Embria Health

Review of sIgA’s major role as a first line of immune defense and new indications regarding inflammation and gut health

Larry E. Robinson, Ph.D. and Stuart Reeves, Ph.D., ARCS, Scientific Affairs

Introduction
Embria Health Science’s dietary supplement ingredient EpiCor has been shown in multiple published human clinical trials to help strengthen the immune system through several mechanisms and modes of action. One of EpiCor’s most important functions is to increase levels of secretory IgA (sIgA),1, 2 a vital antibody in the body’s first line of defense.

sIgA is the antibody that plays a key role in mucosal immunity. Mucosal immunity refers to the portion of the immune system that provides protection to various mucous membranes against invasion by potentially pathogenic microbes. The mucous membranes are on the surface of cavities that are exposed to the external environment, such as the digestive and respiratory tracts.

Recent science shows that sIgA may also have other beneficial effects in overall immunity through reduced inflammation in the digestive tract. This paper will review sIgA’s known effects on mucosal immunity and describe the emerging research that shows its beneficial impact on digestive health.

sIgA in Mucosal Immunity
sIgA is the main antibody found in mucous secretions, including tears, sweat, saliva, milk, and colostrum. More sIgA is produced in mucosal linings than all other types of antibody combined; between three and five grams are secreted into the intestinal lumen each day.3 Nearly 15% of the total immunoglobulin produced in the entire body is sIgA.

The mucosal system’s role in overall immunity is critical because it lines all bodily passages that are exposed to the environment, such as parts of the digestive and respiratory tracts. In turn, sIgA plays a key role in the first line of immune defense by neutralizing toxins and viruses found in the mucosa and preventing adhesion of microbial pathogens to mucosal epithelial cells.4,5 Through a process known as immune exclusion, sIgA promotes the clearance of antigens and pathogenic microorganisms from the intestinal lumen by blocking access to epithelial receptors and entrapping them in mucus, thus facilitating their removal by peristaltic and mucociliary activities.

It is the unusual structure of sIgA (discussed more in the following paragraph) that provides protection against microbes that multiply in bodily secretions by binding to them in the lumen of the gut, causing them to pass through harmlessly. The fact that microbes are not able to adhere to the gut wall means they cannot colonize the gut and cause infection and disease. In fact, the results from EpiCor’s two human clinical trials showing reduction in cold symptoms6,7 may be in part due to increased levels of sIgA.

Structure and synthesis of IgA
sIgA can be produced in a variety of ways, but the predominant method is via the Peyer’s Patches in the GALT (Gut Associated Lymphoid Tissue). sIgA is derived from serum IgA, a monomer found throughout the body in the blood stream. There are discrete areas of the gut surface that sense the presence of foreign bacteria and respond to generate sIgA through several steps.


The diagram to the right shows dendritic cells (immune cells that are part of a class of “antigen presenting cells” or APC’s) sampling bacteria from the lumen. The dendtritic cells then migrate to the center of the Peyer’s Patch and stimulate B cells to mature and produce IgA. Monomeric IgA is transported across gut epithelial cells to the lumen by polymeric Ig receptor (pIgR).8In the process, two monomers of IgA are covalently bound to form a dimer by a polypeptide called J-chain. Dimers enter the intestinal lumen and function as secretory IgA.9
 
The fact that the two chains are linked via their “tails” allows the sIgA to cross-link bacteria, thereby preventing bacterial adhesion to the lumen wall and increasing the likelihood of the bacteria passing harmlessly through the gut. Additionally, the sIgA has another protein associated with it called the secretory component, a protein derived from pIgR. The secretory component protects the sIgA from proteases and helps it to adhere to mucosal surfaces.

Systemic response to localized IgA stimulation
Once IgA production has been stimulated in one region, usually via the GALT, the B cells and plasma IgA cells can travel to other parts of the lymphoid tissue, and the response can be detected in these regions.


Stimulation of mucosal-associated lymphoid tissue in the GALT allows a systemic response even from local antigenic stimulation (i.e. a response not confined to the initial stimulation site, but one that works throughout the body).

It is becoming increasingly obvious that sIgA is not only a major part of the body’s first active response to infection, but is also a major part of the body’s overall immune response, significantly contributing to the maintenance of a strong and balanced immune system.10 Yet it should be emphasized that this will only be a part of the story of sIgA.

