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IrsiCaixa's new study:Researching new tools for diagnosing CFS:HELP with the fundraising campaign!

Helen

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Thanks Bob for the slide presentation.

Anyone, how does their results (slide 14) so far correspond to the results from treatment with Rituximab?
 
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Bob, I just came here to post the same link and saw you already got it. That's the same presentation I got, so that is good than.
 
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@Helen, these results do not correspond with the Ritumixab trial, because they have not published any results regarding phonotyping (immune markers).

But the results correspond with the results of three previous immune marker studies done over three continents . Anushka has written over a period of one year about the immune abnormalities found in three studies and what they indicate. I posted the link above. Results also correspond with the recent results from the team in Australia http://omicsonline.org/immune-abnor...algic-encephalomyelitis-2155-9929.1000152.pdf . A summary of this study, and how Tregs in combination with IL's and other immune cells cause T cell exhaustion and suppression, you can find here http://www.mecfsforums.com/index.php/topic,16077.60.html

What I can tell you in short is that an increase in T regulatory cells puts the autoimmune theory very much in questions. (That does not mean RX does not work)

In short, in humans, an increase in CD4+CD25+ T cell numbers has been detected in the blood of patients with cancers of diverse nature, including oesophageal and gastric, colon, pancreas and breast, melanomas, hepatocarcinoma, cervical and endometrial , ovarian and lung carcinoma and Hodgkin's disease.

Interestingly, regulatory T-cell activity has also been reported to increase in several infectious contexts, such as retro-viral infections, mycobacterial infections, various parasitic infections including Leishmania and Malaria.

In autoimmune diseases Tregs are usually decreased in numbers or dysfunctional.

I also suggest you read this post here http://moms4science.weebly.com and a reviewby Richard A. Peterson, GlaxoSmithKline summarized here http://moms4science.weebly.com/i-read-and-share.html

Enjoy
 
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Helen

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@bambi

Thanks for your informative post. Most valuable for me. Agree with the authors in one of the studies, that I have read so far, that it is important to use the Canadian Consensus Criterias when choosing the patients.
 
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@Helen, your welcome.

I don't understand why everyone is suddenly talking about using the CCC, if we have the ME ICC and especially the ME ICC for Medical Practitioners which is so much better? It took 11 years to get this done, why step back in time and loose so much good work.

Any good reason why the ME ICC should not be used ?
 

Bob

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I don't understand why everyone is suddenly talking about using the CCC, if we have the ME ICC and especially the ME ICC for Medical Practitioners which is so much better? It took 11 years to get this done, why step back in time and loose so much good work.

Any good reason why the ME ICC should not be used ?
Helen was probably making a general reference to the CCC being used in research, as a minimum standard.

I think many/most of us would agree that the ICC is probably better to use than the CCC, as it may define a more homogeneous cohort.
 
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I think many/most of us would agree that the ICC is probably better to use than the CCC, as it may define a more homogeneous cohort.
Agree. Just wondering……..I read it quiet often that patients, and also certain physicians who actually signed the ME ICC, demanding that the CCC to be implemented as a diagnostic criteria. Personally, I find it quiet puzzling. And why ask for the minimum ? Why compromise; especially when it could possible skew research results because the patients selected do not really represent ME patients pure ?
 
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Bob

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Agree. Just wondering……..I read it quiet often that patients, and also certain physicians who actually signed the ME ICC, demanding that the CCC to be implemented as a diagnostic criteria. Personally, I find it quiet puzzling. And why ask for the minimum ? Why compromise; especially when it could possible skew research results because the patients selected do not really represent ME patients pure ?
My take on it is that...
I think they are going for what is now a well-known criteria and realistic to achieve, in terms of encouraging people to use it.
It's been used in quite a number of studies now so it's becoming an acceptable standard criteria to use in research.
Not many people, outside our community, have heard of the ICC, and it's not likely to get much traction yet.
I think researchers may also like to use a criteria that the govt. funding bodies are familiar with, to increase the likelihood of getting funded.
 
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Anyway, I hope people keep posting and forwarding the link to donate. It would be a shame if they cannot continue; they have a good team at their disposal.
 
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I will once more try to explain the whole CD marker stuff a bit more in detail and give an example how it is used to diagnose Leukemia.

CD markers are used widely for research, differential diagnosis, monitoring and treatment of disease.

CD markers are cell surface markers. Cell surface markers are proteins expressed on the surface of cells that often conveniently serve as markers of specific cell types. For example, T cell and B cell surface markers identify their lineage and stage in the differentiation process. These lymphocytes differentiate into multiple cell subtypes, necessary for specific biological processes. During this process, lymphocytes express different surface receptors, which can be used to identify cellular subtypes, such as progenitor cells or terminally differentiated T helper cells. Inappropriate cellular ratios of differentiated white blood cells, such as the relative amounts of Th1 and Th2 cells, occur in pathophysiological conditions such as autoimmunity. The presence of cell surface markers can also determine if a cell type expresses the specific receptor important for a biological response. Testing for surface marker expression is also essential to determine if an experimental drug or ligand will be recognized by the cell type of interest. Many markers for specific cell types are known, however, there are others remaining to be discovered, such as novel T cell subtypes.

