Autoimmunity

I was not born in the USA. I landed late in life, at the spot where Ponce de Leon sought the Fountain of Youth, and found instead a land of accelerated ageing.

Three-quarters of all Americans are now overweight or obese (1). A 2018 survey found that only 12.2% of Americans were metabolically healthy (2). A mere four years later (post-Covid), that figure had fallen to 7% (3). Metabolic stress speeds up the aging process. It is not surprising that non-communicable diseases are occurring earlier in life, and that life expectancy is falling (see below).

American public health is a slow-motion car crash, and American medics are trained as crash repair specialists. They have degrees in part replacement, tinkering and custom bodywork but little interest in maintenance. Keeping patients out of the pits does not generate income.

Even if they want to help their patients stay on the road, the medical profession doesn’t know how to do it. They understand pharmaceutical pharmacology, but only a few understand that Big Pharma’s drugs are a road to medeconomic ruin (4). The fork in the road that society must take to achieve better health, is set at the table of a better diet (4).

Americans’ profoundly unhealthy relationship with food has multiple knock-on effects. One telling example: their most intimate interactions with the outside world, and with themselves, have become extremely dysfunctional. Their immune systems are on the fritz.

Before 1900, allergy hardly existed (5). Today 25.7% of US adults have a seasonal allergy, 7.3% have eczema, and 6.2% have a food allergy. Generation Alpha is no better; 18.9% of US children have a seasonal allergy, 10.8% have eczema, and 5.8% have a food allergy (6).

Then there is the growing problem of autoimmunity, defined as the presence of adaptive immune components such as antibodies that are self-reactive. This is not harmful in itself, but it predicts the development of autoimmune disease where these components are now causing disease symptoms (7).

In the USA the number of people with anti-nuclear antibodies, the most commonly used marker for autoimmunity, increased by roughly 50% in the last quarter century (8). Over that same time period the frequency of autoimmune diseases in the population rose from 3% to as high as 8% in the USA (9). In the UK, that frequency now exceeds 10% (10).

These figures are stunning.

In 1969, when I was taught about autoimmune diseases, our professors described them as uncommon. They are now not only the third most common disease category after cancer and heart disease, but they have also become considerably more diverse. At the turn of the century only 20 autoimmune diseases were recognized. There are now well over 100.

It is also becoming apparent that many of these diagnostic entities may actually be syndromes consisting of multiple variants, driven by different genetic pathways (11, 12).

The usual narrative about increasing degenerative disease being an inevitable consequence of longer life expectancy fails here, comprehensively. American life expectancy has been trending down for some time, and in 2022 it fell below the 2000 watermark (13, 14).

What is going wrong?

In the search for causes of diseases, or changing patterns of disease, epidemiology often provides early and subsequent clues.

Autoimmune diseases began to increase about 40 years ago in the West, and more recently in the developing nations (15). Right now, the most rapid increases in ie IBD are occurring in the Middle East and in East Asia (16), which had not seen them previously.

One can immediately see a possible delayed association with the change-over to fast and ultra-processed foods, which started circa 1940 and has gathered speed ever since (ie 17). The US and UK are the two nations which consume the highest amounts of ultra-processed foods, and they appear to have the highest rates of autoimmune disease (15). Could there be a connection?

Let’s review non-food factors first.

The risk is significantly greater among persons with dual X chromosomes, formerly known as women. While there is emerging evidence of X-chromosome-derived proteins (and RNA) playing a contributory role in autoimmune disease (18), the ratio of women to men has remained annoyingly stable (despite the best efforts of the Tavistock Institute) and is therefore unlikely to be the problem here.

Thymectomy increases the risk of autoimmune disease (ie 19), as does thymic cancer (20). These factors don’t fit the epidemiology, as they are both relatively uncommon and have not significantly increased. Scabies, a sexually transmitted inflammatory skin infection, appears to increase the risk also (21). As the incidence of scabies is rising (ie 22), likely driven by promiscuity (23, 24), this may be contributing to the autoimmunity trend.

