New hypothesis - abnormal NETosis

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New hypothesis - abnormal NETosis

Postby Wrinkles » Sun Jun 16, 2013 3:11 pm

Autoimmune diseases may result from increased induction of NETosis in lymphocytes. In the case of MS, peptidylarginine deiminases released with NETs could be causing abnormal citrullination of myelin. ... 1/abstract
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Re: New hypothesis - abnormal NETosis

Postby Annesse » Sun Jun 16, 2013 9:09 pm

Thank you Wrinkes~

Here is the the body of the study which states increased polyamines are involved.

Increased polyamines alter chromatin and stabilize autoantigens in autoimmune diseases
Wesley H. Brooks*
Department of Chemistry, University of South Florida, Tampa, FL, USA
Polyamines are small cations with unique combinations of charge and length that give them many putative interactions in cells. Polyamines are essential since they are involved in replication, transcription, translation, and stabilization of macro-molecular complexes. However, polyamine synthesis competes with cellular methylation for S-adenosylmethionine, the methyl donor. Also, polyamine degradation can generate reactive molecules like acrolein. Therefore, polyamine levels are tightly controlled. This control may be compromised in autoimmune diseases since elevated polyamine levels are seen in autoimmune diseases. Here a hypothesis is presented explaining how polyamines can stabilize autoantigens. In addition, the hypothesis explains how polyamines can inappropriately activate enzymes involved in NETosis, a process in which chromatin is modified and extruded from cells as extracellular traps that bind pathogens during an immune response. This polyamine-induced enzymatic activity can lead to an increase in NETosis resulting in release of autoantigenic material and tissue damage.

You can trace every symptom and valid scientific finding in MS directly back to missing enzymes called DNase 1 and protease, including elevated polyamines.

Protease digest dietary proteins and release essential amino acids. Research shows that MS patients lack numerous essential amino acids-including phenylalanine.

J Neurol Neurosurg Psychiatry. 1979 July; 42(7): 640–641.
Plasma and cerebrospinal fluid tryptophan in multiple sclerosis and degenerative diseases.
F Monaco, S Fumero, A Mondino, and R Mutani

“…Tryptophan and competing neutral amino acid levels were found to be diminished in the plasma of patients with multiple sclerosis and degenerative diseases…Tryptophan, leucine, isoleucine, valine, tyrosine, and phenylalanine were all diminished in the plasma of patients with multiple sclerosis…”

Phenylalanine is needed for the synthesis of dopamine. Phenylalanine>Tyrosine>Dopamine

Research shows that MS patients lack dopamine.

Zh Nevrol Psikhiatr Im S S Korsakova. 2012;112(2 Pt 2):34-40.
The role of dopamine in the regulation of the interaction between nervous and immune systems in multiple sclerosis.
Orlova EV, Pashchenkov MV, Davydovskaia MV, Klimova SV, Khozova AA, Mugutdinova BT, Boĭko AN
“…The results suggest the involvement of dopamine in the pathogenesis of depression in MS as assessed by dopamine and its metabolites levels.”

Dopamine regulates prolactin. The less dopamine, the more prolactin.

Research shows that MS patients have elevated prolactin.

Journal of the Neurological Sciences Volume 102, Issue 1, March 1991, Pages 61–66
Hyperprolactinemia in multiple sclerosis.

"…Serum prolactin levels were found to be significantly higher in MS patients than in healthy controls in both sexes…All relapsing-remitting patients with hyperprolactinemia showed a rise in prolactin levels in the acute stage of the relapse and a decrease during the recovering stage and the following remission phase…”

In humans, prolactin acts to (1) increase arginase activity, (2) stimulate ornithine decarboxylase activity, and (3) enhance the rate of transport of polyamines... All result in increased spermine and spermidine synthesis (polyamines)... ... prolactin/

This is from Wiki~The enzyme ornithine decarboxylase (ODC) catalyzes the decarboxylation of ornithine (a product of the urea cycle) to form putrescine. This reaction is the committed step in polyamine synthesis.

So yes, I would say this is a small piece of the puzzle. But of course, it doesn't explain missing essential amino acids, low dopamine, elevated prolactin or even why polyamines are increased in autoimmune disease.

A lack of protease and DNase 1 even explain the NETs the researcher believes are involved. For instance, research has found that the lack of DNase1 is a "causative" factor of lupus. Here are a few studies on this.

Lupus and deoxyribonuclease.
Lachmann, P.J., 2003. Lupus 12(3):202-6.
“Mice whose DNase 1 gene is knocked out are known to develop lupus and to be otherwise normal.”

Mutation of DNASE1 in people with systemic lupus erythematosus.
Yasutomo, K., T. Horiuchi, S. Kagami, H. Tsukamoto, C. Hashimura, M. Urushihara, Y. Kuroda. 2001. Nat. Genet. 28(4):313-4.
“These data are consistent with the hypothesis that a directconnection exists between low activity of DNASE1 and progression of human SLE.”

This missing enzyme results in bits of proteins and DNA ending up in the bloodstream. The immune system targets these proteins and DNA and forms the NETs. Here is a picture of one of these NETs in a lupus patients bloodstream. Notice in the last paragraph where it states lupus patients lack the enzyme DNase 1. ... 161423.htm

A lack of DNase 1 also explains the low levels of uric acid found in patients with MS. Uric acid is the final breakdown product of dietary DNA. DNase1 breaks down dietary DNA. A lack of DNase1 would lead to low levels of uric acid.
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Re: New hypothesis - abnormal NETosis

Postby Wrinkles » Mon Jun 17, 2013 8:29 am

I think MSers should read more than just the abstract to see what is new with this hypothesis. It explains how EBV (or other viruses or bacteria) can potentially lower the threshold for NETosis. And it explains some of the selectivity for autoantigens.
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Re: New hypothesis - abnormal NETosis

Postby leonardo » Mon Jun 17, 2013 11:26 am

Too difficult to understand for me :(

I noticed that SAMe is mentioned in this study.
Is it good to supplement S-adenosylmethionine?
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Re: New hypothesis - abnormal NETosis

Postby Wrinkles » Mon Jun 17, 2013 12:25 pm

S-adenosylmethionine is sometimes mentioned as a supplement that can help with suppression of inflammation but I am not a doctor so consult with your doctor before taking it. I am not familiar with how SAM gets into cells. It may be that methionine and adenosine are taken up and the cell makes SAM as needed. SAM is used in methylation which is important in gene control (DNAand histone methylation) and intracellular trafficking/localization of proteins and RNA to get them to their correct compartments once they are synthesized. Methylation is also important in suppressing invading viral DNA.
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