Leprosy Mailing List – November 16, 2016
Ref.: (LML) I was dreaming
From: Ben Naafs, Munnekeburen, the Netherlands
Dear Pieter,
I was dreaming, may be half a sleep, last night, trying to understand nerve damage in leprosy.
A person is infected by M.leprae. Thereafter he will have bacilli alive, or dead and decaying, circulating in his blood. These antigens will be exposed to the innate and adaptive immune system. Most of the antigens will be opsonised by macrophages. He may develop or has already developed a more or less effective immune reaction depending on his genetic constitution, the place of entry of the mycobacteria and earlier contact with other bacteria or antigens relevant for the immune response to M.leprae.
The nerves of the person are exposed to micro traumata being stretched by bending joints (elbow, wrist, knee, ankle) or other traumata (Weddell). The vasculature in the traumatised area will develop receptors for cleaning and repairing cells, among them the bacilli and antigen containing macrophages (Scollard). These than will enter the traumatised area: the endoneurium, containing these blood vessels. The macrophages will die or change, take up more material and will expose Schwann cells to their antigenic material ao LAM, PGL1 and bacilli. It is difficult for them to leave the endoneurium, for the endoneurium has no lymph vessels while the perineurium is not permeable.
The bacilli may have started to multiply inside the macrophage or not. In 80% of the infected people they may not, because the macrophage either destroys the bacilli or deprives them from the nutrients and enzymes which they need to survive. Then the bacilli, if still alive, or at least their antigens particularly LAM, come in contact with the Schwann cell lying around or in contact with axons. The bacilli may enter the Schwann cell the way Rambukana proposed and may just stay as persisters, multiply or disintegrate. LAM may come in contact with the Schwann cell and activates the complement system as proposed by El Idrissi and Das. This may cause a little inflammation but most importantly it will lead to formation of MAC which will make “holes” in the Schwann cell and whereas the Schwann cell will disintegrate, the demyelisation will be a fact. The hall mark of leprosy: segmental demyelination.
The demyelisation may be minute, even not detectable with the methods used. This may be the case in contacts. But it may as well continue and give further demyelination in particular in MB patients (by now they have become patients since the nerve damage may become detectable). In PB patients a CMI against M.leprae antigenic determinants develops with granuloma which may destroy perineurium and endoneurium and even may cause abscesses.
In course of time reactions T1R and T2R may happen. T1R in Borderline patients and T2R in Borderline and lepromatous patents.
In T1R the CMI gives rise to oedema. Since the perineurium is not permeable and since there are no lymph vessels in the endoneurium the pressure inside will increase. This will lead to further demyelisation and compression of the axons, which will collapse and prevent nutrients from reaching the peripheral part of the axon. In due time the distal part of the axon will die. This can beautifully be shown by Nerve Conduction Studies as have been done by Garbino who found a decreasing conduction speed and a smaller surface of the compound action potential during T1R, a reaction which may take many months to resolve and leaves a lot of damage.
In T2R there is an inflammation due to immune complex formation and consequently complement activation. These reactions last for about one week till one month (as written by De Souza Arauyo already in 1929). These will lead to severe compression on the axons in the endoneurium and even to a conduction block (Garbino). Since the reaction is relatively short it will not do much damage, but will cause problems when it happens too often.
Occasionally, when the reaction has abated the pressure in the nerves remains high. This could be due to the fact that arterioles and venules obliquely pass through the often thickened perineurium. They are then being compressed due to the endoneural pressure. This diminishes the outflow of the venules which pressure is lower than that of the arterioles and which maintains the endoneural pressure and causes more oedema (Naafs). Further damage will be the result which may lead to anoxaemia when the inflow through the arterioles becomes less. In the end there will be only a near fibrosed nerve left. Still there may be reactions and demyelisation due to remnant antigens and pressure on the nerve. Neuropathic pain may persist in a further near almost useless nerve.
Finally something about Lepra bonita. There is no demyelisation because most likely there is no complement activation by LAM. The Lucio phenomenon is just a blocking of the venules in the skin due to the number of bacilli which leads to infarction.
Ben Naafs
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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