Immune Supportive Agents and Considerations for Autoimmunity

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Cclogo.svgDr Carrie Decker ND explores the role of a number of nutrients in the management of immune responses to challenges. The topic of infection and related illness are often of concern in the autumn and through the winter, with many people having increased exposures with children back at school and confined to the indoors. The use of immune supportive supplements is common practice for many individuals both as a preventative as well as for treatment of acute infection. Keeping healthy in the face of exposure to infection and supporting the body to recover from an illness when it does occur are both considerations, and many supplements such as probiotics, vitamin D, vitamin C, and vitamin A are commonly utilised for this purpose.

The use of probiotics for the prevention of upper respiratory tract infections (URTI) was the subject of a recent Cochrane review.[1] From the evaluation of 13 randomised controlled trials, it was determined that probiotics were more effective than placebo for reducing the number of individuals experiencing an acute URTI, the mean duration of an acute URTI, antibiotic use and cold-related school absence. It is useful to have the support of a Cochrane review that shows evidence for the use of probiotics for prevention of upper respiratory infections, however anyone who has experience in using or recommending probiotics as therapies is well aware that a wide array of different bacterial strains can be found on the market.

One probiotic strain that has evidence specifically for stimulating immune function is heat-killed Lactobacillus plantarum L-137. Heat-killed L. plantarum has been found in human studies to increase the T helper (Th) 1 type immune response, which generally speaking represents an increased cell-mediated response to an infection.[2] The use of heat-killed L. plantarum L-137 has also been specifically studied in the setting of URTI.[3] In this study, the incidence of URTI was significantly lower in the group taking this probiotic daily. Negative correlations also were seen with URTI duration and severity relative to the duration of intake of the probiotic.

The yeast strain Saccharomyces boulardii is often thought of for prevention of antibiotic-associated diarrhea, but it also supports mucosal immune response and production of secretory IgA (sIgA).[4] Mucosal sIgA is one of the first lines of defense of the upper respiratory epithelium as well as the oral cavity, gastrointestinal tract, and genitourinary tract. Secretory IgA functions as part of both the adaptive and innate immune systems, binding with antigens, neutralising toxins, and interfering with microbial binding and infectious process.[5],[6],[7] By supporting production of sIgA, S. boulardii helps to protect the body from infection.

In recent years there have been numerous clinical studies looking at the impact vitamin D levels may have on the risk of infectious disease. Lower vitamin D levels have been associated with larger tonsil size and recurrent tonsillopharyngitis in children.[8] Average serum values of vitamin D 25-OH were shown to be higher in healthy controls versus children with recurrent tonsillitis, and 78% of children undergoing tonsillectomy had vitamin D levels less than 75nmol/L (30ng/mL).[9] Vitamin D levels below this same threshold is also associated with an increased incidence of URTI and community acquired pneumonia.[10],[11] The association between low vitamin D levels and increased risk of URTI is even higher in populations with asthma and chronic obstructive pulmonary disease. Vitamin D supplementation may be particularly helpful for prevention of URTI in children with asthma.[12]

Vitamin C has long been used as a treatment for illness such as the common cold. Vitamin C improves the function of antimicrobial and natural killer cell activities, lymphocyte proliferation and chemotaxis, and also functions as an antioxidant and a cofactor in numerous enzymatic reactions.[13] Vitamin C has been observed to shorten the duration and severity of colds.[14] In individuals subject to high levels of physical exercise, supplementation with vitamin C has been shown to reduce the risk of experiencing a cold as well.[15] Clinically, severe vitamin C deficiency is uncommon (resulting in scurvy), however under situations which are associated with chronically higher oxidative stress levels (such as smoking) increased intake may be necessary.[16]

Vitamin A plays a role in immune balance as well as T cell activation in the setting of infection.[17] Vitamin A depletion is associated with increased risk of developing infectious disease.[18],[19] Vitamin A supplementation in children with diarrhoea and acute lower-respiratory-tract infections was found to reduce severity and overall incidence of diarrhoea.[20] Supplementation of children with vitamin A was shown in a meta-analysis to reduce all cause mortality by 24%, with the most significant impact on diarrhoea.[21] High doses of vitamin A (200,000IU on two consecutive days) also has been shown to reduce the risk of mortality and pneumonia-specific mortality in children.[22]

Autoimmune disease and immune support

A topic of concern with immune support and stimulation is the issue of autoimmunity. In individuals with autoimmune disease, when the immune system is activated, this can be associated with increased attack on self-antigens and worsening symptoms of disease. With autoimmune disease immune tolerance for normal self-antigens is deficient, leading to over-reactivity of the immune system against self and other antigens. Natural therapies that encourage the development of immune tolerance can reduce symptomatic presentation and disease progression for individuals with autoimmune disease.

Adequate vitamin D status may be protective against autoimmune disease, as well mental illness, cardiovascular disease, cancer, and other health conditions.[23] T-cells, particularly the development of suppressor regulatory T-cells, exhibit direct responses to 1,25-dihydroxyvitamin D.[24],[25] Retinoic acid, a metabolite of vitamin A, also promotes a T-cell regulatory response and reduction of autoimmunity.17,[26] The probiotic strain L. plantarum was shown in an in vivo randomised double-blind study to modulate cellular pathways that correlated with the establishment of immune tolerance in healthy adults.[27] This suggests that the probiotics strain L. plantarum may be useful for individuals with autoimmune disease on an ongoing basis, not just for prevention of infection or illness.

