Sjogren's and Missing Enzymes

[Nat]

It has been awhile since I last posted. I have been busy doing research for a multiple sclerosis book I am working on. While doing the research I ran across some interesting studies I thought would be of interest to everyone.
I do have permission to reprint these studies. They are included in my book. I thought the following study was very interesting.

In the study when fifty-eight Sj?gren syndrome (SS) patients with neurologic manifestations associated with SS had magnetic resonance imaging (MRI) of the brain, the researchers found that 70% of the patients had white matter lesions and 40% met the radiologic criteria for MS.


Neurologic manifestations in primary Sj?gren syndrome: a study of 82 patients.
Delalande, S., J. de Seze, A.L. Fauchais, E. Hachulla, T. Stojkovic, D. Ferriby, S. Dubucquoi, J.P. Pruvo, P. Vermersch, P.Y. Hatron. 2004. Medicine (Baltimore) 83(5):280-91.

??We retrospectively studied 82 patients (65 women and 17 men) with neurologic manifestations associated with primary SS, as defined by the 2002 American-European criteria?Thirty-three patients had brain involvement and 13 patients had optic neuropathy. The disease mimicked relapsing-remitting multiple sclerosis (MS) in 10 patients and primary progressive MS in 13 patients? Thirty percent of patients (all with CNS involvement) had oligoclonal bands? Fifty-eight patients had magnetic resonance imaging (MRI) of the brain. Of these, 70% presented white matter lesions and 40% met the radiologic criteria for MS??



The underlying disease pathways for MS and Sjogrens are really exactly the same. I think the difference in getting a diagnosis of MS versus Sjogrens is really just a matter of doing an MRI and finding lesions. These diseases are just being identified by their primary manifesting symptoms.


I also think the evidence shows MS and Sjogrens originate with missing enzymes (as do all autoimmune diseases) called protease and DNase 1. These enzymes digest dietary proteins. For instance, here is a study that shows these enzymes are involved in MS.

In the study, from Mayo College of Medicine, the researchers stated that an ?array of studies? implicate protease in MS pathogenesis.

The multiple sclerosis degradome: enzymatic cascades in development and progression of central nervous system inflammatory disease.
Scarisbrick, I.A. 2008. Curr Top Microbiol Immunol. 318:133-75.

?An array of studies implicate different classes of protease and their endogenous inhibitors in multiple sclerosis (MS) pathogenesis based on expression patterns in MS lesions, sera, and/or cerebrospinal fluid (CSF). Growing evidence exists regarding their mechanistic roles in inflammatory and neurodegenerative aspects of this disease??



These enzymes originate in the "exocrine" pancreas. Research has also found that the majority of Sj?gren?s syndrome patients have ?subclinical? (having no noticeable clinical symptoms) exocrine pancreatic insufficiency.

In the following study the researchers identified subclinical exocrine pancreatic insufficiency in not only Sj?gren?s syndrome, but in rheumatoid arthritis (RA) patients as well. In the Sj?gren?s patients tested, 58.3% had a ?significant decrease? in pancreatic enzymes.

Pancreatic duct antibodies and subclinical insufficiency of the exocrine pancreas in Sj?gren?s syndrome.
D?Ambrosi, A., A. Verzola, P. Buldrini, C. Vavalle, S. Panareo, S. Gatto, R. La Corte, L. Vicentini, A. Boccafogli, R. Scolozzi. 1998. Recenti Prog Med 89(10):504-9.

?In previous studies we reported evidence of subclinical exocrine pancreatic insufficiency in primary or secondary Sj?gren?s syndrome (SSI, SSII) and rheumatoid arthritis (RA)?test results, compared to controls, showed a statistically significant decrease in duodenal juice volumes, bicarbonates and enzymes in 58.3% of SSI, and in 30% of RA??

You can trace every symptom and valid scientific finding in these diseases directly back to these missing enzymes.

[SjoAmy]

Wow.  What a finding!  We oughta sticky this one, mods. 

[Linda196]

In the past, when "stickying" posts, articles , special requests, etc., we found that the entire first page of topics became static, with new posts and questions appearing only on the second page and therefore being missed.

