Leprosy Mailing List – January 4, 2025
Ref.: (LML) Vit D and self-healing in HD
From: Joel Almeida, Mumbai, India
Dear Pieter and colleagues,
Thanks to Ben Naafs for the interesting additional reference about vit D. (Ref.: (LML) Vit D and self-healing in HD, 19 Dec 2004)
Self-healing without sequelae or stigma is one of the most remarkable and frequent outcomes of infection with the HD (leprosy) bacillus. It also undermines irrational fear of HD.
What happens when an infectious HD patient is introduced into a residential facility for senior citizens in an affluent country where signs of HD have not been reported for years except among those who have spent some time in endemic countries?
Lymphocyte transformation tests using HD bacillary sonicate done about a year after the said introduction show LTT positivity among 83% of 30 staff with an average age of 44 yrs, and 76% of 33 seniors with an average age of 83 yrs.(1) In short, transmission of HD bacilli may well have occurred to the vast majority of contacts, within a year of exposure. Yet, the occurrence of physical signs of the apparent infection is vanishingly rare in such countries.
Why?
Self-healing without sequelae, apparently.
Accordingly, it seems likely that as many as billions of people in endemic countries may have been infected with the HD bacillus at some point in their lives, but have self-healed without sequelae or stigma. A small minority of them might well have dormant bacilli that could produce signs of disease in later life, but that is extremely rare.
How does self-healing occur, and without sequelae too? Those who do not have a genetic predisposition to LL (lepromatous) HD, and do not lack vit D, simply kill bacilli via the vit D-induced cathelicidin anti-microbial peptide axis. (2-10) This natural defence is remarkable because it can achieve rapid healing without inflammation or sequelae. It is as if the body's defences have an inbuilt accelerator and brake. The self-regulated interaction of molecules at cellular level allows an infected person to strike a balance between killing bacilli and destroying host proteins, lipids and nucleic acids. When vit D is lacking, the person has trouble maintaining this healthy balance even if their genome does not predispose them to LL HD. They tend to develop signs of disease, and if then neglected they can suffer nerve damage and deformity.
What practical implications follow from all this?
Vit D supplements seem important, especially among low-income people or those who tend to have very little exposure of skin to sunlight (e.g., adolescent girls in some cultures). Also, interventions such as drugs which reduce vit D levels (11) by inducing hepatic enzymes (e.g., the enzyme CYP3A4) can unintentionally disrupt the body's beneficial cathelicidin anti-microbial peptide axis. This can permit both bacillary proliferation and inflammation leading to nerve damage, deformity and even transmission. Even drugs that simply kill the bacilli without reducing vit D levels can alter the body's natural balance and lead to nerve damage and visible deformity. That is because live HD bacilli and killed HD bacilli respectively evoke differing responses from cells of the immune system. (12-15)
Therefore, in vitro and animal experiments with drugs (e.g., using armadillos as a model of nerve damage) seem more ethical than experiments among asymptomatic human beings. Every asymptomatic individual presumed to be infected with the bacillus deserves to escape sequelae or stigma. (16) If anti-microbials are somehow given to an asymptomatic person infected with the bacillus, the opportunity for self-healing without sequelae is much reduced. Every such recipient thereafter needs to be monitored for nerve function impairment for a few years. Otherwise "silent neuropathy" can too often lead to deformity.
Supporting the vit D-cathelicidin anti-microbial peptide axis seems wise. Vit D supplements seem important especially among low-income people in endemic areas. The body's own natural accelerator and brake then have the best chance of tackling the bacilli without damaging nerves and causing visible deformity.
With all sincerity,
Joel Almeida
References
1. Dockrell H et al, Possible transmission of Mycobacterium leprae in a group of UK leprosy contacts. Lancet. Volume 338, Issue 8769 p739-743September 21, 1991
2. de Oliveira ALG et al. Reduced vitamin D receptor (VDR) and cathelicidin antimicrobial peptide (CAMP) gene expression contribute to the maintenance of inflammatory immune response in leprosy patients. Microbes and Infection
Volume 24, Issues 6–7, September 2022, 104981
3. Mandal D, Reja AHH, Biswas N et al Vitamin D receptor expression levels determine the severity and complexity of disease progression among leprosy reaction patients. New Microbe and New Infect.(2015) 6: 35-39.
