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Men and COVID-19: Autoimmunity, OH MY!

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As COVID-19 social distancing practices are relaxed, new COVID-19 infections continue to be reported. There have been several disturbing reports regarding long-term post-infection consequences, including new evidence that COVID-19 infections may contribute to long-term changes in neurophysiology, glucose-insulin dysregulation, and increased autoimmune risks. The evidence for neurological changes is available in our recent CME webinar “LONG COVID-19: Unravelling the neurological consequences”. Clinicians must be alert to the possibility of post-COVID autoimmunity, because it does not follow the typical gender distribution for most autoimmune disorders – after a COVID-19 infection, the risk of autoimmune disease is highest in men.

 

Risk of post-COVID-19 autoimmunity

It's no secret that the majority of autoimmune conditions affect women, with females making up 78% of autoimmunity patients. While several autoimmune conditions specifically target men, such as myocarditis, Wegener granulomatosis, idiopathic pulmonary fibrosis, diabetes, and ankylosing spondylitis, most autoimmune conditions target women. Surprisingly, men may be at a higher risk of post-COVID autoimmunity than women. There is currently no consensus regarding the cause of the gender skewing in autoimmune disorders, however gender-based differences in the expression of certain types of immune response receptors vary in men and women. However, at least one of these receptors, toll-like receptor 9 (TLR9), participates in innate viral responses, has been implicated in several autoimmune conditions and is highly expressed in women.

A quick review of the primary COVID-19 risk factors gives the first clue about male predominance in COVID autoimmunity; COVID-19 infection risk factors include male gender, increasing age, and the presence of pre-existing chronic inflammatory conditions such as obesity, diabetes, heart disease, etc. The increased risk is primarily due to infection-associated tissue damage. COVID-19 infection inflames the vascular system, reducing capillary circulation of oxygen and nutrients. If prolonged, the loss of circulation in small vessels and capillaries results in tissue damage and cell death. Hypoxia and cell damage both result in the release of pro-inflammatory mediators that can result in both local and systemic inflammation.

While early studies indicated that only severe COVID-19 cases had an increased risk of autoimmunity, later studies suggest that even men with mild COVID-19 infection may carry increased autoimmunity risk. So, what is going on?

 

The liver is part of the immune system

The answer may lie in the liver. COVID-19 infection affects multiple organs, including the liver. Much of this liver damage occurs in the liver sinusoidal cells that normally induce tolerance and homeostasis, much like the gut mucosal surface. The sinusoid damage affects normal cross-talk on the liver-gut-microbiome axis. The damage has metabolic effects because the liver controls glucose/insulin metabolism, fat metabolism, and much of the body’s amino acid interconversion and metabolism. Multiple lines of evidence support liver involvement in post-COVID-19 autoimmunity, and the atypical male gender skewing:

  • Accumulating evidence from human studies indicates that the risk factors for developing a fatty liver are remarkably similar to risk factors for COVID-19 susceptibility: male gender, increasing age, high blood pressure, obesity, and pre-existing inflammation.
  • New studies indicate that after the resolution of the initial COVID-19 respiratory infection, COVID-19 may be shed in the stool for months. This viral shedding may indicate a more chronic gastrointestinal COVID-19 viral infection in some patients. Inflammatory signaling from this chronic COVID gut infection may continue to disrupt the liver-gut-microbiome axis and other immune responses.
    • Recent evidence indicates that disruptions to the gut microbiome (stress, illness, medications) may also contribute to the development of fatty liver. Studies associate microbiome disruptions with several autoimmune conditions.
  • Metabolic syndrome and fatty liver are mediated in part by overnutrition (excess fats, sugars, calories) via TLR9, which is also activated when a viral pathogen has been detected. TLR9 activation has also been implicated in the predominantly female association for most autoimmune conditions.
  • Liver fat metabolism is mediated by local histamine signaling. Histamine levels increase during COVID-19 infection or due to hypoxia and tissue damage.
  • Comorbid and pre-existing metabolic syndrome or type II diabetes pre-dispose for the development of additional autoimmune conditions. Both COVID-19 and severe acute respiratory (SARS) infection increase a survivor’s risk for glucose-insulin dysregulation and type II diabetes. The increased risk is due to infection-associated tissue damage in the pancreas and liver. A damaged liver cannot properly regulate glucose-insulin metabolism, fat metabolism, homeostasis or immune tolerance.

Damage to liver tissues may suppress other hepatic regulatory functions. Suppression of these liver regulatory functions may further predispose COVID-19 survivors for autoimmunity. The liver is the primary organ that removes circulating Ig (antibody) immune complexes. Higher circulating levels of auto- and environmental antibodies are common in autoimmune conditions; their deposition into joints and tissues results in pain, local inflammation and joint stiffness. The antibody complexes bind to, and are removed from, circulation by the liver receptor FcγRIIb2. While normally inhibitory and tolerant, FcγRIIb2 dysfunction develops with the occurrence of fatty liver fibrosis (damage), inflammation or other comorbid autoimmune conditions.

