Leprosy Mailing List – February 4, 2020
Ref.: (LML) All is different than you think: to re-interpret with the present findings what was seen by clinicians in the past
From: Ben Naafs, Munnekeburen, the Netherlands
Dear Pieter,
With considerable interest I follow the recent arguments on advices for the diagnosis and treatment of leprosy, the opinions concerning use of serology, PCR and clinical symptoms, type and duration of treatment and follow up of patients with different classifications and management of complications. I have studied, contributed, and read articles and theories about nerve damage and the importance of the cellular immunology in leprosy. And I start to wonder about the basis for these advices and discussions. At the beginning of this millennium I wrote two articles: "Leprosy treatment; science or politics1" and also: "Treatment duration of reversal reaction: A reappraisal. Back to the past2". The words: [i]"science or politics and back to the past" express my worry about the way modern leprosy management is directed. Where are these advices based on? Certainly not on what is already known (see: Robert Gelber in LML) and not on new basic research or reinterpretation of old research against new knowledge (see: recent LML contributions from Diana Lockwood and from Joël Almeida).
I start to realize more and more that I do not know what kind of disease leprosy is. It is not just an immunological reaction against a mycobacterium which is known as to be harmless unless the immune system leads to collateral or direct damage. It is assumed that the infection spreads directly or indirectly from person to person, either via mucous membranes or via the skin. More recently the armadillo was accused of transmitting the disease to human beings3.
What should one think of recent publications that show the presence of viable M. leprae in the patients' environment like soil and water (bathing pond) in association with the free living pathogenic protozoa, Acanthamoeba4.
The "infection"
In an endemic environment there are M.leprae bacilli everywhere, most are dead but some are able to cause the infectious disease leprosy4 . The dead bacteria are far in the majority and consist of "antigens" e.g. PGL1, Lipoarabinomannan and many others, specific DNA and even for some time RNA too. They are able to "infect". Because the nose can be considered as a kind of vacuum cleaner, the bacilli and the antigens will certainly enter the nose and adhere to the mucosa5. When present in a bathing pond both the living and the dead bacilli and their antigens will surely contaminate the skin and may penetrate the skin via small scratches or other breakages. Armadillo's or other animals that can be infected when living in such endemic area become victims like humans and contribute to the infective pool. When the antigens or live bacilli have entered the nose or the skin, they will consequently enter the blood and /or be gobbled by macrophages. Thereafter they will circulate in the lymph and blood either as antigens or as living bacilli. They may multiply in the macrophages, at least in the individuals who are able to sustain living M. leprae (less than 20%). They circulate everywhere in blood and lymph and expose the immune system. Both the humeral as well as the cellular adaptive immune system will react to them, whether their host will develop leprosy or not.
It is generally thought that the Schwann cells in the peripheral nerves and in the skin are the places where the bacilli multiply and survive. But how do they get in these nerves? There are no lymph vessels in the endoneurium. It was Weddell who observed that damage occurs in places where there is movement. This happens at wrist, elbow, knee, ankle, skin and sometimes at the subcutes. Such a movement leads to micro-traumata which need to be repaired. The cells needed for repair are, among many, the macrophages. In order to get those cells into the endoneurium the endothelial cells of the blood vessels where there is microtrauma, will express adhesion molecules. The macrophage loaded with M. leprae and antigens will adhere and via diapedesis arrive in the endoneurium and come into contact with the Schwann cell. M. leprae may penetrate the Schwann cell the way Anura Rambukkana suggests with PGL-1 and other surface molecules which may lead to multiplication and/or demyelination6, 7. However, some researchers showed that PGL-1 expressed by the macrophages can lead to demyelination as well8. Nawal Bahia El Idrissi, Pranab Das and Frank Baas showed that another important M. leprae antigen, lipoarabinomannan, could by complement activation (MAC) also cause demyelination9,10. Thus, one does not need live bacilli, one only needs the antigens to cause damage to the nerve. It is important to realize that PGL-1 is broken down fairly quickly where lipoarabinomannan may be present for years and still may cause damage11.
Another way in which damage to the nerves can be caused is via the adaptive immune system which is stimulated by and which may respond to M. leprae antigens and their determinants. Leprosy is considered a cell-mediated immune disease12,13. Autoimmunity may happen during the bacterial infection but happens especially during the so-called reactions14. Type 1 reaction is cell immune-mediated, Type 2 reaction is an immune complex disease15. One should realize that the damage may be caused by a bystander effect or a reaction particularly directed against the antigenic determinants of the cells in the nerve which are identical to the M. leprae antigenic determinants14,16. All this damage does not require live bacteria but may also happen due to continuous exposure to M. leprae antigens from the environment. This can be considered as an autoimmune disease. A third important cause of damage is pure physical, oedema inside the nerve leads to compression and damage to the axons. This type of damage can continue when a venostatic oedema occurs in the endoneurium due to compression of the perineurium and the oblique crossing blood vessels through that perineurium, particular the veins.17
In 1943 Fite stated that there was no leprosy without nerve damage18. In 1977 Shetty and Antia published that nerves in early leprosy and in contacts showed signs of demyelination in nerve conduction studies and in histopathology19. In 2017 Diogo Fernandes dos Santos presented during the Brazilian leprosy congress that with nerve conduction studies demyelination in contacts was seen, with and without a positive anti PGL-1 serology20. Last year Glauber Voltan and Marco André Frade found enlarged nerves in contacts using ultrasound (personal communication). The enlargement was related to the amount of exposure. In the studies, no clinical symptoms due to nerve dysfunction in these nerves were demonstrated. It is assumed that this only can be detected when less than 80% of nerve fibres are functioning.