The proton pump inhibitors (PPI’s) are equally likely candidates. First introduced in 1989, they have recently been associated with a significantly increased risk of autoimmune disease (25). PPI’s are widely prescribed; sales are currently valued at US$ 2.8 billion, and are projected to hit US$ 4.9 billion by 2033 (26). This reflects the increasing numbers of individuals with conditions such as GERD / GORD due to overweight, obesity and an inactive lifestyle (27, 28).

Current thinking is that the PPI’s may disturb the immune system via changes in the microbiota, and the theory seems plausible (29-31). And as obesity, GERDS and dysbiosis have all taken off due to dietary shifts, this takes us back to food – and, again, the microbiota.

There has been a dramatic reduction in our intake of prebiotic fiber (32). This has caused wide-spread dysbiosis which impacts directly on immune functions, damages colonic epithelial barrier function and enables the translocation of enteric bacteria to sites elsewhere in the body (31, 33). In 2018, this was definitively shown (in my opinion) to be an important cause of autoimmune disease (33).

The theory holds that enteric microbes are now infecting cells in sites outside the gut. Those cells express fragments of the microbes on their surfaces, the immune system grapples with those fragments and our cells in the target tissue become collateral damage. Some autoimmune disease responds to those antibiotics which can enter cells … (34, 35).

There may be another dietary problem.

Most of the antigens that our immune systems react to are proteins or polysaccharides, present on the surface of pathogenic microorganisms. Our immune systems do not generally react to the proteins or polysaccharides (such as glycogen) that we make in our bodies. These are labeled as self / benign, as opposed to foreign / hostile. Which brings us to the redoubtable Polly Matzinger.

Former bartender, carpenter, jazz musician, playboy bunny and dog trainer, and currently a sheep farmer and head of a major lab within the NIH, Polly’s beautiful ‘danger theory’ of immune function, first published in 1994 (36), re-cast some of the very foundations of immunology.

Some basics for non-life scientists.

The ‘danger theory’ explains how immune responses can occur without infection – such as, for example, the sterile inflammation in osteoarthritis or in coronary artery disease. It proposes that immune systems did not evolve to enable self/non-self discrimination, but to identify, neutralize and clear anything causing tissue damage.

When the immune system reacts to an antigen such as one of the peanut proteins, it is actually reacting specifically and stereotactically to one or more epitopes. Epitopes are parts / shapes of the antigen that immune system components such as antibodies recognize and bind to – and these generally do not include the body’s own complex molecules, if these are intact.

In coronary artery disease, however, (and by implication in most other chronic inflammatory conditions), there is a local accumulation of oxidatively modified epitopes (OSE’s).

OSEs are signs of tissue damage, and are inter alia markers of excessively oxidized cell membranes. They occur in dead and dying cells, and in oxidized LDL cholesterol fractions and proteins. They look very like some of the epitopes (PAMPs) present on many pathogenic microorganisms, and they trigger a substantial, sterile immune (inflammatory) response (ie 37, 38).

OSEs are an important sub-class of the Danger- or Damage-Associated Molecular Patterns, aka DAMPs, described previously (39); and due to our appallingly unhealthy lifestyle, we are forming more OSEs and the wider categories of DAMPs and lifestyle-associated molecular patterns (LAMPs) in our bodies than ever before (39). This is one of the most important reasons why we are experiencing more chronic inflammation, and more chronic degenerative disease.

OSEs, DAMPs and LAMPs can all be cleared by the body, but if rates of formation exceed rates of clearance the pro-inflammatory epitopes accumulate. This creates progressively more tissue damage, mediated by the innate and the adaptive immune systems.

Extended activation of the adaptive immune system via OSE accumulation has now been linked to an increased risk of autoimmunity (40, 41 and especially 42). This link may conceivably extend to other LAMPs also (43, 44).

Proteins modified by lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) appear to be lead OSEs in triggering autoimmunity (40). These particular OSEs are formed in the body after excessive cell death and excessive oxidative stress. They are undoubtedly increased by the modern diet, which has replaced many of the traditional antioxidant phytonutrients with empty and pro-inflammatory calories.

They are also formed after the ingestion of fish oils unprotected by their natural chaperones, the amphiphilic polyphenols (44).