4. Singh I, Lavania M, Pathak VK, Ahuja M, Turankar RP, Singh V, et al. VDR polymorphism, gene expression and vitamin D levels in leprosy patients from North Indian population. PLoS Negl Trop Dis (2018) 12(11): e0006823. https://doi.org/10.1371/journal.pntd.0006823
5. Hemshekhar M, Choi KG, Mookherjee N Host Defense Peptide LL-37-Mediated Chemoattractant Properties, but Not Anti-Inflammatory Cytokine IL-1RA Production, Is Selectively Controlled by Cdc42 Rho GTPase via G Protein-Coupled Receptors and JNK Mitogen-Activated Protein Kinase. Front. Immunol.(2018) 9:1871. doi: 10.3389/fimmu.2018.01871
6. Rowe-Magnus DA, Kao AY, Prieto AC et al (2019) Cathelicidin peptides restrict bacterial growth via membrane perturbation and induction of reactive oxygen species. mBio 10:e02021-19. https://doi.org/10.1128/mBio.02021-19.
7. Roy S, Frodsham A, Saha B, Hazra SK, Mascie-Taylor CG, Hill AV. Association of vitamin D receptor genotype with leprosy type. J Infect Dis(1999) 179:187–91. 10.1086/314536
8. Yuk J-M, Shin D-M, Lee H-M, Yang C-S, Jin HS, Kim K-K, et al. Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe(2009) 6:231–43. 10.1016/j.chom.2009.08.004
9. Kim DW, Teles RMB, Haile S, Liu PT, Modlin RL. Vitamin D status contributes to the antimicrobial activity of macrophages against Mycobacterium leprae PLoS Negl Trop Dis
.2018 Jul 2;12(7):e0006608. doi: 10.1371/journal.pntd.0006608
10. Chung C, Silwal P, Kim I, Modlin RL, Jo E-K. Vitamin D-Cathelicidin Axis: at the Crossroads between Protective Immunity and Pathological Inflammation during Infection. Immune Netw. 2020 Feb 11;20(2):e12. doi: 10.4110/in.2020.20.e12
11. Williamson B et al. Induction of Influx and Efflux Transporters and Cytochrome P450 3A4 in Primary Human Hepatocytes by Rifampin, Rifabutin, and
Rifapentine. Antimicrobial Agents and Chemotherapy. December 2013 Volume 57 Number 12:. 6366–6369
12. Marolia J, Mahadevan PR Superoxide production from macrophages of leprosy patients after stimulation with Mycobacterium leprae. J. Biosci., (1987).12(3): 273-279.
13. Medeiros RCA, Girardi KdCdV, Cardoso FKL et al. Subversion of Schwann Cell Glucose Metabolism by Mycobacterium leprae. J Biol Chem. 2016 Aug 23;291(41):21375–21387. doi: 10.1074/jbc.M116.725283
14. Souza BJd, Mendes MA, Sperandio da Silva GM et al. Gene Expression Profile of Mycobacterium leprae Contribution in the Pathology of Leprosy Neuropathy. Front. Med. (2022) 9:861586. doi: 10.3389/fmed.2022.861586
15. Brugger LMdO, Monnerat M, dos Santos L, Lara FA, Mietto BS (2023). What happens when Schwann cells are exposed to Mycobacterium leprae - A systematic review. IBRO Neuroscience Reports. 15:11-16.
16. Radhakrishna S, Nair NG. Association between regularity in dapsone (DDS) treatment and development of deformity. Int J Lepr 1987 Sep;55(3):425-34.