I would suggest that if anyone finds a particular article or link to be worthy of future reference, you bookmark the link as your personal resource.

It is also an option for the author of a topic to copy it to the Useful Links page. In an instance like this, double posting is permissible with the original thread (this one) offering the bulk of the information, and the secondary thread on the Useful Links page giving a summary and the link to the article.

[Joe S.]

Fascinating!

[Velcro]

Wow!  So is this an enzyme that can be supplemented I wonder?

[Nat]

Sorry about the ? marks in the original posts. I copied the information from my book and have no idea why it did that when posted.

Hi Velcro~DNase 1 does not exist in supplement form. Protease does, but although the lack of protease and DNase 1 does explain every aspect of the disease process of autoimmune disease, simply trying to replace protease through supplementation may lead to more harm than good. Research shows that supplemental protease can destroy the bodys lipases, these are the enzymes that digest fats. As serious a problem as the inability to digest proteins is, it would be equally as serious if the body could not digest fats. I want to provide a little more information that I think will be of interest to the board members and then we can discuss some of  the ways to go about restoring the function of the pancreas and the entire GI tract.



These missing enzymes can answer in a direct biological manner some of the most bewildering questions we have had about autoimmune disease.  Such as: Why do women get autoimmune diseases more so than men? What is the connection to the Epstein-Barr virus? Why does stress make autoimmune disease symptoms worse?
What is activating the B cells?

There are two components to autoimmune disease. One of course is the activated immune system. The other is the nutritional deficiency component. I can use lupus as an example of what I mean by this.

Research has found that lupus patients lack these enzymes (protease and DNase 1).
These enzymes digest dietary proteins and dietary DNA. Without these enzymes, you would not be able to release essential amino acids from dietary proteins. Nor would you be able to bind and transport vitamin B12. Vitamin B12 is only found attached to dietary animal proteins.  So, the lack of essential amino acids and vitamin B12 would comprise the nutritional deficiency component of autoimmune disease. 

Therefore, we should find evidence of a lack of essential amino acids and vitamin B12 in patients with lupus.


In the following study the researchers discovered that lupus patients were deficient in all of the essential amino acids.

The researchers found that all ketogenic and glucogenic amino acids were significantly dampened in lupus. A glucogenic amino acid is an amino acid that can be converted into glucose. These would include the essential amino acids phenylalanine, valine, threonine, tryptophan, isoleucine, and methionine. Ketogenic amino acids are converted into ketone bodies. These would include the essential amino acids leucine and lysine.

Metabolic disturbances associated with systemic lupus erythematosus.
Wu, T., C. Xie, J. Han, Y. Ye, J. Weiel, et al. 2012. PLoS ONE 7(6): e37210. doi:10.1371/journal.pone.0037210

?all ketogenic and glucogenic amino acids (with the exception of arginine) were also significantly dampened in SLE?"


Lupus patients also lack vitamin B12 (cobalamin). In the following study the researchers discovered that vitamin B12 levels were significantly lower in lupus (SLE) patients.

Serum cobalamin and transcobalamin levels in systemic lupus erythematosus.
Molad, Y., B. Rachmilewitz, Y. Sidi, J. Pinkhas, A. Weinberger. 1990. Am J Med. 88(2):141-4.

??Cobalamin levels were found to be significantly lower in the SLE group compared with a normal control group??


Essential amino acids and vitamin B12 are necessary for a wide variety of functions in the human body, so a lack of these nutrients will have profound ramifications. And, since protease are necessary for the proper metabolism of essential amino acids and vitamin B12, you would not be able to address their absence at the "cellular" level through the use of supplements. 

The inability to digest dietary proteins and release essential amino acids and vitamin B12 would comprise the nutritional deficiency component of autoimmune disease. A lack of these enzymes will also lead to unbroken down protein particles and DNA entering the bloodstream. This is what triggers the inflammatory immune system. The immune system targets these "foreign" DNA and protein particles and forms neutrophil extracellular traps or NETs. These NETs can become lodged in organs and tissues and lead to organ failure and tissue damage.