Anti-inflammatory effects of sIgA
One of sIgA’s important modes of action is its ability to regulate inflammation. It has been shown that sIgA can bind to pathogens such as Shigella flexneri resulting in a beneficial down-regulation of inflammation.8 Less inflammation was reflected by lower levels of proinflammatory cytokines and by preservation of the intestinal barrier. Additionally, the authors speculate that transport of antigen-sIgA complexes may contribute to tolerance of harmless allergens. In fact, high intestinal sIgA in early life is associated with minimal intestinal inflammation and indicates reduced risk for IgE-associated allergic diseases.12

Therefore, increased sIgA may partially explain how EpiCor was able to significantly reduce certain allergy symptoms in a recent human clinical study.2 Interestingly, levels of sIgA significantly increased in subjects who were also experiencing reduced allergy symptoms while on an EpiCor regimen. These results indicate that EpiCor, while helping mitigate the allergic response of allergy sufferers, continues to help maintain strong immune response through increased production of sIgA.

Moreover, one could speculate that increased sIgA may have been a contributing factor for the anti-inflammatory effects found when EpiCor was tested in two well-established animal models.13

sIgA’s regulation of homeostasis
Immune homeostasis (the body’s ability to provide stable and proper immune responses in the face of constantly changing conditions) is very important for good health. The research on new roles for sIgA responses is not restricted to interactions with pathogens, but also its response to Gram-positive and negative commensal microorganisms, which helps to maintain homeostasis.11,14

For example, it is now known that sIgA can inhibit inflammatory effects in the body by inducing T-regulatory cells through interaction with commensal bacteria. The anti-inflammatory effects can be seen through elimination of Gram-negative bacteria, thereby reducing levels of LPS and production of NF-ҡB mediated pro-inflammatory cytokines, resulting in a general anti-inflammatory effect.15

sIgA’s ability to maintain homeostasis may also explain EpiCor’s beneficial effects in the digestive tract. In validated gut simulation models, EpiCor has been shown to act in a prebiotic-like manner. Results have shown EpiCor to alter the balance of gut bacterial populations towards the more beneficial species that positively interact with sIgA and likely down-regulate pro-inflammatory responses.16

Additionally, this research has shown EpiCor changes the resulting short chain fatty acid profile, increasing the production of butyric acid, a short chain fatty acid with known anti-inflammatory effects. Secondary trials from this work using CaCo2 cells have shown EpiCor can down-regulate the cells production of a pro-inflammatory cytokine (IL-8) when stimulated with a pro-inflammatory cocktail.

Conclusions
sIgA is the most abundant and vital antibody in the body’s first line of active defense. It not only protects mucosal areas directly exposed to airborne pathogens, but also the intestinal epithelium from pathogenic microorganisms.  New research indicates that sIgA plays an important role in overall immunity, including its ability to maintain homeostasis in the digestive tract and reduce inflammation.

Key take-aways from the paper include:

  • EpiCor increases levels of sIgA.
  • The special structure of sIgA as a dimer explains its ability to prevent bacterial adhesion to the lumen wall, thereby possibly supporting healthy gut function.
  • Increases in sIgA may help explain EpiCor’s role in reducing allergy symptoms.
  • sIgA produces anti-inflammatory effects by reducing bacteria-induced pro-inflammatory responses, which may help explain some beneficial affects seen in animal models.
  • Even a local antigenic stimulation can result in a systemic response by sIgA.
  • sIgA can inhibit inflammatory effects in the body through interaction with commensal bacteria.
  • sIgA is not only a major part of the body’s first active response to infection, but is also a major part of the body’s overall immune response.
  • Among EpiCor’s many modes and mechanisms of action that helps strengthen the immune system, its ability to increase sIgA helps explain some of the multiple beneficial effects it has on human health.

References:
1.  Jensen, G. S.; Patterson, K. M.; Barnes, J.; Schauss, A. G.; Beaman, R.; Reeves, S.; Robinson, L., A Double-Blind Placebo-Controlled, Randomized Pilot Study: Consumption of a High-Metabolite Immunogen from Yeast Culture has Beneficial Effects on Erythrocyte Health and Mucosal Immune Protection in Healthy Subjects. The Open Nutrition Journal, 2008, 2, 68-75.