Unfortunately, the unprotected group includes most commercial fish oil supplements (45); which, if taken long-term, have been shown to drive increased oxidative stress (46, 47), increased levels of MDA and HNE and therefore increased formation of OSEs (48-51). This helps to explain why commercial fish oils do not provide any health advantages (52), and appear to raise the risk of a number of pathologies including atrial fibrillation (53).

NB. Omega 3 HUFA’s consumed in fish, which is the way we always used to obtain them, are not linked to autoimmune problems – and do not appear to be arrhythmogenic (54). In oily fish the omega 3’s are co-ingested with algal-derived chaperone polyphenols (55), which prevent or at least minimize the formation of toxic lipid peroxidation products (55).

It now appears that the huge sales of poorly formulated fish oil may, via OSE production, have contributed to the pandemic of autoimmune disease. In my view it is time to have these ineffective and probably toxic products removed from the marketplace.

Vitamin D appears to be involved in helping to reduce risk (56), which could be interpreted as a call for spending a little more time in the sun.

There is one last missing link, namely our old friends (57). Immunologists know exactly what these are, but for non-specialists these are a large group of commensals, non-pathogenic micro-organisms that used to live in our immediate environment, were involved in ‘training’ our immune systems and have been substantially removed (58).

Some of these old friends have recently been shown to reduce the intensity and/or risk of autoimmune reactions in pre-clinical models (59, 60), and the case for restoring our companion microbes is becoming very persuasive (61, and see next week).

If we ban badly formulated fish oils and put prebiotic fibers, antioxidants, anti-inflammatory compounds and a few old friends back into our diet, I predict that autoimmune disease will again become, as it once was, uncommon.

Next week: Why good fences make good neighbors. Polly Matzinger, meet Graham Rook