Another observation goes back to Stanley Browne in Belgian Congo, who observed that many leprosy contacts had hypopigmented patches with no obvious sensory loss which disappeared in most of the contacts, however a small percentage developed clinical leprosy21. Pran Das and Caroline Le Poole suggested that this hypopigmentation in leprosy could be an autoimmune reaction to melanocytes or melanin synthesis as in vitiligo22.
For all these observations one does not need live bacteria since contact with antigens is sufficient. It will, however, get worse if the contact is able to sustain M. leprae with the result that the bacilli will multiply. When these patients are treated and the treatment has discontinued, the environment in endemic circumstances will still afford contact with antigens and live bacilli. To make it even worse after treatment of multibacillary patients there may be persisters who can start a relapse when the right circumstances are present.
It is clear from nature's experiment (HIV infection) that in more than 80 percent of the infected persons even severe depressed Cell Mediated Immunity does not give rise to a leprosy disease. There is obviously more to it than just a not well functioning adaptive immune system23.
The old adagio that one needs 2 out of 3 cardinal symptoms to diagnose leprosy still holds. Just an enlarged nerve or hypopigmented patch does not diagnose leprosy. Skin smears alone do not prove it either.
All new diagnostic methods only detect individuals who have had contact with M. leprae and not all of them and detect patients with an active infection with live bacilli and again not all of them. Serology for PGL1, LID1 and for any other M. leprae unique antigenic determinant only detects the antibodies against this determinant on living and dead bacilli or on circulating antigens. The same is the case for Cell Mediated Immune tests: Mitsuda, LTT, Gamma-interferon test or any CMI test23. DNA is everywhere, even RNA may be present for some time. Therefore, only doing PCR provides just an indicative test. Histopathology will show a cellular reaction to the antigens. This is more specific for M. leprae antigens, but only in multibacillary leprosy, when an Acid-fast stain is unequivocally positive. If there is an abnormality detected in contacts is that leprosy as a disease or just a reaction to antigens? Should the reaction in and around nerves as seen in histopathology considered to be a reaction to antigens or should this be considered a reaction to living and dividing bacilli of the host? Can one ever become free from live M. leprae and leprosy antigenic determinants in an endemic country? I think I noticed less relapses in non-endemic countries than in endemic. However, in these non-endemic countries relapses were also present after 10 years or even more. Is one "cured" after completed treatment? One doubts it when considering persisters, enhanced immune-reactivity and a reaction to M. leprae antigens from bacilli in the environment.
Economic development, better medical care and living conditions, with enough safe drinking and washing water and less crowdedness are better than postexposure chemoprophylaxis and vaccination. Already Armauer Hansen visiting the Bergen colonists in North America in the early twentieth century noticed that with better housing and living conditions the immigrants stopped spreading leprosy and leprosy did not behave like an infectious disease anymore. Up until recently, immigrants in North West European countries did not spread leprosy in their new countries. However, in the current situation in which immigrants are "surviving" in Europe and America in camps and illegally in crowded unhygienic situations, M. leprae will spread and secondary cases are very likely to be seen.
The economic elite in these Western countries must create better socio-economic circumstances for the immigrants or they have to from a human right and dignity point of view develop a test that indicates which persons can develop the infectious disease leprosy followed by the provision of lifelong prophylaxis.
Ben
References:
1. Naafs B. Treatment of leprosy: science or politics? TM&IH 11 (2006) 268- 278
2. Naafs B. Treatment duration of reversal reaction: A reappraisal. Back to the past. Lepr. Rev. 74 (2003) 328-336
3. da Silva MB, et al. Evidence of zoonotic leprosy in Pará, Brazilian Amazon, and risks associated with human contact or consumption of armadillos.
PLoS Negl Trop Dis 2018. PMID 29953440
4. Turankar RP, Lavania M, Darlong J, Siva Sai KSR, Sengupta U, Jadhav RS. Survival of Mycobacterium leprae and association with Acanthamoeba from environmental samples in the
inhabitant areas of active leprosy cases: A cross sectional study from endemic pockets of Purulia, West Bengal.
