parvovirus B19: another predisposing factor for CRPS?
 

Over the last year, there has been some focus on the board on Lyme disease, as a predisposing factor to CRPS, apparently through triggering a general inflammatory process.

However, I recently came across another pathogen that may be of interest, specifically because it gives a context to those who are looking at anti-TNF therapies as a treatment for CRPS. Specifically, I found an article showing that while people with CRPS had statistically significant level of Ig(G) antibodies to something called parvovirus B19, they weren't sure what it meant in practice. But it is clearly a predisposing factor, where 71.7% of the CRPS-1 patients tested showed up positive for it - as compared to only 40% of the controls - as did 100% of those with CRPS-2. "Increased seroprevalence of parvovirus B 19 IgG in complex regional pain syndrome is not associated with antiendothelial autoimmunity," Oliver Gross, European Journal of Pain 11 (2007) 237–240:

The etiology of complex regional pain syndrome (CRPS) is unclear yet. Recently autoantibodies and antecedent viral infections have been discussed to be involved in the pathogenesis of CRPS. We investigated sera from 39 CRPS patients and healthy controls for parvovirus B19 IgG and the occurrence of antiendothelial autoantibodies (AECA). CRPS patients showed a higher seroprevalence of parvovirus B19 IgG than controls (p < 0.01). All CRPS 2 patients were positive. 10.2% of the CRPS patients and 10.0% of the controls had AECA (n.s.) and AECA were not associated with parvovirus B19 seropositivity. Our findings suggest the involvement of parvovirus B19, but not autoantibody-mediated endothelial cell damage, in the pathogenesis of CRPS.

PMID: 16545972 [PubMed - indexed for MEDLINE] http://www.ncbi.nlm.nih.gov/sites/entrez

In the testing, anyone with a score over 1.0 was considered positive. I then called my neurologist and arranged to have this run at UCLA and it came back at a 4.5!

I then pulled a series of articles on parvovirus B19, and as suggested in the following articles, I suspect that Drs. Gross, et al. may have been unduly restrictive in limiting their investigation - once they had found markedly high level of antibodies for parvovirus B19 among CRPS subjects, to simply antiendothelial autoimmunity, where the following articles suggest that it may prove to be far more interesting. For one thing, a parvovirus B19 infection could result in higher levels of TNF signaling, that could in turn contribute to the development of nociceptive sensitization following injury. That said, I recognize - as Vic used to suggest - that I may be just stringing words together, and this stuff is significantly above my pay grade, but it is interesting nevertheless. So here we go, the authors' abstract follows each citation, along with a link to the full article, where available:

1. “Regulation of Tumor Necrosis Factor Alpha Promoter by Human Parvovirus B19 NS1 through Activation of AP-1 and AP-2,” Yi Fu et al, Journal of Virology, June 2002, p. 5395–5403 Vol. 76, No. 11:

Human parvovirus B19 frequently causes acute and chronic arthritis in adults. The molecular mechanism of B19 arthritis, however, remains poorly understood. We previously showed that the transmission of B19 from rheumatoid synoviocytes to monocytic cells is associated with enhanced secretion of tumor necrosis factor alpha (TNF-alpha), which triggers inflammation, and interleukin-6. To determine the role of B19 in the production of TNF-alpha, we focused on the function of its nonstructural protein, NS1, and established monocytic U937 lines transduced with the NS1 gene under the control of an inducible promoter. Production of TNF-alpha mRNA and protein was elevated in a manner associated with NS1 expression. Reporter assays revealed that AP-1 and AP-2 motifs on the TNF-alpha promoter were responsible for NS1-mediated up-regulation. Electrophoretic mobility shift assay showed specific binding of nuclear proteins from NS1 gene-transduced cells with the AP-1 or AP-2 probe. Antibodies against transcription factors AP-1 and AP-2 and anti-NS1 antibody inhibited the binding of nuclear proteins to the corresponding probes. These data indicate that NS1 up-regulates TNF-alpha transcription via activation of AP-1 and AP-2 in monocytic cells. The molecular mechanisms of NS1-mediated TNF-alpha expression would explain the pathogenesis of B19-associated inflammation.

