(2):188. doi:10.3390/cells8020188
   PubMed Web of Science ®Google Scholar
• Coe DJ, Kishore M, Marelli-Berg F. Metabolic regulation of regulatory T cell development and function. Front Immunol. 2014;5:590. doi:10.3389/fimmu.2014.00590
   PubMed Web of Science ®Google Scholar
• Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol. 2006;177:8338–8347. doi:10.4049/jimmunol.177.12.8338
   PubMed Web of Science ®Google Scholar
• Valmori D, Tosello V, Souleimanian NE, et al. Rapamycin-mediated enrichment of T cells with regulatory activity in stimulated CD4+ T cell cultures is not due to the selective expansion of naturally occurring regulatory T cells but to the induction of regulatory functions in conventional CD4+ T cells. J Immunol. 2006;177:944–949. doi:10.4049/jimmunol.177.2.944
   PubMed Web of Science ®Google Scholar
• Turnquist HR, Raimondi G, Zahorchak AF, Fischer RT, Wang Z, Thomson AW. Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance. J Immunol. 2007;178:7018–7031. doi:10.4049/jimmunol.178.11.7018
   PubMed Web of Science ®Google Scholar
• Strauss L, Czystowska M, Szajnik M, Mandapathil M, Whiteside TL. Differential responses of human regulatory T cells and effector T cells to rapamycin. PLoS One. 2009;4:e5994. doi:10.1371/journal.pone.0005994
   PubMed Web of Science ®Google Scholar
• Zeiser R, Leveson-Gower DB, Zambricki EA, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood. 2008;111:453–462. doi:10.1182/blood-2007-06-094482
   PubMed Web of Science ®Google Scholar
• Chapman NM, Chi H. mTOR signaling, Tregs and immune modulation. Immunotherapy. 2014;6(12):1295–1311. doi:10.2217/imt.14.84
   PubMed Web of Science ®Google Scholar
• Delgoffe GM, Kole TP, Zheng Y, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30:832–844. doi:10.1016/j.immuni.2009.04.014
   PubMed Web of Science ®Google Scholar
• Haxhinasto S, Mathis D, Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med. 2008;205:565–574. doi:10.1084/jem.20071477
   PubMed Web of Science ®Google Scholar
• Galgani M, De Rosa V, La Cava A, Matarese G. Role of metabolism in the immunobiology of regulatory T cells. J Immunol. 2022;2022:2569–2575.
   Google Scholar
• Howie D, Waldmann H, Cobbold S. Nutrient sensing via mTOR in T cells maintains a tolerogenic microenvironment. Front Immunol. 2014;5:409. doi:10.3389/fimmu.2014.00409
   PubMed Web of Science ®Google Scholar
• Matarese G, Procaccini C, De Rosa V, Horvath TL, La Cava A. Regulatory T cells in obesity: the leptin connection. Trends Mol Med. 2010;16(6):247–256. doi:10.1016/j.molmed.2010.04.002
   PubMed Web of Science ®Google Scholar
• Kempkes RW, Joosten I, Koenen HJ, He X. Metabolic pathways involved in regulatory T cell functionality. Front Immunol. 2019;10:2839. doi:10.3389/fimmu.2019.02839
   PubMed Web of Science ®Google Scholar
• Sun IH, Oh MH, Zhao L, et al. mTOR complex 1 signaling regulates the generation and function of central and effector Foxp3+ regulatory T cells. J Immunol. 2018;201(2):481–492. doi:10.4049/jimmunol.1701477
   PubMed Web of Science ®Google Scholar
• Saini C, Siddiqui A, Ramesh V, Nath I. Leprosy reactions show increased Th17 cell activity and reduced FOXP3+ tregs with concomitant decrease in TGF-beta and increase in IL-6. PLoS Negl Trop Dis. 2016;10:e0004592. doi:10.1371/journal.pntd.0004592
   PubMed Web of Science ®Google Scholar
• Salgame P, Yamamura M, Bloom BR, Modlin RL. Evidence for functional subsets of CD4+ and CD8+ T cells in human disease: lymphokine patterns in leprosy. Chem Immunol. 1992;54:44–59.
