Immunotoxicity of Mycotoxins-Immune Evasion:
The literature on trichothecenes list their immunotoxicity as possibly their most significant pathology. T-2 Toxin appears to represent the most toxic of the trichothecenes. Studies show T-2 toxin impairs the mouse response to Reovirus with suppressed immunoglobulin and interferon (Li, M. et al 200619). Pestka, J.J. et al 200420 found immune suppression by Deoxynivalenol and other trichothecenes with initial immune stimulation then suppression as the dose increased. Studies by Obremski, K. et al 201321 showed T-2 Toxin suppressed CD4, CD8 and CD21 in pig ileal Peyer’s patches. Wu, Q. et al 201822report downregulation of interferon, TGF-beta and Toll-like Receptors(TLR) with immune evasion. This could explain the recalcitrance of treatment against fungi. It also opens up the possibility to the use of the new PD-1/PD-L1 pathway inhibitors in ALS patients.
II. Biomarkers for ALS and Mycotoxins :
Biomarkers for ALS :
There are extensive lists of biomarkers for ALS. Lucas, T.V. & Bowser, R. 201723 reviewed the fluid-based biomarkers for ALS divided into neurofilament proteins, inflammatory markers, mRNA such as C0orf72 and metabolic biomarkers. It is interesting to compare the biomarkers for ALS with the biomarkers listed for common mycotoxins. The pattern of inflammatory biomarkers and metabolites are similar in mycotoxin toxicity compared to the pathology with ALS.
Biomarkers of Mycotoxins :
Mycotoxins have garnered increasing scrutiny given their prevalence in food and human environmental exposure. Vidal, A. et al 201824 did a comprehensive review of mycotoxin biomarkers. The development of ultra-high-performance liquid chromatography-high resolution mass spectroscopy has improved the accuracy and sensitivity of detecting food borne mycotoxins. The main mycotoxins found were trichothecenes from Fusarium species, Deoxynivalenol, one of the most frequently occurring fungal contaminants in food and feed worldwide. Nivalenol, Fusarenon-X, T-2 Toxin and Diacetoxyscirpenol are biomarkers of Fusarium species in food.
Fumonisins are secondary metabolites of Fusarium species found mainly in maize. They cause hepatotoxicity, nephrotoxicity and are possibly carcinogenic. They are notable for causing neurologic disease such as Equine Leukoencephalopathy as well as swine pulmonary edema, esophageal cancer and neural tube defects.
Ochratoxin A and Citrinin are products of Penicillium and Aspergillus found in cereals. They are possibly carcinogenic, but notable for nephrotoxicity along with neurotoxicity and immunotoxicity.
Zearalenone is a Fusarium metabolite known as a powerful estrogen mimic causing birth defects and breast cancer.
Aflatoxins are secondary metabolites of Aspergillus species. Of all the mycotoxins in human food, aflatoxins have the strongest association with cancer. Sterigmatocystin is precursor of aflatoxin produced by Aspergillus species. It has been associated with cancer in humans.
Mitochondrial Dysfunction & Biomarkers :
Mitochondrial dysfunction is a major finding in both ALS and with poisoning by trichothecenes neurotoxins. Kreb cycle intermediates in urine rise. Erythrocyte Protoporphyrins and Urine Fractionated Porphyrins are abnormal in a pattern suggesting a toxic exposure.
Immunologic Biomarkers :
One of the most prominent abnormal findings in both ALS and mycotoxin exposure is the suppression of the immune system. Immune deficits would be potential early clues to help follow the course of ALS or mycotoxin exposure. Suggested blood tests would be, IgG Subclass, IgA, IgM, IgE
Lymphocyte Mitogen Proliferation
Cytokines, IL-6, IL-2, Interferon-gamma
Immune Evasion :
Studies for PD-1/PD-L1 pathway abnormalities could uncover evidence of immune evasion. This could explain the recalcitrance of ALS to treatments.
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William K. Reid, M.D. Date
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