Tuesday, 7 November 2017

The turn of the fungi

Fungal infections have not been widely studied in MS, many lines of evidence are consistent with a fungal etiology.
Front Neurol. 2017 Oct 16;8:535. doi: 10.3389/fneur.2017.00535. eCollection 2017.

The Role of Fungi in the Etiology of Multiple Sclerosis.

Benito-León J, Laurence M.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Infectious triggers of MS are being actively investigated. Substantial evidence supports the involvement of the Epstein-Barr virus (EBV), though other viruses, bacteria, protists, and fungi are also being considered. Many links between fungi and diseases involving chronic inflammation have been found recently. Evidence linking MS and fungi is reviewed here. The HLA-DRB1*15 allele group is the most important genetic risk factor of MS, and is a risk factor in several other conditions linked to fungal infections. Many biomarkers of MS are consistent with fungal infections, such as IL-17, chitotriosidase, and antibodies against fungi. Dimethyl fumarate (DMF), first used as an industrial fungicide, was recently repurposed to reduce MS symptoms. Its mechanisms of action in MS have not been firmly established. The low risk of MS during childhood and its moderate association with herpes simplex virus type 2 suggest genital exposure to microbes (including fungi) should be investigated as a possible trigger. Molecular and epidemiological evidence support a role for infections such as EBV in MS. Though fungal infections have not been widely studied in MS, many lines of evidence are consistent with a fungal etiology. Future microbiome and serological studies should consider fungi as a possible risk factor for MS, and future clinical studies should consider the effect of fungicides other than DMF on MS symptoms.



MS is a disease without a cause, making it for all intense and purposes a disease without a scope. It is important not to lose sight of the latter, since, it is all too easy to forget that we're not in fact treating the disease, but all the paraphernalia and manifestations that ensues afterwards. The potential plausible causes for MS are manifold, ranging from genetics through to environmental risk factors, and not surprisingly, as the immune system is involved infections are a natural choice for the theorists. In this review, J Benito-Leon and M Laurence impress upon the readers to consider fungal infections as another potential risk factor for MS.

So what evidence do they provide to support their assertions?


1) Genetic susceptibility -  HLA-DRB1*15, the strongest genetic association for MS has also been described in other chronic inflammatory disorders, such as allergic bronchopulmonary aspergillosis (an airway disorder) that have been linked to increased sensitivity to fungi.


2) Mannoproteins - immune recognition of mannoproteins found in fungal cell walls is recognized by the MMR (macrophage mannose receptor) on macrophages, which is also expressed by macrophages in active MS lesions, but not in inactive disease or in controls.


3) IL-17 - a cytokine produced by T cells (Th 17 cells) and innate immune cells in response to bacterial and fungal infections. C. albicans, a yeast, its surface mannoproteins readily induce IL-17 production compared to bacterial antigens. The response is so sensitive that even low fungal loads in the CNS may provoke an immune response.


4) Chitotriosidase - is a protein produced by activated macropages and breaks down chitin a sugar found in fungal cell walls. Elevated chitotriosidase levels have been reported in the CSF of PwMS.


5) Calprotectin - an antimicrobial complex produced predominantly by neutrophils (part of innate immune system) and fungi are particularly susceptible to its effects compared to bacteria. Elevated levels of CSF calprotectin have been noted during MS relapses. 


6) Dimethyl fumarate - interestingly is used to protect food from fungal infections and has also been used in psoriasis (an immune-mediated skin disorder) to improve symptoms. Psoriasis is well known to improve with anti-fungal agents, including nystatin, ketoconazole and itraconazole. Oral nystatin may also improve MS symptoms by acting in the gut.


The table below summarizes the findings linking MS to various infections:



Overall, I'm uncertain whether the authors provide sufficient evidence for a strong fungal aetiology in MS, when we compare it to the likes of EBV. This may well be due to a lack of enthusiasm in this area of research, rather than a true lack of good evidence. Undoubtedly, there is strong evidence for an infectious aetiology in MS; whether it be inside the CNS or outside of it, such as from the gut. But, it is also unclear by what mechanism(s) these agents increase the likelihood of developing autoimmune disorders.

18 comments:

  1. Great post

    This get the innate immune system in the mix also

    Obrigado

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  2. In going to get laughed at. But I notice when my athletes foot gets bad, my ms is at worse. Noticeable. I'm not sure if causal or not. But definitely a consistent observation.

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    1. Interesting observation. I've always wondered how much of worsening of MS symptoms after UTIs etc was exactly due to an augmented immune response. It's definitely seen in other autoimmune disorders, such as Stiff Person Syndrome.