2.  Moyad, M. A.; Robinson, L. E.; Kittelsrud, J. M.; Reeves, S. G.; Weaver, S. E.; Guzman, A. I.; Bubak, M. E., Immunogenic yeast-based fermentation product reduces allergic rhinitis-induced nasal congestion: a randomized, double-blind, placebo-controlled trial. Adv Ther, 2009. 26(8), 795-804.

3.  Conley, M. E.; Delacroix, D. L., Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defense? Ann Intern Med, 1987, 106(6), 892-9.

4.  Corthesy, B., Secretory immunoglobulin A: well beyond immune exclusion at mucosal surfaces. Immunopharmacol Immunotoxicol, 2009. 31(2), 174-9.

5.  Mestecky, J.; Russell, M. W.; Elson, C. O., Intestinal IgA: novel views on its function in the defence of the largest mucosal surface. Gut, 1999, 44(1), 2-5.

6.  Moyad, M. A.; Robinson, L. E.; Zawada, E. T., Jr.; Kittelsrud, J. M.; Chen, D. G.; Reeves, S. G.; Weaver, S. E., Effects of a modified yeast supplement on cold/flu symptoms. Urol Nurs, 2008, 28(1), 50-5.

7.  Moyad, M. A.; Robinson, L. E.; Zawada, E. T.; Kittelsrud, J.; Chen, D. G.; Reeves, S. G.; Weaver, S., Immunogenic yeast-based fermentate for cold/flu-like symptoms in nonvaccinated individuals. J Altern Complement Med, 2010, 16(2), 213-8.

8.  Boullier, S.; Tanguy, M.; Kadaoui, K. A.; Caubet, C.; Sansonetti, P.; Corthesy, B.; Phalipon, A., Secretory IgA-mediated neutralization of Shigella flexneri prevents intestinal tissue destruction by down-regulating inflammatory circuits. J Immunol, 2009, 183(9). 5879-85.

9.  Longet, S.; Miled, S.; Lotscher, M.; Miescher, S. M.; Zuercher, A. W.; Corthesy, B., Human plasma-derived polymeric IgA and IgM antibodies associate with secretory component to yield biologically active secretory-like antibodies. J Biol Chem, 2013, 288(6), 4085-94.

10.  Corthesy, B., Role of secretory IgA in infection and maintenance of homeostasis. Autoimmun Rev, 2013, 12(6), 661-5.

11.  Mantis, N.J.; N. Rol; B. Corthesy, Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol, 2011. 4(6), 603-11.

12.  Kukkonen, K.; Kuitunen, M.; Haahtela, T.; Korpela, R.; Poussa, T.; Savilahti, E., High intestinal IgA associates with reduced risk of IgE-associated allergic diseases. Pediatr Allergy Immunol, 2010, 21(1 Pt 1), 67-73.

13.  Evans, M.; Reeves, S.; Robinson, L. E., A dried yeast fermentate prevents and reduces inflammation in two separate experimental immune models. Evid Based Complement Alternat Med, 2012, 2012, 973041.

14.  Shroff, K.E.; Meslin, K.; Cebra, J.J.,  Commensal enteric bacteria engender a self-limiting humoral mucosal immune response while permanently colonizing the gut. Infect Immun, 1995. 63(10): p. 3904-13.

15.  Wolf, H. M.; Fischer, M. B.; Puhringer, H.; Samstag, A.; Vogel, E.; Eibl, M. M., Human serum IgA downregulates the release of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6) in human monocytes. Blood, 1994, 83(5), 1278-88.

16.  Possemiers, S.; Pinheiro, I.; Verhelst, A.; Van den Abbeele, P.; Maignien, L.; Laukens, D.; Reeves, S. G.; Robinson, L. E.; Raas, T.; Schneider, Y. J.; Van de Wiele, T.; Marzorati, M., A Dried Yeast Fermentate Selectively Modulates both the Luminal and Mucosal Gut Microbiota and Protects against Inflammation, As Studied in an Integrated in Vitro Approach. Journal of Agricultural and Food Chemistry, 2013, 61(39), 9380-9392.9392.

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