References

1. CDC National Center for Health Statistics, Obesity and Overweight, https://www.cdc.gov/nchs/fastats/obesity-overweight.htm
2. Araújo J, Cai J, Stevens J. Prevalence of Optimal Metabolic Health in American Adults: National Health and Nutrition Examination Survey 2009-2016. Metab Syndr Relat Disord. 2019 Feb;17(1):46-52. 
3. O’Hearn M, Lauren BN, Wong JB, Kim DD, Mozaffarian D. Trends and Disparities in Cardiometabolic Health Among U.S. Adults, 1999-2018. J Am Coll Cardiol. 2022 Jul 12;80(2):138-151.
4. https://drpaulclayton.eu/blog/end-of-the-road/
5. Platts-Mills TA. The allergy epidemics: 1870-2010. J Allergy Clin Immunol. 2015 Jul;136(1):3-13. 
6. CDC National Center for Health Statistics, Press Release January 26, 2023 https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/20220126.htm
7. Selmi C, Ceribelli A, Generali E, Scirè CA, Alborghetti F, Colloredo G, Porrati L, Achenza MI, De Santis M, Cavaciocchi F, Massarotti M, Isailovic N, Paleari V, Invernizzi P, Matthias T, Zucchi A, Meroni PL. Serum antinuclear and extractable nuclear antigen antibody prevalence and associated morbidity and mortality in the general population over 15 years. Autoimmun Rev. 2016 Feb;15(2):162-6.
8. Dinse GE, Parks CG, Weinberg CR, Co CA, Wilkerson J, Zeldin DC, Chan EKL, Miller FW. Increasing Prevalence of Antinuclear Antibodies in the United States. Arthritis Rheumatol. 2020 Jun;72(6):1026-1035.
9. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997 Sep;84(3):223-43.
10. Conrad N, Misra S, Verbakel JY, Verbeke G, Molenberghs G, Taylor PN, Mason J, Sattar N, McMurray JJV, McInnes IB, Khunti K, Cambridge G. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet. 2023 Jun 3;401(10391):1878-1890.
11. Rivas-Larrauri F, Yamazaki-Nakashimada MA. Systemic lupus erythematosus: Is it one disease? Reumatol Clin. 2016 Sep-Oct;12(5):274-81. 
12. Catalina MD, Owen KA, Labonte AC, Grammer AC, Lipsky PE. The pathogenesis of systemic lupus erythematosus: Harnessing big data to understand the molecular basis of lupus. J Autoimmun. 2020 Jun;110:102359.
13. Arias E. United States Life Tables, NVSS, Dec 19, 2002 https://www.cdc.gov/nchs/data/nvsr/nvsr51/nvsr51_03.pdf
14. Yan BW, Arias E, Geller AC, Miller DR, Kochanek KD, Koh HK. Widening Gender Gap in Life Expectancy in the US, 2010-2021. JAMA Intern Med. 2023 Nov 13:e236041. 
15. Lerner A, Jeremias P, Matthias T. The World Incidence and Prevalence of Autoimmune Diseases is Increasing. Int J Coeliac Dis. (2105) 3(4), 151-155
16. Chen X, Xiang X, Xia W, Li X, Wang S, Ye S, Tian L, Zhao L, Ai F, Shen Z, Nie K, Deng M, Wang X. Evolving Trends and Burden of Inflammatory Bowel Disease in Asia, 1990-2019: A Comprehensive Analysis Based on the Global Burden of Disease Study. J Epidemiol Glob Health. 2023 Dec;13(4):725-739. 
17. Pressler M, Devinsky J, Duster M, Lee JH, Glick CS, Wiener S, Laze J, Friedman D, Roberts T, Devinsky O. Dietary Transitions and Health Outcomes in Four Populations – Systematic Review. Front Nutr. 2022 Feb 9;9:748305.
18. Dou DR, Zhao Y, Belk JA, Zhao Y, Casey KM, Chen DC, Li R, Yu B, Srinivasan S, Abe BT, Kraft K, Hellström C, Sjöberg R, Chang S, Feng A, Goldman DW, Shah AA, Petri M, Chung LS, Fiorentino DF, Lundberg EK, Wutz A, Utz PJ, Chang HY. Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell. 2024 Feb 1;187(3):733-749.e16.
19. Lin TM, Chang YS, Hou TY, Hsu HC, Lin SH, Chen WS, Kuo PI, Lin YC, Chen JH, Chang CC. Risk of incident autoimmune diseases in patients with thymectomy. Ann Clin Transl Neurol. 2020 Jul;7(7):1072-1082.
20. Singhal S, Hellyer J, Ouseph MM, Wakelee HA, Padda SK. Autoimmune Disease in Patients With Advanced Thymic Epithelial Tumors. JTO Clin Res Rep. 2022 Apr 21;3(5):100323. 
21. Liu JM, Chiu FH, Lin CY, Chang FW, Hsu RJ. Incidence of autoimmune diseases in patients with scabies: a nationwide population-based study in Taiwan. Rheumatol Int. 2017 Jul;37(7):1125-1134. 