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    2. I remember when this study came out

      https://www.nhs.uk/news/medication/athletes-foot-cream-could-also-treat-multiple-sclerosis/

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    3. There doesn't appear to have been any traction from these findings as far as clinical studies in PwMS are concerned. Worth considering...

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  3. I've read that medicinal mushrooms might help with remyelination in MS, (in mouse models). Willow bracket mushroom (Phellinus igniarius), mushroom extract.

    It would be kind of odd if MS aetiology was due to fungus, but fungus in the form of certain mushroom extract helped MS remyelination.

    Any thoughts on this?

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    1. This can get confusing, although a mushroom is a fungus there are different types of fungi; some harmful some not. Candida and Aspergillus are harmful. People have often studied medicinal properties of mushrooms and looking through pubmed there are a variety of publications looking at a extracts aiding myelination in petri dishes.

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    2. I might also add that fingolimod is based on myriocin, a fungal secondary metabolite...

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  4. This comes as no surprise to me at all. 19 years ago I went from overwhelming and painful fatigue that had lasted for 18 months (every afternoon was spent in bed recovering from the morning) to feeling pain free and full energy in 3 days. The only adjustment I had made was to remove all yeast from my diet. I was shocked and delighted in equal measure, as was my family. Some might say it must be the gluten in the bread but I carried on eating wheat bread that wasn't made with yeast.

    For obvious reasons I don't bother mentioning it very often, but I don't need validation from other people to know the stark difference it made to my health, it was a very swift and obvious life changer.

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  5. What I don't understand is how immunosuppression works if there is an active fungal or bacterial infection. Wouldn't it make it to exacerbate? Any infection that activates the immune system makes the MS worse as the opposite mechanism to immunosuppression.
    I really can get my head around the idea of an active infection and MS...

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    1. Firstly, we can't absolutely be sure of the level of infection or the immune response, or if their is still active infection present. But sometimes it's the balance between the two. I'll use Tuberculous meningitis (TBM) as an example. It is good to get an immune response but in some cases the chronic inflammation (because TB is quite indolent) with immune cells seeping out of blood vessels, the vessels become friable (vasculitis is the medical term). This can result in large brain infarctions as the blood supply is compromised. So we immunosuppress in these instances and it improves outcomes, with the fight against the infection continuing at a low grade.
      It is probably confusing, because many things might be happening at the same time and at different times, with no clear unifying trend (if that makes sense?).

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    2. Thank you Doc for your reply, thats really interesting!!
      Would we need to change the theory of the way MS is inherited? Because viruses can change the DNA easier and can infect the sperm/eggs (retroviruses at least). In that case I guess that there is an unknown predisposition and if you get a certain infection you can create autoimmunity, right (I am talking about the heritability of a.i.d. that runs families even when there is no known infection)?

      The EBV problem is that is a very common infection, so we might just prove ourselves without solid evidence.

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    3. This is what researchers are saying; HLA-DR15 haplotype and EBV are two of the strongest contenders for multiple sclerosis risk, and may be linked.

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  6. I've been concerned about fungal infections and catheters, leading to UTI's and worsening MS. Including candida.
    Sugar feeds fungus, so I've been cutting back on sugar in my diet.

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    1. With catheters its normally Candida and usually follows antibiotic use. Sometimes being diabetic doesn't help either. Fungal toe nail infections are one to watch out for and can lead to blood spread, so these should be treated whenever possible.

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  7. Have there been clinical studies looking at fungicides/antibiotics and MS-biomarkers (new lesions or progression) and what were the results?

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    1. Not that I'm aware of. In a letter to the editor of MSJ Griseofulvin was discussed as a potential treatment option but no evidence:

      "Griseofulvin, a microtubule antagonist, is an old antifungal agent whose immunomodulatory action has been known by dermatologists for many years; interestingly it has been found beneficial for several inflammatory skin disorders such as lichen planus,6 plasma cell cheilitis,7 systemic sclerosis,8 pigmented purpuric dermatosis (a skin capillaritis presenting as asymptomatic, purpuric macules on the lower extremities)9 and morphea.10
      The immunomodulatory effects of griseofulvin have been attributed to its potent inhibition of VCAM-1 and partial inhibition of E-selectin on endothelium, along with downregulation of basal L-selectin expression on neutrophils. It also inhibits the chemotaxis of neutrophils".

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  8. Inlusive Fingolimod is derived from miriocin (ISP-1) a metabolite of the fungus Isaria Sinclairii.

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