 

Mitochondrial function supports both liver and immune system

Both liver and immune system functions are reliant upon healthy mitochondrial function. Mitochondrial dysfunction occurs when there are increased levels of oxidative stress, inflammatory signaling, hypoxia and tissue damage Once on a dysfunctional path, it is difficult to re-establish normal mitochondrial function without external intervention. US BioTek’s dried urine Organic Acids profile can provide an overview of mitochondrial function, NAD+ and antioxidant status. Once interpreted, a supportive nutritional protocol can be developed:

 

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Decreasing the overall levels of histamine and circulating antibodies may also help prevent or minimize symptoms of autoimmunity. Avoidance of allergy (IgE/IgG4) or sensitivity (IgG/A) antigens, may decrease histamine and circulating antibody-antigen complexes from environmental sources: 

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Environmental (food or inhalant) antibody levels can be evaluated via IgE/IgG4 allergy or IgG/A sensitivity testing.

295 Food & Inhalant IgE Sample Report-nowatermarkSample Report - 208 Food Panel - IgA_IgG_IgG4-nowatermark

Conclusion

After a COVID-19 infection, mild or severe, there is an increased risk of developing neurological after-effects, metab olic syndrome/type II diabetes or an autoimmune disease. The autoimmune risks appear to be highest in men, and that risk may be increased by pre-exisiting inflammatory disorders, new onset metabolic syndrome or disruption of the gut-liver axis.

 

Clinicians must be aware of these risks and use all the tools at their disposal to evaluate such patients, such as US BioTek’s allergy and sensitivity testing and the Organic Acids profile. Decreasing environmental antibody excess, and supporting mitochondrial function, can decrease inflammation and improve health, immune tolerance and clinical success in the treatment of COVID-19 survivors.

 

References

Bwire GM. Coronavirus: Why Men are More Vulnerable to Covid-19 Than Women? SN Compr Clin Med. 2020;2(7):874-876. doi: 10.1007/s42399-020-00341-w.

Chang SE, Feng A, Meng W, Apostolidis SA, Mack E, Artandi M, Utz PJ. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat Commun. 2021 Sep 14;12(1):5417. doi: 10.1038/s41467-021-25509-3.

De Luca F, Shoenfeld Y. The microbiome in autoimmune diseases. Clin Exp Immunol. 2019;195(1):74-85.

Fairweather D, Frisancho-Kiss S, Rose NR. Sex differences in autoimmune disease from a pathological perspective. Am J Pathol. 2008;173(3):600-609.

 Gracia-Ramos AE, Martin-Nares E, Hernández-Molina G. New Onset of Autoimmune Diseases Following COVID-19 Diagnosis. Cells. 2021;10(12):3592.

Huang YP, Zhang S, Zhang M, et al. Gender-specific prevalence of metabolic-associated fatty liver disease among government employees in Tianjin, China: a cross-sectional study. BMJ Open. 2021;11(12):e056260.

Liu, Y., Ebinger, J.E., Mostafa, R. et al. Paradoxical sex-specific patterns of autoantibody response to SARS-CoV-2 infection. J Transl Med 19, 524 (2021).

Luci C, Bourinet M, Leclère PS, Anty R, Gual P. Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies. Front Endocrinol (Lausanne). 2020;11:597648.

Martín-Mateos R, Albillos A. The Role of the Gut-Liver Axis in Metabolic Dysfunction-Associated Fatty Liver Disease. Front Immunol. 2021 Apr 16;12:660179.

 Misto A, Provensi G, Vozella V, Passani MB, Piomelli D. Mast Cell-Derived Histamine Regulates Liver Ketogenesis via Oleoylethanolamide Signaling. Cell Metab. 2019 Jan 8;29(1):91-102.e5.

 Natarajan A, Zlitni S, Brooks EF, Vance SE, Dahlen A, Hedlin H, Bhatt AS. Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection. Med (N Y). 2022 Apr 13. doi: 10.1016/j.medj.2022.04.001. Epub ahead of print.

 Shepard CR. TLR9 in MAFLD and NASH: At the Intersection of Inflammation and Metabolism. Front Endocrinol (Lausanne). 2021 Jan 29;11:613639.

 Shetty S, Lalor PF, Adams DH. Liver sinusoidal endothelial cells - gatekeepers of hepatic immunity. Nat Rev Gastroenterol Hepatol. 2018 Sep;15(9):555-567.

Smith KG, Clatworthy MR. FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol. 2010 Sep;10(9):674.

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