21 Responses

  1. Justin
    Justin at | | Reply

    Neuropathy is the result of damage to nerves which causes pain and numbness usually in hands and feet. In leprosy the neuropathy causes extensive damage to nerve endings as well as to the skin. Macrophages have been shown to be major contributors of neuropathy as the engulf cellular debris around damaged areas in order to allow the bodies repair mechanisms to infiltrate and fix the damaged nerve. As a result macrophages also cause harm to the nerve endings. Furthermore, leprosy bacteria seem to avoid the destroying effects of macrophages. The mechanism of why macrophages have trouble destroying the infection is unknown, but this study shows that macrophages eventually settle in one place and begin destroying the myelin sheath of the nerve. Another study showed that leprosy showed a major increase in cytokine activity necessary for macrophage function. Cytokine IFN gamma showed a major increase in tuberculoid leprosy as well as TNF alpha. Increased IFN could be a major contributor to this damage of nerves. IFN alpha is a major activator of macrophages. If macrophages are not attacking the proper area but still being activated by IFN alpha there would be a surplus of these macrophages attacking the wrong area. Furthermore, TNF alpha plays a role in cell signaling and is related to side effects, such as, fever and inflammation. If this cytokine shows an increase, as it does in leprosy, it may cause an increase in genes that should not necessarily be produced resulting in further damage to the nerve and increasing macrophage activation. The relationship between leprosy, macrophages, and cytokines is still unclear because of the difficulty in studying the disease but I believe that the link between the three is an important step in discovering its exact mechanism.

    1. Byron P. Lee
      Byron P. Lee at | | Reply

      In a study by de Sousa et al., discovered a novel cytokine IL-37 in macrophages from patients with the lepromatous leprosy (LL) form. (JR de Sousa 2017) Alternatively, IL-37 expression was much higher in keratinocytes, endotheliocytes, and lymphocytes from patients with the tuberculoid (TT) form. IL-37 negatively affects TNF-alpha in both macrophages and T lymphocytes in the skin (dermis). Since there is such a high level of IL-37 in the LL form, this may suggest that M2 macrophages are responding. This may be the missing link that you were asking for.

      JR de Sousa 2017

      1. Byron P. Lee
        Byron P. Lee at | | Reply

        I got way ahead of myself! Here is the actual link.

        DOI: 10.1016/j.cyto.2017.10.016

    2. Sarah Leeann Smart
      Sarah Leeann Smart at | | Reply

      A study published in Cellular Microbiology in 2014 studied how the Mycobacterium leprae utilizes cholesterol in its process to establish infection. The mycobacterium, once inside the host cell, resides in the phagosomes where it promotes cholesterol synthesis and exogenous uptake by upregulating genes associated with this metabolic pathway. By doing so, this is believed, in part, to turn infected macrophages into foam cells. It is shown that Mycobacterium leprae has substantial effects on lipid biogenesis, and significantly blocks lipid degredation. This “foamy” appearance has been witnessed in infected Scwhann cells near the ends of damaged nerves as well. Studies indicated that blocking lipid metabolism markedly decreased the bacteria’s survival, revealing a possible new method for therapeutics.


      1. Nate
        Nate at | | Reply

        This is an interesting find Sarah! It’s great that research is finding new methods of treatment for M. Leprae to use instead of the triple drug cocktail that is currently being used. Currently treatment includes clofazimine, dapsone, and rifampicin (1). Hopefully the new therapeutic agents will be less toxic and have fewer side effects on patients. Also, hopefully these finding will lead to drugs that won’t need to be taken like the current ones over a 6-12-month period (1).

        1. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184107

      2. Kingsley Nwaobasi
        Kingsley Nwaobasi at | | Reply

        Sarah Leeann Smart,
        To further understand your comment and cited work, I looked up a study which revealed that cholesterol metabolism in the intracellular survival of Mycobacterium laprae is not coupled to central carbon metabolism and energy production (1). In this study, it was observed that the bacteria M. laprae eagerly incorporated cholesterol, converted it to cholestenone both in vitro and in vivo. However, the study suggested that M. laprae has lost the capacity to degrade and utilize cholesterol as a nutritional source but it retained the enzyme responsible for its oxidation to cholestenone. Therefore, just like you suggested, I believe an understanding of cholesterol metabolism in the host cell will provide sufficient evidence on how this lipid supports M. leprae intracellularly hence, better therapies for leprosy will be developed.