FREE FULL TEXT VERSION AT: http://www.pubmedcentral.nih.gov/art...medid=11991968

2. “TNF signaling contributes to the development of nociceptive sensitization in a tibia fracture model of complex regional pain syndrome type I,” Ilya Sabsovich, et al, Pain 37 (2008) 507-519:

Tibia fracture in rats initiates a cascade of nociceptive, vascular, and bone changes resembling complex regional pain syndrome type I (CRPS I). Previous studies suggest that the pathogenesis of these changes is attributable to an exaggerated regional inflammatory response to injury. We postulated that the pro-inflammatory cytokine tumor necrosis factor alpha (TNF) might mediate the development of CRPS-like changes after fracture. RT-PCR and EIA assays were used to evaluate changes in TNF expression and content in skin, nerve, and bone after fracture. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured using microcomputed tomography. Lumbar spinal cord Fos immunostaining was performed for quantification of Fos positive neurons. After baseline testing, the distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were subcutaneously injected either with a soluble TNF receptor type 1 (sTNF-R1, 5mg/kg/d) or saline every 3 days over 28 days and then were retested at 4 weeks post-fracture. Tibia fracture chronically upregulated TNF expression and protein levels in the hindpaw skin and sciatic nerve. After fracture the rats developed hindpaw mechanical allodynia and unweighting, which were reversed by sTNF-R1 treatment. Consistent with the behavioral data, spinal Fos increased after fracture and this effect was inhibited by sTNF-R1 treatment. Collectively, these data suggest that facilitated TNF signaling in the hindlimb is an important mediator of chronic regional nociceptive sensitization after fracture, but does not contribute to the hindlimb warmth, edema, and bone loss observed in this CRPS I model.

PMID: 18035493 [PubMed - indexed for MEDLINE] http://www.ncbi.nlm.nih.gov/sites/entrez

3. “Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS),” Frank Birklein and Martin Schmelz, Neuroscience Letters (2008) 199-202:

This review explains symptoms and nature of neuropeptide signaling and its importance for clinical symptoms of CRPS. Neurogenic inflammation regularly accompanies excitation of primary afferent nociceptors. It has two major components-plasma extravasation and vasodilatation. The most important mediators are the calcitonin gene-related peptide (CGRP) and substance P (SP). After peripheral trauma immune reaction (e.g. cytokines) and the attempts of the tissue to regenerate (e.g. growth factors) sensitize nociceptors and amplify neurogenic inflammation. This cascade of events has been demonstrated in rat models of CRPS. Clinical findings in these animals strongly resemble clinical findings in CRPS, and can be prevented by anti-cytokine and anti-neuropeptide treatment. In CRPS patients, there is meanwhile also plenty of evidence that neurogenic inflammation contributes to clinical presentation. Increased cytokine production was demonstrated, as well as facilitated neurogenic inflammation. Very recently even "non-inflammatory" signs of CRPS (hyperhidrosis, cold skin) have been linked to neuropeptide signaling. Surprisingly, there was even moderately increased neurogenic inflammation in unaffected body regions. This favors the possibility that CRPS patients share genetic similarities. The future search for genetic commonalities will help us to further unravel the "mystery" CRPS.

FREE FULL TEXT VERSION AT: http://www.rsds.org/2/library/articl...in_Schmelz.pdf

4. “Increased expression and secretion of interleukin-6 in human parvovirus B19 non-structural protein (NS1) transfected COS-7 epithelial cells,” T.-C. Hsu et al, Clinical and Experimental Immunology (2006), 144: 152-157:

Human parvovirus B19 (B19) has been associated with a variety of autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We have demonstrated previously that B19 non-structural protein (NS1) induced apoptosis through the mitochondria cell death pathway in COS-7 epithelial cells and that B19 NS1 may play a role in the pathogenesis of autoimmune diseases. In order to examine the expression profiles of cytokines and chemokines in B19 NS1 transfected COS-7 cells, we constructed the NS1 gene in the pEGFP-C1 vector named enhanced green fluorescence protein gene (EGFP)-NS1. COS-7 cells were transfected with EGFP or EGFP-NS1 plasmid. The expression profiles of cytokines and chemokines, including interleukin (IL)-1beta, IL-5, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, granulocyte-macrophage colony-stimulating factor (GM-CSF), growth-related oncogene alpha (GROalpha), interferon gamma-inducible protein (IP)-10, stromal cell derived factor (SDF)-1, macrophage inflammatory protein (MIP)-1beta, monocyte chemoattractant protein (MCP)-1, regulated upon activation normal T cell expressed and secreted (RANTES), Fractalkine, CX3CR1, CCR2, CCR5 and CCR11 were examined in COS-7 cells, EGFP and EGFP-NS1 transfected cells using enzyme-linked immunosorbent assay (ELISA) or reverse transcription-polymerase chain reaction (RT-PCR). Increased expression and levels of IL-6 were found in EGFP-NS1 transfected cells using RT-PCR and ELISA. There were no significant increases in the expression of IL-1beta, IL-8, IP-10, SDF-1, RANTES, Fractalkine, CX3CR-1, CCR2, CCR5, CCR11, TNF-alpha, GM-CSF and TGF-beta using RT-PCR. There were no significantly increased levels of IL-5, IL-10, TNF-alpha, TGF-beta, GROalpha, MIP-1beta and MCP-1 found by ELISA in this study. Our results show that increased expression and secretion of IL-6 in B19 NS1 transfected epithelial cells may play a role in the pathogenesis of autoimmune diseases.