Vitamin C also may offer benefit to individuals with autoimmune disease. Vitamin C has been observed to dose dependently inhibit the levels of LPS-induced monocytes producing interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in vitro.[28] Vitamin C also has been shown to inhibit nuclear factor kappa beta (NF-κB) activation by TNF-α by various pathways in vitro.[29],[30] Vitamin C also supports the sparing of glutathione, a major antioxidant in the body, which is often subject to depletion in individuals with autoimmune disease.[31],[32]

References

[1] Hao, Q, Dong BR, Wu T. Probiotics for preventing acute upper respiratory tract infections. Cochrane Database Syst Rev. 2015 Feb 3;2:CD006895. View Abstract

[2] Hirose Y, et al. Daily intake of heat-killed Lactobacillus plantarum L-137 augments acquired immunity in healthy adults. J Nutr. 2006 Dec;136(12):3069-73. View Full Paper

[3] Hirose Y, et al. Oral intake of heat-killed Lactobacillus plantarum L-137 decreases the incidence of upper respiratory tract infection in healthy subjects with high levels of psychological stress. J Nutr Sci. 2013 Dec 6;2:e39. View Full Paper

[4] Buts JP, et al. Stimulation of secretory IgA and secretory component of immunoglobulins in small intestine of rats treated with Saccharomyces boulardii. Dig Dis Sci. 1990 Feb;35(2):251-6. View Abstract

[5] Mantis NJ, Rol N, Corthésy B. Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 2011 Nov;4(6):603-11. View Full Paper

[6] Brandtzaeg P. Secretory IgA: Designed for Anti-Microbial Defense. Front Immunol. 2013 Aug 6;4:222. View Full Paper

[7] Royle L, et al. Secretory IgA N- and O-glycans provide a link between the innate and adaptive immune systems. J Biol Chem. 2003 May 30;278(22):20140-53. View Full Paper

[8] Yildiz I, Unuvar E, Zeybek U, Toptas B, Cacina C, Toprak S, Kilic A, Aydin S. The role of vitamin D in children with recurrent tonsillopharyngitis. Ital J Pediatr. 2012 Jun 8;38:25. View Full Paper

[9] Reid D, Morton R, Salkeld L, Bartley J. Vitamin D and tonsil disease–preliminary observations. Int J Pediatr Otorhinolaryngol. 2011 Feb;75(2):261-4. View Abstract

[10] Ginde AA, Mansbach JM, Camargo CA Jr. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009 Feb 23;169(4):384-90. View Full Paper

[11] Quraishi SA, Bittner EA, Christopher KB, Camargo CA Jr. Vitamin D status and community-acquired pneumonia: results from the third National Health and Nutrition Examination Survey. PLoS One. 2013 Nov 15;8(11):e81120. View Full Paper

[12] Xiao L, et al. Vitamin D supplementation for the prevention of childhood acute respiratory infections: a systematic review of randomised controlled trials. Br J Nutr. 2015 Aug 27:1-9. View Abstract

[13] Shaik-Dasthagirisaheb YB, et al. Role of vitamins D, E and C in immunity and inflammation. J Biol Regul Homeost Agents. 2013; 27(2):291-295. View Abstract

[14] Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. 2013 Jan 31;1:CD000980. View Abstract

[15] Hemilä H. Vitamin C and common cold incidence: a review of studies with subjects under heavy physical stress. Int J Sports Med. 1996 Jul;17(5):379-83. View Full Paper

[16] Traber MG, Stevens JF. Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radic Biol Med. 2011 Sep 1;51(5):1000-13. View Full Paper

[17] Raverdeau M, Mills KH. Modulation of T cell and innate immune responses by retinoic Acid. J Immunol. 2014 Apr 1;192(7):2953-8. View Full Paper

[18] Field CJ, Johnson IR, Schley PD. Nutrients and their role in host resistance to infection. J Leukoc Biol. 2002 Jan;71(1):16-32. View Full Paper

[19] Stephensen CB. Vitamin A, infection, and immune function. Annu Rev Nutr. 2001;21:167-92. View Abstract

[20] Barreto ML, et al. Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil. Lancet. 1994 Jul 23;344(8917):228-31. View Abstract

[21] Imdad A, et al. Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD008524. View Abstract

[22] Huiming Y, Chaomin W, Meng M. Vitamin A for treating measles in children. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD001479. View Abstract

[23] Pludowski P, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence. Autoimmun Rev. 2013 Aug;12(10):976-89. View Abstract

[24] Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc. 2012 Feb;71(1):50-61. View Abstract

[25] Ooi JH, Chen J, Cantorna MT. Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors? Mol Aspects Med. 2012 Feb;33(1):77-82. View Full Paper

[26] Manicassamy S, et al. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat Med. 2009 Apr;15(4):401-9. View Full Paper

[27] van Baarlen P, et al. Differential NF-kappaB pathways induction by Lactobacillus plantarum in the duodenum of healthy humans correlating with immune tolerance. Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2371-6. View Full Paper

[28]Härtel C, et al. Effects of vitamin C on intracytoplasmic cytokine production in human whole blood monocytes and lymphocytes. Cytokine. 2004 Aug 21-Sep 7;27(4-5):101-6. View Abstract

[29] Cárcamo JM, et al. Vitamin C suppresses TNF alpha-induced NF kappa B activation by inhibiting I kappa B alpha phosphorylation. Biochemistry. 2002 Oct 29;41(43):12995-3002. View Abstract

[30] Bowie AG, O’Neill LA. Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase. J Immunol. 2000 Dec 15;165(12):7180-8. View Abstract

[31] Meister A. Glutathione-ascorbic acid antioxidant system in animals. J Biol Chem. 1994 Apr 1;269(13):9397-400. View Full Paper

[32] Perricone C, et al. Glutathione: a key player in autoimmunity. Autoimmun Rev. 2009 Jul;8(8):697-701. View Abstract

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