      3. Owlette
        Owlette at | | Reply

        While the destruction of the Schwann cells indicates hypersensitivity as the cause for nerve damage in some forms of leprosy, Kumar et al discovered that hypersensitivity may play a lesser role in other forms of leprosy. Using electron microscope imaging to identify the structures of Schwann cells in various forms of Leprosy, the researchers were able to gather that borderline lepromatous (BL) and lepromatous leprosy (LL) had little to do with hypersensitivity reactions. However, hypersensitivity was revealed to be the primary cause for nerve damage in tuberculoid type (TT) and borderline tuberculoid (BT) leprosy.

        Source: https://www.ncbi.nlm.nih.gov/pubmed/24460757

    3. Robert Taylor IV
      Robert Taylor IV at | | Reply

      The macrophages can clear the nerve damage, but the problem with Leprosy is that it can permanently hide from the immune system. Therefore as one area is cleared another area is affected. It would be interesting to see the specific research on the focus of the bacteria removal with leprosy. Some treatments consist of drug cocktails but what if the underlying condition could be remedied to allow the nerve healing to be more efficient.


      1. Robert Taylor IV
        Robert Taylor IV at | | Reply
        1. Robert Taylor IV
          Robert Taylor IV at | | Reply

          Didn’t mean to post this link

  2. Zach M
    Zach M at | | Reply

    This paper proposes a great argument with regards to the function of macrophages in the immune response to leprosy and their role in nerve degeneration as part of the pathology. However, I am skeptical that it is solely the macrophages responsible for the action of demyelination and axonal degradation. I have found an interesting article by El Idrissi et al discussing additional mechanisms of the pathophysiology of Mycobacterium leprae illustrating the importance of the co-localization of CD3+ T-cells and the complement protein C3d in the paucibillary lesions to attract additional CD68+ macrophages to the site of infection. Skin biopsies were taken from patients presenting with lesions associated with M. leprae infections and in every sample tested CD3+ T-cells and C3d proteins were present and localized at the center of the lesion. The paper suggests that the T-cells and complement proteins are acting as homing beacons for CD68+ macrophages to be recruited to the area. While it is accepted that macrophages are responsible for nerve damage in these patients, I believe that it may also be likely that CD3+ T-cells, and potentially the complement pathway, may both also be implicated in this process given the co-localization demonstrated at the skin lesion sites in M. leprea infections.



    1. Rouzbeh Teimouri
      Rouzbeh Teimouri at | | Reply

      It is interesting that you mention that the suggested pathophysiological mechanism in the above article may not be the only one in action, and that the CD3 T cells may also be playing a role. Among the reasons why the pathophysiology of the disease is still surprisingly unknown is because our knowledge of the bacterium itself is also limited.
      There has been suggestions to increase focus on the molecular biology aspects of Mycobacterium leprae’s genome in order to better understand the bacterium’s mechanism of action, as well as all of the players that may partake in the disease (including our own cells). Understanding the molecular aspects of the disease takes precedence in tackling its symptoms. [1]
      This is also important because, as regards the means of fighting the disease (as antibiotics do not always work) there are ongoing efforts into creating vaccines for the disease; which, once again, would require the understanding of the molecular aspects of the disease. [1,2]
      [1] http://www.academia.edu/30036144/Leprosy_now_epidemiology_progress_challenges_and_research_gaps
      [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323495/

    2. Raeesa
      Raeesa at | | Reply

      Zach, You make a good point. I find it interesting that you ask this question.
      Leprosy is caused by a mycobacterium, which the macrophages can become infected with. Leading me to further this line of thought and ask if the infective nature of the bacteria is restricted to only macrophages or other phagocytic cells such a neutrophils?
      Tuberculosis, another disease caused by a Mycobacterium, also exhibits an infected macrophage response. In a study performed on zebra fish, it was found that the presence of infected mycobacterium is not what alerts neutrophils to respond. Rather, dying infected macrophages release caspase mediated signals to recruit neutrophils. The scientists also found that the neutrophils recruited to the infection sites containing infected macrophages were able to phagocytose the infected macrophages and effectively kill both the macrophage and its bacterial contents using oxidative mechanisms. However, very few neutrophils directly phagocytosed M. tuberculosis and even less became infected, suggesting that Mycobacterium have evolved to avoid neutrophils and recruit macrophages to aid in their spread through the body (1). It would be interesting to see similar connections being made with regards to M. leprae and M. lepromatosis and their interactions with neutrophils and other phagocytic cells such as dendritic cells.