PMID: 16542377 [PubMed - indexed for MEDLINE] http://www.ncbi.nlm.nih.gov/sites/entrez

5. “Human Pavrovirus B19 NSI Protein Modulates Inflammatory Signaling by Activation of STAT3/PIAS3 in Human Endothelial Cells,” Anja Duetchting et al, Journal of Virology, Aug. 2008, 7942–7952:

The pathogenic mechanism by which parvovirus B19 may induce inflammatory cardiomyopathy (iCMP) is complex but is known to involve inflammatory processes, possibly including activation of JAK/STAT signaling. The nonstructural B19 protein NS1 acts as a transactivator triggering signaling cascades that eventually lead to activation of interleukin 6 (IL-6). We examined the impact of NS1 on modulation of STAT signaling in human endothelial cells (HMEC-1). The NS1 sequences were identified from B19 DNA isolated from the myocardia of patients with fatal iCMP. B19 infection as well as NS1 overexpression in HMEC-1 cells produced a significant upregulation in the phosphorylation of both tyrosine(705) and serine(727) STAT3 (P < 0.05). The increased STAT3 phosphorylation was accompanied by dimerization, nuclear translocation, and DNA binding of pSTAT3. In contrast, NS1 expression did not result in increased STAT1 activation. Notably, the expression levels of the negative regulators of STAT activation, SOCS1 and SOCS3, were not altered by NS1. However, the level of PIAS3 was upregulated in NS1-expressing HMEC-1 cells. Analysis of the transcriptional activation of target genes revealed that NS1-induced STAT3 signaling was associated with upregulation of genes involved in immune response (e.g., the IFNAR1 and IL-2 genes) and downregulation of genes associated with viral defense (e.g., the OAS1 and TYK2 genes). Our results demonstrate that B19 NS1 modulates the STAT/PIAS pathway. The NS1-induced upregulation of STAT3/PIAS3 in the absence of STAT1 phosphorylation and the lack of SOCS1/SOCS3 activation may contribute to the mechanisms by which B19 evades the immune response and establishes persistent infection in human endothelial cells. Thus, NS1 may play a critical role in the mechanism of viral pathogenesis in B19-associated iCMP.

FREE FULL TEXT VERSION AT: http://www.pubmedcentral.nih.gov/art...medid=18550668

I hope (if I can keep organized enough) to be doing some more digging into these articles and other sources in neuro-immunology because it seems quite clear to me now – at something just beyond an intuitive level – that there is something of a gold mind here.

That said, I apologize for the length of this posting and will be happy to email copies of any of the articles mentioned here that can’t be directly linked to. Just drop me a PM with your email address, and please specify which of the articles you would like to see. (These articles can be shared for personal/non-commercial purposes only, please.) Thanks.

Mike

Thanks!!!
 

Hi Mike,

Thanks so very much for your research. Please, please keep us informed. Do you know if there are any treatments that can address this?

I, for one, am concerned and suspicious of an infection connection. In fact, my daughter is scheduled to have two different Lymes tests done today. It is not that I am paranoid, but I could not forgive myself if we do not investigate this and later learn that we should have.

I plan to take your research on this in to her doctor. Your efforts are much appreciated.

Thanks again,
Jeanne

My veterinarian is my good friend of 35 years. He's been helping me all along with figuring out the medical part of CRPS studies and so on --- I copied this info and emailed to him. I can't wait to hear what he is going to tell me about this. Human parvo is bound to be different than the parvo he is used to working with, but still...

Thanks Mike!!!!

And, thanks again for telling me about Shinzen Young. That was a turning point for me.

Dear Mike,

Your postings always give good cause for serious consideration.