Here is a picture of one of these NETs in a lupus patients bloodstream. [Pay special attention to the last paragraph where it states lupus patients lack the enzyme DNase 1.]

http://www.sciencedaily.com/releases/2010/05/100503161423.htm


In the next post, I will show that this is the exact same disease process is taking place in MS.

[lighthouse33]

PANCREAS ENZYME REPLACEMENT THERAPY

WHAT NURSES NEED TO KNOW

http://magazine.nursing.jhu.edu/2012/07/pancreas-enzyme-replacement-therapy/

Everything You Ever Wanted to Know about Digestive Enzymes

whole9life.com/2012/09/digestive-enzymes-101/

But Which Enzymes Should You Use?

The fact is you'll benefit from any good vegetarian based digestive enzyme supplement. But look for one that contains:

?   A variety of proteases, including Papain (to aid in the digestion of protein). Papain, which comes from papaya, is so effective in digesting proteins that it is often used as a meat tenderizer.
?   Amylase (for the digestion of starches and carbohydrates).
?   Lipase (to digest fats).
?   Cellulase (invaluable in breaking down fiber cellulose into smaller units).
?   Lactase (which works in the digestion of dairy products).
?   I also used to recommend using large amounts of bromelain in the formula --not so much anymore.

o   Bromelain is a great proteolytic enzyme found in pineapples. It digests protein, and it helps reduce inflammation and swelling in joints. Unfortunately, a significant number of people are subject to side effects--such as diarrhea and stomach and intestinal discomfort--when they use bromelain. It can also cause allergic reactions, especially in people who have other allergies. 

But There's Even More

Pancreatic enzymes are part of a substance called pancreatin (or pancreas juice) produced in the pancreas. This complex includes the enzymes protease, amylase, and lipase and is released both into the intestines and the bloodstream.

In the intestines, pancreatin works to help digest the proteins, carbohydrates, and starches of our meals. Supplementation with digestive enzymes along with a meal helps share the workload of your body's own pancreatic enzymes and can aid in digestion. But what happens if you take enzymes between meals?

As mentioned earlier, pancreatic enzymes are not only released into the small intestine, but also directly into the bloodstream. Why?

Protein molecules that are only partially digested in the small intestine are absorbed into the bloodstream. Once in the bloodstream, the immune system treats them as invaders provoking an immune reaction. Antibodies couple with these foreign protein invaders to form circulating immune complexes (CIC's). Now, in a healthy person, these CIC's may be neutralized in the lymphatic system. But if the immune system is in any way compromised, CIC's accumulate in the blood, where they initiate an "allergic" reaction. As the number of CIC's builds, the kidneys max out and can no longer excrete all of the CIC's, so they begin to accumulate in the body's soft tissues, causing inflammation.

It is here that the pancreatic enzymes in our bloodstream come into play. Pancreatic enzymes are able to break down CIC's so that they can pass through the kidneys for excretion.
What does that mean for us? Well, if enzymes are taken between meals, the body doesn't need the enzymes for digesting food, so they make their way directly into the bloodstream to aid in the elimination of CIC's.

But it gets even better. Because of their ability to digest foreign proteins, pancreatic enzymes (both those produced in the body and those absorbed into the bloodstream from taking supplemental digestive enzymes) work to clear out infecting organisms such as viruses, scar tissue, and the products of inflammation. For this reason, pancreatic enzymes are frequently used by Naturopaths to treat a variety of conditions, including lung infections, tooth infections, bone fractures, and as a body strengthener before surgery. Specifically, pancreatic enzymes have been used by many healers to aid in a variety of disease conditions, including inflammation, viral disease, multiple sclerosis, and cancer.

Note: A dedicated proteolytic enzyme (high protease) formula, will be even more effective in this regard than a digestive enzyme formula forced to do double duty. Ideally, you should use a dedicated digestive enzyme formula with your meals and a dedicated high protease formula between meals.

jonbarron.org/article/enzyme-story

[quietdynamics]

Thank you Nat...
I have been reading about Metabolism,Tryptohan degradation: there are studies on Sjogrens, MS, autoimmune (including ) Asthma, Arthritis , etc.