      1) Neutrophils exert protection in the early tuberculous granuloma by oxidative killing of mycobacteria phagocytosed from infected macrophages (https://www.ncbi.nlm.nih.gov/pubmed/22980327)

  3. Panda Southtown
    Panda Southtown at | | Reply

    What a huge step forward for the mechanisms behind neuropathogenesis in leprosy!

    A few years ago, in 2014, another team of scientists were on the right track by looking at phenolic glycolipids (PLG-1, -2, and -3, respectively), along with p-hydroxybenzoic acid, for their potential in modulating different cytokines. Dr. Elsaidi and Dr. Lowary made their own analogues of PLG’s after studying their respective structures carefully and evaluating their abilities to modulate cytokines that help induce the inflammatory response: TNF-, IL-1, IL-6, MCP-1. Local levels of nitric oxide were also evaluated. Although these analogues ended up having little to no effect on these known cytokines, I felt it pertinent to give them some credit here for being on the right track.

    Another study, long ago in 2002, we can read more about the previous thinking involving Schwann cells in the PNS. Rambukkana and others recognized that demyelination is often linked to the inflammatory immune response, as in Wallerian Degeneration, Mycobacterium leprae was used in both in vitro nerve tissue cultures and in live Rag-1(-/-) mice, in order to observe demyelination in hosts that lack immune Effector cells (specifically B-cells and T-cells in the knockout mice). Schwann cells go on to demyelinate and reproduce even more of the unmyelinated Schwann cells, causing havoc by shirking their responsibilities and harboring the pathogen.


  4. Nate
    Nate at | | Reply

    A study published in 2015 found that the major virulence factor associated with M. Leprae, known as lipoararbinomannan (LAM), is the key activator of complement through the lectin pathway. A key finding was that neurons were found to be co-localized with LAM and membrane attack complexes (MAC) on their axons. Both MAC and LAM were found to contribute to nerve injury, by LAM interacting with the component that activates the complement cascade. This activation of the complement pathway leads to release of chemokines and chemo-attractant molecules which ultimately causes an inflammatory response and macrophage recruitment. It would be interesting to see if these findings are caused by the congregation of macrophages discussed in the blog, or if the two processes work simultaneously by different modes of attack in the destruction of nerve cells.

    Reference: https://link.springer.com/article/10.1007/s00401-015-1404-5

    1. Zach M
      Zach M at | | Reply

      It is interesting that LAM is found to be co-localized with the MAC at the sites of neuronal damage because I have found a recent paper showing LAM as a potential alternative lipid A conjugate for anti-tuberculosis vaccines. Wang et al propose a synthetic carbohydrate-based conjugate vaccine using LAM in place of the traditional monophophoryl lipid A (MPLA) molecule used in current Mycobacterium tuberculosis vaccines. The paper proves that the LAM substituted vaccine was able to illicit a “strong IgG antibody response, similar to that of the MPLA vaccine.” Given the implication of this molecule in the aggressive pathology of M. leprae and its proposed role in nervous damage, I am surprised that anyone would be looking at this for a potential vaccine target.



    2. Anthony Kram
      Anthony Kram at | | Reply

      Nate, it is very interesting to learn that lipoararbinomannan is thought to be the key activator complementary to the lectin pathway. After reading your comment, and learning also about how neurons we discovered to be co-localized with LAM and MAC on their respective axons, I located an article noted that, in mice, intraneural injections of M. leprae sonicate induces MAC deposition while resulting in changes to the nerves of the mouse (1). On the other hand, when inhibited, MAC actually preserves myelin and axons found in the mouse (1). In the article, it also was important to note that from their findings, they believe that in the leprosy nerves, LAM and MAC immunoreactivity was robust and largely greater in multibacillary when compared to paucibaillary donors (1). This also led to the finding of a noticeable association between LAM and MAC in samples believed to be diseased (1). They concluded that MAC is a contributor to damage found within the nerves of a M. leprae-induced injusry to the nerve, and the inhibition that occurs is believed to be neuroprotective (1).