22. Reichert F, Schulz M, Mertens E, Lachmann R, Aebischer A. Reemergence of Scabies Driven by Adolescents and Young Adults, Germany, 2009-2018. Emerg Infect Dis. 2021 Jun;27(6):1693-1696.
23. Chosidow O. Clinical practices. Scabies. N Engl J Med. 2006;354:1718–27.
24. Otero L, Varela JA, Espinosa E, Sánchez C, Junquera ML, del Valle A, Vázquez F. Sarcoptes scabiei in a sexually transmitted infections unit: A 15-year study. Sex Transm Dis. 2004;31:761–5.
25. Lin SH, Chang YS, Lin TM, Hu LF, Hou TY, Hsu HC, Shen YC, Kuo PI, Chen WS, Lin YC, Chen JH, Chang CC. Proton Pump Inhibitors Increase the Risk of Autoimmune Diseases: A Nationwide Cohort Study. Front Immunol. 2021 Sep 30;12:736036.
26. Future Market Insights: https://www.globenewswire.com/news-release/2023/06/29/2697107/0/en/Global-Proton-Pump-Inhibitors-Market-is-Set-to-Reach-US-4-9-Billion-by-forecast-ending-2033-at-a-CAGR-of-5-2-Data-analysis-by-Future-Market-Insights-Inc.html  Accessed 29.3.24
27. El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol. 2007 Jan;5(1):17-26. 
28. Yamasaki T, Hemond C, Eisa M, Ganocy S, Fass R. The Changing Epidemiology of Gastroesophageal Reflux Disease: Are Patients Getting Younger? J Neurogastroenterol Motil. 2018 Oct 1;24(4):559-569.
29. Freedberg DE, Lebwohl B, Abrams JA. The impact of proton pump inhibitors on the human gastrointestinal microbiome. Clin Lab Med. 2014;34:771–85.
30. Singh A, Cresci GA, Kirby DF. Proton pump inhibitors: risks and rewards and emerging consequences to the gut microbiome. Nutr Clin Pract. 2018;33:614–24.
31. https://drpaulclayton.eu/blog/a-place-for-everything/
32. https://drpaulclayton.eu/blog/the-mandible-claw/
33. Manfredo Vieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Khan N, Costa FRC, Tiniakou E, Greiling T, Ruff W, Barbieri A, Kriegel C, Mehta SS, Knight JR, Jain D, Goodman AL, Kriegel MA. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science. 2018 Mar 9;359(6380):1156-1161.
34. Rosman Y, Lidar M, Shoenfeld Y. Antibiotic Therapy in Autoimmune Disorders. Clin. Pract. (2014) 11(1), 91–103
35. Walters JD. Characterization of minocycline transport by human neutrophils. J Periodontol. 2006 Dec;77(12):1964-8.
36. Matzinger P. (1994). Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045
37. Leibundgut G, Witztum JL, Tsimikas S. Oxidation–specific epitopes and immunological responses: Translational biotheranostic implications for atherosclerosis. Curr Opin Pharmacol. 2013;13(2):10.1016/j.coph.2013.02.005.
38. Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, Boullier A, Gonen A, Diehl CJ, Que X, Montano E, Shaw PX, Tsimikas S, Binder CJ, Witztum JL. Oxidation–Specific Epitopes Are Danger–Associated Molecular Patterns Recognized by Pattern Recognition Receptors of Innate Immunity. Circ Res. 2011;108(2):235–248.
39. https://drpaulclayton.eu/blog/innately-trained/
40. Wang G, Li H, Firoze Khan M. Differential oxidative modification of proteins in MRL^+/+ and MRL/lpr mice: Increased formation of lipid peroxidation-derived aldehyde-protein adducts may contribute to accelerated onset of autoimmune response. Free Radic. Res. 2012;46:1472–1481.
41. Binder CJ, Papac–Milicevic N, Witztum JL. Innate sensing of oxidation–specific epitopes in health and disease. Nat Rev Immunol. 2016;16(8):485–497.
42. Gershov D, Kim S, Brot N, Elkon KB. C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. J. Exp. Med. 2000;192:1353–1364.
43. Kurien BT, Hensley K, Bachmann M, Scofield RH. Oxidatively modified autoantigens in autoimmune diseases. Free Radic Biol Med. 2006 Aug 15;41(4):549-56. 
44. Krzemień P, Kasperczyk S, Banach M, Kasperczyk A, Dobrakowski M, Tomasik T, Windak A, Mastej M, Catapano A, Ray KK, Mikhailidis DP, Toth PP, Howard G, Lip GYH, Tomaszewski M, Charchar FJ, Sattar N, Williams B, MacDonald TM, Penson PE, Jóźwiak JJ. Serum antinuclear autoantibodies are associated with measures of oxidative stress and lifestyle factors: analysis of LIPIDOGRAM2015 and LIPIDOGEN2015 studies. Arch Med Sci. 2021 Jul 3;19(5):1214-1227.