Mechanisms dependent on tryptophan catabolism regulate immune responses in primary Sjogren's syndrome.
"These data suggest that mechanisms dependent on tryptophan catabolism regulate immune responses in pSS. Tryptophan degradation is enhanced in patients with pSS, and high IDO activity is associated with severity of pSS."  (PMID:16178870) http://europepmc.org/abstract/MED/16178870/reload=0;jsessionid=mvCkdf71iHASZtfSmizK.56

5-Hydroxytryptophan  http://umm.edu/health/medical/altmed/supplement/5hydroxytryptophan-5htp    * Caution and warnings, interactions end of article.
and http://umm.edu/health/medical/altmed/supplement/5hydroxytryptophan-5htp

Case study of with slides of SJS white matter lesions,
DIFUSSE WHITE MATTER ABNORMALITIES AND NEUROLOGIC MANIFESTATIONS IN A PATIENT
WITH ANTI-RO POSITIVE ANTIBODIES. CASE REPORT.
The anti-Ro antibody detects an intracellular RNA-protein complex. It is primarily found in patients with SLE and Sjögren syndrome. This autoantibody is described to have a 54% sensitivity and
82% specificity in pSS and only 0.1% to 0.5% of control samples have tested positive.
Approximately 25% of patients with positive SS-A antibodies and undifferentiated connective tissue disease will evolve into a definite disorder. Neurologic involvement occurs in 20% of the patients with pSS and was present prior to diagnosis in 81% of the patients in a small case series.
Anti-Ro positivity in pSS has been correlated with severe, progressive and large CNS lesions. Yet the role of anti-Ro antibodies in CNS involvement in the absence of clinical and laboratory data of connective tissue disease is undetermined. 
https://www.bcm.edu/departments/neurology/pdf/poster_msc_Sjogren.pdf

Frequency and significance of anti-Ro (SS-A) antibodies in multiple sclerosis patients.
CONCLUSIONS:
ANA, ACA and anti-Ro (SS-A) antibodies in MS patients indicate an underlying autoimmune disease but our series suggests that they are an epiphenomenon of a more diffuse immunological dysfunction.

*These missing enzymes can answer in a direct biological manner some of the most bewildering questions we have had about autoimmune disease.
-Tryptophan (IUPAC-IUBMB abbreviation: Trp or W; IUPAC abbreviation: L-Trp or D-Trp; sold for medical use as Tryptan) is one of the 22 standard amino acids and an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG. Only the L-stereoisomer of tryptophan is used in structural or enzyme proteins,
Such as: Why do women get autoimmune diseases more so than men?
Hormones and hormone-like effect?

There was a study I read that noted woman with MS have less relapse during preganancy...
Prolactin in multiple sclerosis  http://www.ncbi.nlm.nih.gov/pubmed/22933621
(Prolactin was one of the first tests ordered by my PCP)

What is the connection to the Epstein-Barr virus? 
There was a post about here re: MS the studies based on the Faroes Island pop. EBV and MS, theories differing from the work of Kutzke.
But, interesting to read about the age of exposure to EBV and possible resultant disease state, simple childhood exposure vs, adolecent (+) and severity as mentioned with Mono.

Why does stress make autoimmune disease symptoms worse?
"Unfortunately, not only does stress cause disease, but the disease itself also causes significant stress in the patients, creating a vicious cycle. "
Stress includes positive (happy experience) and negative events, durations (acute/chronic), genetics, personality (how we cope with stress), physical and psychological.
"Recent theories have suggested that chronic pain could be partly maintained by maladaptive physiological responses of the organism facing a recurrent stressor."  Add to chronic stress what is termed "sick behavior".


What is activating the B cells?...and T-cells
Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC39784/?page=1

There are two components to autoimmune disease. One of course is the activated immune system. The other is the nutritional deficiency component.
Question: Nutritional deficiency vs. lack of nutritional absorption due to lack of Saliva and necessary stomach fluids?

We are "simply complex"

I believe there are more than two components.