Infect Genet Evol. 2019 Jan 15. pii: S1567-1348(19)30001-2. doi: 10.1016/j.meegid.2019.01.014. [Epub ahead of print)
5. Fokkens WJ, Nolst Trenite GJ, Virmond M, KleinJan A, Andrade VL, van Baar NG, Naafs B. The nose in leprosy: immunohistology of the nasal mucosa.
Int J Lepr Other Mycobact Dis. 1998 Sep;66(3):328-39.
6. Rambukkana A, Zanazzi G, Tapinos N, Salzer JL. Contact-dependent demyelination by Mycobacterium leprae in the absence of immune cells.
Science. 2002 May 3;296(5569):927-31.
7. Rambukkana A. Mycobacterium leprae-induced demyelination: a model for early nerve degeneration.
Curr Opin Immunol. 2004 Aug;16(4):511-8. Review.
8. Madigan CA, Cambier CJ, Kelly-Scumpia KM, Scumpia PO, Cheng TY, Zailaa J, Bloom BR, Moody DB, Smale ST, Sagasti A, Modlin RL, Ramakrishnan L. A Macrophage Response to
Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy. Cell. 2017 Aug 24;170(5):973-985.e10. doi: 10.1016/j.cell.2017.07.030
9. Bahia El Idrissi N, Das PK, Fluiter K, Rosa PS, Vreijling J, Troost D, Morgan BP, Baas F, Ramaglia V. M. leprae components induce nerve damage by complement activation: identification
of lipoarabinomannan as the dominant complement activator. Acta Neuropathol. 2015 May;129(5):653-67. doi: 10.1007/s00401-015-1404-5. Epub 2015 Mar 15
10. Bahia El Idrissi N, Iyer AM, Ramaglia V, Rosa PS, Soares CT, Baas F, Das PK. In Situ complement activation and T-cell immunity in leprosy spectrum: An immunohistological study on
leprosy lesional skin. PLoS One. 2017 May 15;12(5):e0177815. doi: 10.1371/journal.pone.0177815. eCollection 2017.
11. Verhagen C1, Faber W, Klatser P, Buffing A, Naafs B, Das P. Immunohistological analysis of in situ expression of mycobacterial antigens in skin lesions of leprosy patients across the
histopathological spectrum. Association of Mycobacterial lipoarabinomannan (LAM) and Mycobacterium leprae phenolic glycolipid-I (PGL-I) with leprosy reactions.
Am J Pathol. 1999 Jun;154(6):1793-804.
12. Ridley DS, Jopling WH Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis. 1966 Jul-Sep;34(3):255-73.
13. Leiker DL. Classification of leprosy. Lepr Rev. 1966 Jan;37(1):7-15
14. Naafs B, Kolk AH, Chin A Lien RA, Faber WR, Van Dijk G, Kuijper S, Stolz E, Van Joost T. Anti-Mycobacterium leprae monoclonal antibodies cross-react with human skin: an alternative explanation for the immune responses in leprosy. J Invest Dermatol. 1990 May;94(5):685-8
15. Naafs B. Leprosy reactions. New knowledge. Trop Geogr Med. 1994;46(2):80-4.
16. Singh I, Yadav AR, Mohanty KK, Katoch K, Sharma P, Mishra B, Bisht D, Gupta UD, Sengupta U.Molecular mimicry between Mycobacterium leprae proteins (50S ribosomal protein L2
and Lysyl-tRNA synthetase) and myelin basic protein: a possible mechanism of nerve damage in leprosy.
Microbes Infect. 2015 Apr;17(4):247-57. doi: 10.1016/j.micinf.2014.12.015.
17. Naafs B. et Van Droogenbroeck J.B.A. Décompression des névrites réactionnelles dans la lèpre: Justification physiopathologique et méthodes objectives pour en apprécier les
résultats. Méd. Trop. 37 (1977) 763-770
18. Fite GL. Leprosy from histopathologic point of view. Arch Pathol Lab Med 1943. 35:611–644.
19 Shetty VP, Mehta LN., Antia NH., Irani PF. Teased fibre study of early nerve lesions in leprosy and in contacts, with electrophysiological correlates Journal of Neurology, Neurosurgery,
and Psychiatry, 1977, 40, 708-7 11
20. Diogo Fernandes dos Santos. ?Hanseníase Neural Primária? na mesa redonda. 14º Congresso Brasileiro de Hansenologia 2017.
21. Browne SG. Leprosy. Documenta Geigy: Acta clinica , Ciba-Geigy, 1984
22. Das PK1, van den Wijngaard RM, Wankowicz-Kalinska A, Le Poole IC. A symbiotic concept of autoimmunity and tumour immunity: lessons from vitiligo.
Trends Immunol. 2001 Mar;22(3):130-6.
23. Naafs B. World leprosy day 2018: How forward respecting the past? Indian J Med Res. 2018 Jan;147(1):1-3. doi: 10.4103/ijmr.IJMR_109_18.
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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