   PubMedGoogle Scholar
• Saini C, Ramesh V, Nath I. CD4+ Th17 cells discriminate clinical types and constitute a third subset of non Th1, Non Th2 T cells in human leprosy. PLoS Negl Trop Dis. 2013;7(7):e2338. doi:10.1371/journal.pntd.0002338
   PubMed Web of Science ®Google Scholar
• Pérez-Pérez A, Sánchez-Jiménez F, Vilariño-García T, Sánchez-Margalet V. Role of leptin in inflammation and vice versa. Int J Mol Sci. 2020;21(16):5887. doi:10.3390/ijms21165887
   PubMed Web of Science ®Google Scholar
• Reis BS, Lee K, Fanok MH, et al. Leptin receptor signaling in T cells is required for Th17 differentiation. J Immunol. 2015;194:5253–5260. doi:10.4049/jimmunol.1402996
   PubMed Web of Science ®Google Scholar
• Yu Y, Liu Y, Shi F-D, Zou H, Matarese G, La Cava A. Cutting edge: leptin-induced RORγt expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus. J Immunol. 2013;190:3054–3058. doi:10.4049/jimmunol.1203275
   PubMed Web of Science ®Google Scholar
• Saucillo DC, Gerriets VA, Sheng J, Rathmell JC, MacIver NJ. Leptin metabolically licenses T cells for activation to link nutrition and immunity. J Immunol. 2014;192(1):136–144. doi:10.4049/jimmunol.1301158
   PubMed Web of Science ®Google Scholar
• Gerriets VA, Danzaki K, Kishton RJ, et al. Leptin directly promotes T‐cell glycolytic metabolism to drive effector T‐cell differentiation in a mouse model of autoimmunity. Eur J Immunol. 2016;46(8):1970–1983. doi:10.1002/eji.201545861
   PubMed Web of Science ®Google Scholar
• Saini C, Tarique M, Rai R, Siddiqui A, Khanna N, Sharma A. T helper cells in leprosy: an update. Immunol Lett. 2017;184:61–66. doi:10.1016/j.imlet.2017.02.013
   PubMed Web of Science ®Google Scholar
• Tarique M, Naz H, Kurra SV, et al. Interleukin-10 producing regulatory B cells transformed CD4+ CD25− into Tregs and enhanced regulatory T cells function in human leprosy. Front Immunol. 2018;9:1636. doi:10.3389/fimmu.2018.01636
   PubMed Web of Science ®Google Scholar
• Mi Z, Liu H, Zhang F. Advances in the immunology and genetics of leprosy. Front Immunol. 2020;11:567. doi:10.3389/fimmu.2020.00567
   PubMed Web of Science ®Google Scholar
• Shen P, Roch T, Lampropoulou V, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507(7492):366–370. doi:10.1038/nature12979
   PubMed Web of Science ®Google Scholar
• Saini C, Tarique M, Ramesh V, Khanna N, Sharma A. γδ T cells are associated with inflammation and immunopathogenesis of leprosy reactions. Immunol Lett. 2018;200:55–65. doi:10.1016/j.imlet.2018.07.005
   PubMed Web of Science ®Google Scholar
• Liu Y, Shi C, Ma S, et al. The protective role of tissue-resident IL-17A-producing gamma delta T cells in Mycobacterium leprae infection. Front Immunol. 2022;2022:6386.
   Google Scholar
• Sridevi K, Neena K, Chitralekha KT, Arif AK, Tomar D, Rao DN. Expression of costimulatory molecules. (CD80, CD86, CD28, CD152), accessory molecules. (TCR alphabeta, TCR gammadelta) and T cell lineage molecules. (CD4+, CD8+) in PBMC of leprosy patients using Mycobacterium leprae antigen. (MLCWA) with murabutide and T cell peptide of Trat protein. Int Immunopharmacol. 2004;4:1–14. doi:10.1016/j.intimp.2003.09.001
   PubMed Web of Science ®Google Scholar
• Tarique M, Naqvi RA, Ali R, Khanna N, Rao DN. CD4 (+) TCRgammadelta(+) FoxP3(+) cells: an unidentified population of immunosuppressive cells towards disease progression leprosy patients. ExpDermatol. 2017;26:946–948.
   Web of Science ®Google Scholar
• Ochoa MT, Teles R, Haas BE, et al. A role for interleukin-5 in promoting increased immunoglobulin M at the site of disease in leprosy. Immunology. 2010;131:405–414. doi:10.1111/j.1365-2567.2010.03314.x
   PubMed Web of Science ®Google Scholar