      Citation (1): https://www-ncbi-nlm-nih-gov.ezproxy.gsu.edu/pubmed/25772973

  5. Philip Strate
    Philip Strate at | | Reply

    Similar to the above article on leprosy, macrophages in tuberculosis patients are also influenced by an invading pathogen to cause harm. Mycobacterium tuberculosis, the microorganism responsible for tuberculosis, has the ability to regulate inflammation, leading to its survival (1). In their article, Sasindran Et. Al. mentioned that cell mediated immunity resulted in the formation of granulomas, to which macrophages and the pathogen will be associated (1). The thing that is interesting about this is that the formation of granulomas and the introduction of activated T lymphocytes causes macrophage activation and the destruction of Mycobacterium tuberculosis cells. However, this microorganism is able to persist in granulomas in a latent state, due to the continued activation of T cells. The infection goes does dormant in many cases and can then reactivate, depending on the health of the host, but is protected by the granulomas brought about by macrophage involvement (1). Just as in leprosy, macrophages can be influenced by infecting microorganisms, resulting in a latent or persistent infection (1).


    1. A. Ferrell
      A. Ferrell at | | Reply

      Cellular processes that contribute to the evasion of the bacterium make it difficult to determine why Mycobacterium species are not destroyed. M. leprae can be avoided if doctors have immunoassays that detected M. leprae during initial infection. An acid-fast stain can be done to observed the mycobacterium. If done correctly, the acid-fast stain can identify the shape, size, and whether positive for mycolic acid. Unfortunately, acid-fast stains cannot determine the specific species. Moreover, M. leprae is a slow grower and environmental specific, making it difficult to be cultured and detected in the laboratory. The incubation period for M. leprae is approximately 9 months to 20 years which means that it can be days or years before symptoms are expressed, which is why health professional misdiagnosed patients (1). Further, individuals that do not express symptoms cannot provide a culture sample for health-care professionals. As well as, infected individuals that do not express symptoms may not seek medical care. Therefore, they cannot be treated for the disease during the acute phase. An immunoassay is available for the detection of M. leprae known as the Lepromin test. However, the lepromin test detects whether the patient has developed antibodies against the bacterium which can take 2 days to possible 4 weeks to see results of the test. In addition, M. leprae have six symptom classification types and the lepromin results are not sensitive for the final symptom: lepromatous leprosy due to lack of Th1 response which is needed to eradicate the mycobacterium (2). Lack of Th1 cytokines could be the reason the bacterium can hide in the macrophages. Cytokines and interferons are not being produced to recruit healthy effector cells or initiate apoptosis of the infected macrophages.

      1. http://www.sciencedirect.com/topics/medicine-and-dentistry/mycobacterium-leprae
      2. https://www.healthline.com/health/leprosy#types2

    2. Panda Southtown
      Panda Southtown at | | Reply


      I’m glad you chose an article supporting tuberculosis having a similar mechanism to leprosy. I found another article about tuberculosis in Zebrafish providing data supporting that individuals in a population that have cellular lysosomal storage disorders, or the deficiency of lysosomal cysteine cathepsin proteins, are often much more susceptible to to tuberlulosis. These unusual macrophages in this disorder results in amalgamated, undigested material in its lysosomes, thus they can’t continue the process of phagocytosing other dying cells or cell debris. These macrophages then go through apoptosis, which can’t be engulfed by other macrophages with the same disorder, thus the bacterial infection becomes exponentially worse much faster.
      This is also thought to compare to/be a similar mechanism to the typical smoker’s susceptibility to tuberculosis.


  6. Casey Seldon
    Casey Seldon at | | Reply

    This reprogramming of macrophages is presented by the authors of the blog in relation to a surface protein on the mycobacterium causing the macrophages to produce and release a toxic substance that damages mitochondria. Understanding how mycobacterium invade macrophages and alter their activity will be the key to preventing such an occurrence and future damage. A similar article in May of 2016, demonstrated that cell-surface-associated PDIM lipids are used to hide underlying pathogen-associated molecular patterns (PAMPs) which we learned are supposed to differentiate foreign cells/pathogens in our bodies. During repair of damaged tissues and nerves, incorporation of more macrophages is typical of such an immune response especially after damage, but if the fate of macrophages in the presence of the receptors on mycobacterium lies within reversing its benefit, then the treatment option for this bacterium must be incorporated by prevention.

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