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.


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.

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