How do we modulate the autoimmune response? What role do the glutathione and nitric oxide synthase (NOS) systems play in preventing and modulating AI disease? What role does vitamin D play?
Main points of this issue:
- Glutathione is the body’s most important anti-oxidant
- Glutathione plays a significant role in preventing and modulating autoimmune disease
- The lower the glutathione status, the more tissue destruction occurs in autoimmunity
- When the glutathione recycling system fails, there is increased flare ups of autoimmune disease
- Nitric oxide is important in autoimmune modulation
- There are different isomers (forms) of nitric oxide
- Some of these isomers are protective of tissue and some are destructive
- The modulation of these isomers determines how much tissue damage takes place and the recovery of the tissue
- Upregulation of iNOS (inducible nitric oxide synthase)increases intestinal permeability
- Vitamin D is an important modulator of autoimmunity and intestinal permeability
- Vitamin D regulates immune function and acts on the immune system in many ways to suppress systemic inflammation
The Role of Glutathione in Autoimmune Modulation
As we discussed in the previous issue, a healthy glutathione system is a prerequisite in order to prevent autoimmunity. Glutathione, which is produced by the liver, is considered the body’s most important antioxidant and is the main antioxidant for protecting the cellular mitochondria. Glutathione is the antioxidant that “takes the bullet” from the free radical. If this system fails and you don’t have this system to take the bullet, then you get immune activation. Immune activation then triggers inducible nitric oxide synthase (iNOS) which causes tissue destruction and promotes autoimmunity.
Evidence supports the body’s available glutathione stores play a significant role in modulating autoimmune disease:
“A significant correlation between plasma glutathione and SLE severity exists that may aid evaluation of the disease severity and usefulness of the management of SLE.”1
Here’s what this study found:
The lower the glutathione status, the greater destruction of tissue they had. The ones that had highest amount of glutathione activity had the least amount of tissue destruction. Glutathione helps recover tissue and helps support regulatory T cells. This system is absolutely critical for overall modulation of autoimmunity. When this glutathione recycling system fails, we lose the ability to enhance regulatory T-cells which modulate the attacks and flare-ups in these systems. We can’t regenerate the intestinal lining properly leading to increased intestinal permeability and increased autoimmunity.
The Role of Nitric Oxide in Autoimmune Modulation
The other system that is important in autoimmune modulation is the nitric oxide system. Nitric oxide is an important messenger molecule involved in many physiological and pathological processes. It plays both destructive and protective roles in autoimmunity, depending on which isomer is expressed. It can be a compound that helps with tissue recovery or a compound that causes tissue inflammation. There are different isomers of nitric oxide that have different effects on the body.
Nitric Oxide Synthase Isomers
-Optimizes neuronal synapses
-Protects the neurons
-Helps tissue recover and regenerate
-Enhances blood flow
-Dissolves endothelium plaques
-Dilates blood vessels
-Promotes tissue destruction
-Promotes AI attack
In AI disease, there is destruction of tissue due to:
- Increased iNOS (increased tissue destruction)
- Decreased eNOS (cold hands, feet, decreased blood flow)
- Decreased nNOS (decreased brain function)
How these isomers are manipulated or modulated will determine how much destruction of tissue or ability to recover from autoimmune flare-ups a person has.
“Based on these data, it appears that the isoforms of NOS contribute to pathophysiology, and that induced NOS and NO may function, in part, in a protective pathway.”2
“Collectively, these data implicate discrete roles for the NOS isoforms in the emergence of local tissue pathology and underscore the need to define the specific pathways that are being targeted.”3
Upregulation of iNOS increases intestinal permeability
The literature indicates that increased amounts of the iNOS isomer causes increased intestinal permeability:
“iNOS up-regulation and oxidation/nitration of intestinal cytoskeletal proteins, promotes intestinal leakiness. We hypothesized that iNOS inhibitors will inhibit the liver and intestinal barrier cascade.”4
“We conclude that NO plays a critical immunoregulatory role and NO modulation may prevent the onset of autoimmune reactions.”5
“Together, these data indicate that antioxidant modulation of nitric oxide might be a feasible therapeutic tool to interfere with development of autoimmune diabetes.”6
“Interleukin-17 is a proinflammatory cytokine involved in autoimmune disorders. The proinflammatory action of IL-17 depends considerably on its ability to trigger the expression of inducible nitric oxide (iNOS). We propose IL-17 and NO modulation could be relevant forms of therapy for autoimmune disorders.”7
Vitamin D as a Modulator of Autoimmunity and Intestinal Permeability
Vitamin D is also a very important regulator of immune function. Deficiency of vitamin D has been associated with development of intestinal permeability and autoimmune disease.
“Vitamin D deficiency may compromise the mucosal barrier, leading to increased susceptibility to mucosal damage and increased risk of IBD (inflammatory bowel disease)”8
“There is growing appreciation of the importance of the pleiotropic hormone vitamin D in the development of tolerance, immune system defenses, and epithelial barrier integrity.”9
“These observations suggest that vitamin D plays a critical role in mucosal barrier homeostasis by preserving the integrity of junction complexes and the healing capacity of the colonic epithelium.”10
There is also growing evidence that vitamin D regulates immune function and acts on the immune system in many ways to suppress systemic inflammation:
“The common denominator that rises from these studies is that vitamin D affects the immune system at many levels and by a number of mechanisms. It takes part in the genetic regulation of cytokine production, VDR expression and affects important biological processes by which these cells interact. On the whole, vitamin D confers an immunosuppressive effect.”11
Content provided by Datis Kharrazian, D.C., Autoimmune Regulation of the Nitric Oxide and Glutathione Systems, 11/4/10
In part 6 of this 6-part series, we answer the following questions:
- What is the Functional Medicine approach to the treatment of AI disease?
- Why do we support the glutathione and nitric oxide synthase (NOS) systems?
- Why do we address intestinal permeability and the GI tract?
- The role of vitamin D.
1. Correlation of lipid peroxidation and glutathione levels with severity of systemic lupus erythmatosus: a pilot study from single center. J Pharm Pharm Sci. 2008;11(3):30-4
2. Nitric oxide in experimental joint inflammation. Benefit or detriment? Cells Tissues Organs. 2003;174(1-2):26-33
3. Nitric oxide in experimental joint inflammation. Benefit or detriment? Cells Tissues Organs. 2003;174(1-2):26-33
4. Nitric oxide-mediated intestinal injury is required for alcohol-induced gut leakiness and liver damage. Alcohol Clin Exp Res. 2009 Jul;33(7):1220-30. Epub 2009 Apr 9
5. Immunoregulatory role of nitric oxide in Kilham rat virus-induced autoimmune diabetes in DR-BB rats. J Immunol. 2004 Jul 15;173(2):1327-35
6. Immunosuppressive and anti-inflammatory action of antioxidants in rat autoimmune diabetes. J Autoimmun. 2004 Jun;22(4):267-76
7. Inducible nitric oxide synthase activation by interleukin-17. Cytokine Growth Factor Rev. 2004 Feb;15(1):21-32
8. Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G208-16
9. Potential mechanisms for the hypothesized link between sunshine, vitamin D, and food allergy in children. J Allergy Clin Immunol. 2010 Aug;126 (2):217-22
10. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol. 2008 Jan; 294(1):G208-16
11. The Journal of Immunology, 2005, 175: 41194126.