I've never heard of the parovirus B19 before so I googled it, Wikipedia gives a good albeit brief overview of the virus. http://en.wikipedia.org/wiki/Parvovirus_B19

Have my home work cut out for me today. Thanks very much for this research.

Warm wishes.

MsL

Dubious -

Thanks for your comment. I agree that there is no proof that parvovirus B19 causes CRPS, and indeed, some 40% of the control group carried the Ig(G) antibody, but did not have CRPS. Nevertheless, using the chi-squared test, the presence of B19 antibodies in the CRPS patient group was significantly greater than that of the control group (p<0.05). So - by definition - it would be highly unlikely if there weren’t some sort of a causal relationship going on.

As to the point made in the abstract you cited, just because someone carries an antibody doesn't for a second mean that it's responsible for something that happens later on down the road, that makes perfect sense, except when bad things start happening to people carrying the antibody in a statistically significant fashion, which is apparently what we've got here. (Correct me if I'm missing something.) And what makes this more interesting, a fortiori, is that some of the other articles that were included in the post lay out a possible mechanism that could control the observed relationship.

And here's where I admit that I haven't done all of the heavy lifting yet: the study by Gross et all focussed on Ig(G) [or IgG: same thing], which is in some sense almost a binomial marker of antibodies: it basically shows whether you ever had the infection, at any time in your life, on account of which doctors also look at a much larger antibody - Ig(M) - which initially produced to fight antigens but soon decreases and allows Ig(G) to take over. It plays an important but secondary role in autoimmunity. Not to digress too far from the point, check out the discussion under the heading of "Isotopes" in the Wiki article on "Antibody":

Antibodies can come in different varieties known as isotypes or classes. In placental mammals there are five antibody isotypes known as IgA, IgD, IgE,IgG and IgM. They are each named with an "Ig" prefix that stands for immunoglobulin, another name for antibody, and differ in their biological properties, functional locations and ability to deal with different antigens, as depicted in the table.[Woof J, Burton D (2004). "Human antibody-Fc receptor interactions illuminated by crystal structures". Nat Rev Immunol 4 (2): 89–99.]

The antibody isotype of a B cell changes during cell development and activation. Immature B cells, which have never been exposed to an antigen, are known as naïve B cells and express only the IgM isotype in a cell surface bound form. B cells begin to express both IgM and IgD when they reach maturity—the co-expression of both these immunoglobulin isotypes renders the B cell 'mature' and ready to respond to antigen.[Goding J. "Allotypes of IgM and IgD receptors in the mouse: a probe for lymphocyte differentiation". Contemp Top Immunobiol 8: 203–43.] B cell activation follows engagement of the cell bound antibody molecule with an antigen, causing the cell to divide and differentiate into an antibody producing cell called a plasma cell. In this activated form, the B cell starts to produce antibody in a secreted form rather than a membrane-bound form. Some daughter cells of the activated B cells undergo isotype switching, a mechanism that causes the production of antibodies to change from IgM or IgD to the other antibody isotypes, IgE, IgA or IgG, that have defined roles in the immune system.

http://en.wikipedia.org/wiki/Antibody

Anyhow, when my blood was tested at UCLA for B 19, it showed that while the level of Ig(G) was substantially elevated, the Ig(M) level was quite low, indicating that the infection was long gone. And indeed, any number of sources will tell you that B 19 is associated with a mild childhood fever and rash lasting approximately five weeks, commonly known as "Fifth disease." Following up on the suggestion of Mslday, I refer to the Wiki article on B 19 at http://en.wikipedia.org/wiki/Parvovirus_B19

So the question arises, is it possible that this, and presumably other diseases, can so inflame or alter the nervous system that we're set up for CRPS many years later? And if so, what's the mechanism? And it's not an unprecedented area of inquiry: consider the relationship between childhood chicken pox and shingles in old age. The articles I've included appear to illuminate a path, but I will admit for the second time that I really don't understand everything in them.

That's about what I know. I suppose this means it’s time to hit the books.

Mike

Dear Folks,

I also test postive for viral infections as well. As soon as I have my infection mess cleared up. I am supposed to start anti virals. With some people Mike has really hit the nail on the head.

Hugs, Roz

Dear Dubious,

Just a thought, but have you researched HHV-6, HHV-7, EBV Panel, VZV, CMV, HSV 1/2 Elisa, Enterovirus panel as well, on how they could relate to even your RSD??? Since you don't think the Parvovirus could relate to you in anyway.

Hugs, Roz



\