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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From: Leprosy Mailing List <leprosymailinglist@googlegroups.com>
Sent: 04 January 2025 17:12
To: Leprosy Mailing List <leprosymailinglist@googlegroups.com>
Subject: Ref.: (LML) Vit D and self-healing in HD
Leprosy Mailing List – January 4, 2025
Ref.: (LML) Vit D and self-healing in HD
From: Joel Almeida, Mumbai, India
Dear Pieter and colleagues,
Thanks to Ben Naafs for the interesting additional reference about vit D. (Ref.: (LML) Vit D and self-healing in HD, 19 Dec 2004)
Self-healing without sequelae or stigma is one of the most remarkable and frequent outcomes of infection with the HD (leprosy) bacillus. It also undermines irrational fear of HD.
What happens when an infectious HD patient is introduced into a residential facility for senior citizens in an affluent country where signs of HD have not been reported for years except among those who have spent some time in endemic countries?
Lymphocyte transformation tests using HD bacillary sonicate done about a year after the said introduction show LTT positivity among 83% of 30 staff with an average age of 44 yrs, and 76% of 33 seniors with an average age of 83 yrs.(1) In short, transmission of HD bacilli may well have occurred to the vast majority of contacts, within a year of exposure. Yet, the occurrence of physical signs of the apparent infection is vanishingly rare in such countries.
Why?
Self-healing without sequelae, apparently.
Accordingly, it seems likely that as many as billions of people in endemic countries may have been infected with the HD bacillus at some point in their lives, but have self-healed without sequelae or stigma. A small minority of them might well have dormant bacilli that could produce signs of disease in later life, but that is extremely rare.
How does self-healing occur, and without sequelae too? Those who do not have a genetic predisposition to LL (lepromatous) HD, and do not lack vit D, simply kill bacilli via the vit D-induced cathelicidin anti-microbial peptide axis. (2-10) This natural defence is remarkable because it can achieve rapid healing without inflammation or sequelae. It is as if the body's defences have an inbuilt accelerator and brake. The self-regulated interaction of molecules at cellular level allows an infected person to strike a balance between killing bacilli and destroying host proteins, lipids and nucleic acids. When vit D is lacking, the person has trouble maintaining this healthy balance even if their genome does not predispose them to LL HD. They tend to develop signs of disease, and if then neglected they can suffer nerve damage and deformity.
What practical implications follow from all this?
Vit D supplements seem important, especially among low-income people or those who tend to have very little exposure of skin to sunlight (e.g., adolescent girls in some cultures). Also, interventions such as drugs which reduce vit D levels (11) by inducing hepatic enzymes (e.g., the enzyme CYP3A4) can unintentionally disrupt the body's beneficial cathelicidin anti-microbial peptide axis. This can permit both bacillary proliferation and inflammation leading to nerve damage, deformity and even transmission. Even drugs that simply kill the bacilli without reducing vit D levels can alter the body's natural balance and lead to nerve damage and visible deformity. That is because live HD bacilli and killed HD bacilli respectively evoke differing responses from cells of the immune system. (12-15)
Therefore, in vitro and animal experiments with drugs (e.g., using armadillos as a model of nerve damage) seem more ethical than experiments among asymptomatic human beings. Every asymptomatic individual presumed to be infected with the bacillus deserves to escape sequelae or stigma. (16) If anti-microbials are somehow given to an asymptomatic person infected with the bacillus, the opportunity for self-healing without sequelae is much reduced. Every such recipient thereafter needs to be monitored for nerve function impairment for a few years. Otherwise "silent neuropathy" can too often lead to deformity.
Supporting the vit D-cathelicidin anti-microbial peptide axis seems wise. Vit D supplements seem important especially among low-income people in endemic areas. The body's own natural accelerator and brake then have the best chance of tackling the bacilli without damaging nerves and causing visible deformity.