45. https://drpaulclayton.eu/blog/thanks-for-all-the-fish/
46. Tsuduki T, Honma T, Nakagawa K, Ikeda I, Miyazawa T. Long-term intake of fish oil increases oxidative stress and decreases lifespan in senescence-accelerated mice. Nutrition. 2011 Mar;27(3):334-7.
47. Sen CK, Atalay M, Agren J, Laaksonen DE, Roy S, Hänninen O. Fish oil and vitamin E supplementation in oxidative stress at rest and after physical exercise. J Appl Physiol (1985). 1997 Jul;83(1):189-95.
48. Larsson K, Tullberg C, Alminger M, Havenaar R, Undeland I. Malondialdehyde and 4-hydroxy-2-hexenal are formed during dynamic gastrointestinal in vitro digestion of cod liver oils. Food Funct. 2016 Aug 10;7(8):3458-67. 
49. Larsson K, Harrysson H, Havenaar R, Alminger M, Undeland I. Formation of malondialdehyde (MDA), 4-hydroxy-2-hexenal (HHE) and 4-hydroxy-2-nonenal (HNE) in fish and fish oil during dynamic gastrointestinal in vitro digestion. Food Funct. 2016 Feb;7(2):1176-87.
50. Tullberg C, Larsson K, Carlsson NG, Comi I, Scheers N, Vegarud G, Undeland I. Formation of reactive aldehydes (MDA, HHE, HNE) during the digestion of cod liver oil: comparison of human and porcine in vitro digestion models. Food Funct. 2016 Mar;7(3):1401-12.
51. Tullberg C, Vegarud G, Undeland I. Oxidation of marine oils during in vitro gastrointestinal digestion with human digestive fluids – Role of oil origin, added tocopherols and lipolytic activity. Food Chem. 2019 Jan 1;270:527-537.
52. https://drpaulclayton.eu/blog/fish-oil-upgrade-to-snake-oil/
53. Huh JH, Jo SH. Omega-3 fatty acids and atrial fibrillation. Korean J Intern Med. 2023 May;38(3):282-289.
54. Qian F, Tintle N, Jensen PN, Lemaitre RN, Imamura F, Feldreich TR, Nomura SO, Guan W, Laguzzi F, Kim E, Virtanen JK, Steur M, Bork CS, Hirakawa Y, O’Donoghue ML, Sala-Vila A, Ardisson Korat AV, Sun Q, Rimm EB, Psaty BM, Heckbert SR, Forouhi NG, Wareham NJ, Marklund M, Risérus U, Lind L, Ärnlöv J, Garg P, Tsai MY, Pankow J, Misialek JR, Gigante B, Leander K, Pester JA, Albert CM, Kavousi M, Ikram A, Voortman T, Schmidt EB, Ninomiya T, Morrow DA, Bayés-Genís A, O’Keefe JH, Ong KL, Wu JHY, Mozaffarian D, Harris WS, Siscovick DS; Fatty Acids and Outcomes Research Consortium (FORCE). Omega-3 Fatty Acid Biomarkers and Incident Atrial Fibrillation. J Am Coll Cardiol. 2023 Jul 25;82(4):336-349.
55. https://www.greenpasture.org/blog/polyphenols-and-pigments-in-fish-oil/
56. XiaojunY, Xiancui L, Chengxu Z, Xiao F. Prevention of fish oil rancidity by phlorotannins from Sargassum kjellmanianum. J Appl Phycol. 8, 201–203 (1996). Costenbader KH, Cook NR, Lee IM, Hahn J, Walter J, Bubes V, Kotler G, Yang N, Friedman S, Alexander EK, Manson JE. Vitamin D and Marine n-3 Fatty Acids for Autoimmune Disease Prevention: Outcomes at Two Years after VITAL Trial Completion. Arthritis Rheumatol. 2024 Jan 25. doi: 10.1002/art.42811.
57. Rook GA, Lowry CA, Raison CL. Microbial ‘Old Friends’, immunoregulation and stress resilience. Evol Med Public Health. 2013 Jan;2013(1):46-64.
58. Flandroy L, Poutahidis T, Berg G, Clarke G, Dao MC, Decaestecker E, Furman E, Haahtela T, Massart S, Plovier H, Sanz Y, Rook G. The impact of human activities and lifestyles on the interlinked microbiota and health of humans and of ecosystems. Sci Total Environ. 2018 Jun 15;627:1018-1038. 
59. Fahlquist-Hagert C, Sareila O, Rosendahl S, Holmdahl R. Variants of beta-glucan polysaccharides downregulate autoimmune inflammation. Commun Biol. 2022 May 12;5(1):449.
60. Karumuthil-Melethil S, Gudi R, Johnson BM, Perez N, Vasu C. Fungal β-glucan, a Dectin-1 ligand, promotes protection from type 1 diabetes by inducing regulatory innate immune response. J Immunol. 2014 Oct 1;193(7):3308-21.
61. Murdaca G, Greco M, Borro M, Gangemi S. Hygiene hypothesis and autoimmune diseases: A narrative review of clinical evidences and mechanisms. Autoimmun Rev. 2021 Jul;20(7):102845.