[Tivia]

Oh wow well that makes sense, I had pancreatic insufficiency from inflammation  for a few years before I ever developed sjs symptoms. Amazingly they cant figure out why, there are no stones or cysts blocking the biliary ducts, no tumors no chronic pancreatitis, but flares of painful attacks without cause. My pancreas is exocrine and endocrine deficient, my endocrinologist says by all rights I should be type 1 diabetes. I just saw him on this tuesday and he said knock on wood im holding. But I have to take a ton of creon to be able to eat, so exocrine damage is further along than the endocrine damage.

But I was told the pancreas loses exocrine long before the damage shows up in the loss of beta cells. 10 years ago I started losing exocrine function. About 2 years ago they discovered I was loosing beta cells also now, albeit slow (knock on wood)

This is tremendous news to me, and may offer hope into what is causing the painful damaging attacks. Maybe they can fix me. Another thing I asked if I can supplement the lipase , protease and amylase otc..and was promptly informed that no there are no otc enzymes that will work to replace whats missing. I have to take powerful pig enzymes as they are the closest thing to human from the pancreas of pigs. The otc stuff dosent do anything the doc told me, if it did it would be med class because the enzymes needed are very powerful

[Nat]

Hi Tivia~I need to address quietdynamics post and then I would like to comment on your post.

Hi quietdynamics~Thank you for posting, lots of good info!

I'll have to take this in stages.  We can start with the first study you posted on tryptophan. I reference the same study in my autoimmune book. Here is the quote:

"Patients with primary Sj?gren?s syndrome (pSS) were found to have enhanced tryptophan degradation and high IDO activity in the study entitled: ?Mechanisms dependent on tryptophan catabolism regulate immune responses in primary Sj?gren?s syndrome? (Pertovaara, 2005).The researchers concluded, ?Tryptophan degradation is enhanced in patients with pSS, and high IDO activity is associated with severity of pSS.?



This tryptophan degrading pathway is called the kynurenine pathway. Here is some book info on this:

"The body has alternate pathways to metabolize the essential amino acid tryptophan. In one pathway, tryptophan is metabolized through the serotonin pathway. In another, called the kynurenine pathway, tryptophan is used to make niacin (B3). The majority of dietary tryptophan (95%) is oxidized through the kynurenine pathway, and just a small portion is used for the synthesis of serotonin.

Indoleamine 2,3 dioxygenase (IDO) is one of the enzymes that degrades tryptophan in the kynurenine pathway. Tryptophan degradation by IDO is normally very moderate, but if the cytokines interferon-gamma and tumor necrosis factor are elevated, IDO can be upregulated. The upregulation of IDO by interferon-gamma and tumor necrosis factor depletes tryptophan and creates an excess of toxic metabolites such as kynurenic acid, kynurenine, and quinolinic acid."



In the following study the researchers concluded that interferon-gamma, ?in particular?, induced the enzyme IDO.

FASEB J. 1991 Aug;5(11):2516-22.
Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism.
Taylor MW, Feng GS
.
??In particular, interferon-gamma (IFN-gamma) induces an enzyme of tryptophan catabolism, indoleamine 2,3-dioxygenase (IDO), which is responsible for conversion of tryptophan and other indole derivatives to kynurenine??


Elevated interferon-gamma and the subsequent activation of the kynurenine pathway can be traced directly back to DNase 1.

As the following study states,  "DNase I activity has shown a strong negative correlation with the serum concentration of anti-nucleosomal antibodies in the autoimmune (SLE + IBD) cohort, as well as in the separate IBD cohort."

Autoimmune Dis. 2011; 2011: 945861.
Impaired Deoxyribonuclease I Activity in Patients with Inflammatory Bowel Diseases

"Background and Aims. Deoxyribonuclease I (DNaseI) is an endonuclease that facilitates chromatin breakdown and promotes susceptibility to autoimmune disorders...Results. DNase I activity in IBD patients was significantly lower than in healthy individuals, but higher than in SLE patients (P < .0001)... DNase I activity has shown a strong negative correlation with the serum concentration of anti-nucleosomal antibodies in the autoimmune (SLE + IBD) cohort, as well as in the separate IBD cohort. Conclusions. Reduced serum DNase I activity probably has pathogenetic consequences in IBD. Induction of autoantibodies towards nucleosomes could be a reflection of impaired DNase I activity."