With all sincerity,
Joel Almeida
References
1. Dockrell H et al, Possible transmission of Mycobacterium leprae in a group of UK leprosy contacts. Lancet. Volume 338, Issue 8769 p739-743September 21, 1991
2. de Oliveira ALG et al. Reduced vitamin D receptor (VDR) and cathelicidin antimicrobial peptide (CAMP) gene expression contribute to the maintenance of inflammatory immune response in leprosy patients. Microbes and Infection
Volume 24, Issues 6–7, September 2022, 104981
3. Mandal D, Reja AHH, Biswas N et al Vitamin D receptor expression levels determine the severity and complexity of disease progression among leprosy reaction patients. New Microbe and New Infect.(2015) 6: 35-39.
4. Singh I, Lavania M, Pathak VK, Ahuja M, Turankar RP, Singh V, et al. VDR polymorphism, gene expression and vitamin D levels in leprosy patients from North Indian population. PLoS Negl Trop Dis (2018) 12(11): e0006823. https://doi.org/10.1371/journal.pntd.0006823
5. Hemshekhar M, Choi KG, Mookherjee N Host Defense Peptide LL-37-Mediated Chemoattractant Properties, but Not Anti-Inflammatory Cytokine IL-1RA Production, Is Selectively Controlled by Cdc42 Rho GTPase via G Protein-Coupled Receptors and JNK Mitogen-Activated Protein Kinase. Front. Immunol.(2018) 9:1871. doi: 10.3389/fimmu.2018.01871
6. Rowe-Magnus DA, Kao AY, Prieto AC et al (2019) Cathelicidin peptides restrict bacterial growth via membrane perturbation and induction of reactive oxygen species. mBio 10:e02021-19. https://doi.org/10.1128/mBio.02021-19.
7. Roy S, Frodsham A, Saha B, Hazra SK, Mascie-Taylor CG, Hill AV. Association of vitamin D receptor genotype with leprosy type. J Infect Dis(1999) 179:187–91. 10.1086/314536
8. Yuk J-M, Shin D-M, Lee H-M, Yang C-S, Jin HS, Kim K-K, et al. Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe(2009) 6:231–43. 10.1016/j.chom.2009.08.004
9. Kim DW, Teles RMB, Haile S, Liu PT, Modlin RL. Vitamin D status contributes to the antimicrobial activity of macrophages against Mycobacterium leprae PLoS Negl Trop Dis
.2018 Jul 2;12(7):e0006608. doi: 10.1371/journal.pntd.0006608
10. Chung C, Silwal P, Kim I, Modlin RL, Jo E-K. Vitamin D-Cathelicidin Axis: at the Crossroads between Protective Immunity and Pathological Inflammation during Infection. Immune Netw. 2020 Feb 11;20(2):e12. doi: 10.4110/in.2020.20.e12
11. Williamson B et al. Induction of Influx and Efflux Transporters and Cytochrome P450 3A4 in Primary Human Hepatocytes by Rifampin, Rifabutin, and
Rifapentine. Antimicrobial Agents and Chemotherapy. December 2013 Volume 57 Number 12:. 6366–6369
12. Marolia J, Mahadevan PR Superoxide production from macrophages of leprosy patients after stimulation with Mycobacterium leprae. J. Biosci., (1987).12(3): 273-279.
13. Medeiros RCA, Girardi KdCdV, Cardoso FKL et al. Subversion of Schwann Cell Glucose Metabolism by Mycobacterium leprae. J Biol Chem. 2016 Aug 23;291(41):21375–21387. doi: 10.1074/jbc.M116.725283
14. Souza BJd, Mendes MA, Sperandio da Silva GM et al. Gene Expression Profile of Mycobacterium leprae Contribution in the Pathology of Leprosy Neuropathy. Front. Med. (2022) 9:861586. doi: 10.3389/fmed.2022.861586
15. Brugger LMdO, Monnerat M, dos Santos L, Lara FA, Mietto BS (2023). What happens when Schwann cells are exposed to Mycobacterium leprae - A systematic review. IBRO Neuroscience Reports. 15:11-16.
16. Radhakrishna S, Nair NG. Association between regularity in dapsone (DDS) treatment and development of deformity. Int J Lepr 1987 Sep;55(3):425-34.
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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