As I'm sure you know, anti-nucleosome antibodies are also found in Sjogrens. For instance, the researchers stated in the link to the next study, "Apart from SLE, anti-nucleosome antibodies can be observed in other autoimmune diseases, in particular, Sjogrens syndrome.
http://www.ncbi.nlm.nih.gov/pubmed/12504366

TO BE CONTINUED..

[Nat]

PART 2

Specialized immune cells called "dendritic cells" are activated in autoimmune disease in response to anti-nucleosomal antibodies, as the following study confirms.

Semin Nephrol. 2011 Jul;31(4):376-89. doi: 10.1016/j.semnephrol.2011.06.009.
Lupus nephritis: role of antinucleosome autoantibodies.

"The discovery of autoantigen clustering in blebs at the surface of apoptotic cells boosted research on the role of apoptosis in systemic lupus erythematosus (SLE) and led to the discovery of autoantigen modification during apoptosis. Normally, apoptotic cells are cleared efficiently and swiftly. However, it became clear that in SLE insufficient removal of apoptotic material leads to the release of these modified autoantigens. This creates the danger that these modified autoantigens are recognized by the immune system. Indeed, dendritic cells, the professional antigen-presenting cells, phagocytose these modified autoantigens, which leads to maturation and induction of a proinflammatory state of these dendritic cells."


Dendritic cells release proinflammatory cytokines such as tumor necrosis factor (TNF) and interferon gamma, which would activate the kynurenine pathway. For instance, in the following study the researchers concluded that patients with MS had high levels of IFN-gamma, TNF, and IL-6 secreting dendritic cells.

J Neuroimmunol. 1999 Sep 1;99(1):82-90.
Multiple sclerosis is associated with high levels of circulating dendritic cells secreting pro-inflammatory cytokines.
Huang YM, Xiao BG, Ozenci V, Kouwenhoven M, Teleshova N, Fredrikson S, Link H.

?Recent evidence emphasises a pivotal role for dendritic cells (DC) in the control of immunity by priming and tolerising T cells. DC capture and process antigens, express co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses?Patients with MS had higher levels of IFN-gamma, TNF-alpha and IL-6 secreting DC than healthy subjects??


Here is a study that shows the same process is taking place in Sjogens.

Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sj?gren?s syndrome

"The activation of IFN pathways led us to investigate whether plasmacytoid dendritic cells were recruited in salivary glands. These IFN-producing cells were detected by immunohistochemistry in all patients with pSS, whereas none was observed in controls."
http://www.pnas.org/content/103/8/2770

In conclusion:

Low DNase 1>Anti-Nucleosomal Antibodies>Dendritic cells>Inflammatory Cytokines (Interferon-Gamma, Tumor Necrosis Factor)>Activated Kynurenine Pathway

[Nat]

As the research in the previous post confirms, a lack of DNase 1(enzyme that digests dietary proteins and DNA) leads to the activation of "dentritic cells".

This is the inflammatory immune system component of autoimmune disease. Dentritic cells release proinflammatory cytokines such as interferon gamma and tumor necrois factor. The previous study I posted concluded that interferon-gamma producing dendritic cells were detected in ALL patients with pSS, whereas none was observed in controls.

Dendritic cells are the prime initiators and mediators of autoimmune disease, as the following study confirms.

Dendritic cells in autoimmune diseases.
Maddur, M.S., J. Vani, J.D. Dimitrovi, K.N. Balaji, S.Lacroix-Desmazes, S.V. Kaveri, J. Bayry. 2010. The Open Arthritis Journal, 3, 1-7 1 1876-5394/10 2010 Bentham Open

?Dendritic cells are the prime initiators and mediators of autoimmune diseases?Dendritic cells (DCs) are professional antigen presenting cells, which play a crucial role both in maintaining immune tolerance and in inducing adaptive immune responses?Therefore, DCs are the most sought after cells in inciting autoimmunity and its sustenance to autoimmune diseases. ?DCs act in concert with adaptive and other innate immune cells in moulding the autoimmune response...Individuals with autoimmune disease show a high number of aberrantly activated DCs either in circulation or in the autoimmune lesions secreting large amounts of proinflammatory cytokines that mediate inflammation??