Very few diseases are diagnosed with only one single test. Usually it is a set of tests and those are than correlated clinically. For example in Leukemia CD markers , flow cytometry, are part of the diagnosis .

This test can be used to see if the lymphocytes in a sample of blood contain CLL cells. It can also be used to look for CLL cells in bone marrow or other fluids. CLL cells can have many of the same markers as normal B-cells, but they also have a marker called CD5 that is normally found on T-cells. For someone to have CLL, there must be at least 5,000 of these cells (per mm3) in the blood.

Flow cytometry can also be used to test for substances called ZAP-70 and CD38 on the cells. These substances seem to be linked to the type of B lymphocyte involved in the leukemia.

Other tests may be done to measure the amount of certain chemicals in the blood, but they are not used to diagnose leukemia. In patients already known to have CLL, these tests help detect liver or kidney problems caused by the spread of leukemia cells or due to the side effects of certain chemotherapy (chemo) drugs. These tests also help determine if treatment is needed to correct low or high blood levels of certain minerals. If treatment with the drug rituximab (Rituxan®) is planned, the doctor may order blood tests to check for previous hepatitis infection (this is discussed further in the section "Monoclonal antibodies for chronic lymphocytic leukemia").

Blood immunoglobulin (antibody) levels may be tested to see if the patient has enough antibodies to fight infections, especially if they have recently had many infections. Another blood protein called beta-2-microglobulin may be measured. High levels of this protein indicate a more advanced CLL.

More information on how many tests are done to establish and monitor CCL you can find here

http://www.cancer.org/cancer/leukem...dguide/leukemia-chronic-lymphocytic-diagnosis
 
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To show you that increased levels T regulatory cells, CD4+CD25+ FoxP3 (Tregs) are not just some abstract concept, but are associated with severe diseases like cancer and chronic infections, I post some snap shots of studies showing an increase of TREGS in various clinical setting.

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We determined the number and functional status of CD4+CD25high regulatory T cells (Treg) in blood samples from patients with metastatic carcinoma, and evaluated their sensitivity to a single intravenous infusion of cyclophosphamide. Treg numbers were significantly higher in 49 patients with metastatic cancer (9•2% of CD4+ T cells) compared to 24 healthy donors (7•1%).http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219383


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Compared with healthy controls, AML patients had a higher proportion of CD4(+)CD25(high) T cells in peripheral blood. These cells were CD45-RA(-), CD69(-), CD45-RO(+), CD95(+), and intercellular CTLA-4(+), and secreted low levels of TNF-alpha and IL-10, but no IL-2, IL-4, IL-5, and IFN-gamma. They inhibited the proliferation and cytokine production (IL-2, IFN-gamma) of CD4(+)CD25(-) T cells, but improved IL-10 production under the co-culture of both subsets with stimulation, thus behaving as T-reg. Notably, CD4(+)CD25(high) T cells in AML patients presented significantly higher apoptosis and proliferation than that of healthy individuals.http://www.ncbi.nlm.nih.gov/pubmed/16313258


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However, increased percentages of CD4+CD25+ T cells were observed in the non-small cell lung cancer tumor-infiltrating lymphocytes and ovarian cancer tumor-associated lymphocytes. Furthermore, these CD4+CD25+ T cells were found to secrete transforming growth factor-β, consistent with the phenotype of regulatory T cells. .http://cancerres.aacrjournals.org/content/61/12/4766.long


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An increased frequency of Treg was demonstrated in both peripheral blood and mesenteric lymph nodes of patients with colorectal cancer (CRC) compared with either healthy controls or patients with inflammatory bowel disease (IBD). Depletion of Treg from peripheral blood mononuclear cells (PBMC) of CRC patients unmasked CD4+ T cell responses, as observed by IFNc release, to the tumor associated antigen 5T4, whereas no effect was observed in a healthy age-matched control group. Conclusions/Significance. Collectively, these data demonstrate that Treg capable of inhibiting tumor associated antigen- specific immune responses are enriched in patients with CRC. These results support a rationale for manipulating Treg to enhance cancer immunotherapy.



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Foxp3+CD4+CD25+ regulatory T cells are increased in patients with Coxiella burnetii endocarditis The population of CD4+ T cells that expressed both CD25 and Foxp3 was significantly (P < 0.001) increased in patients with Q fever endocarditis compared with controls. Our data suggest that the expansion of Tregs may be critical for the chronic evolution of Q fever.


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Chronic activity of hepatitis B is thought to involve aberrant immune tolerance of unknown mechanism. In this study, we examined the role of CD4+CD25+Foxp3+ regulatory T cells in disease activity and viral clearance in hepatitis B. Patients with chronic active hepatitis B (CAH) and asymptomatic HBV carriers (AsC) exhibited a significantly high frequency of CD4+CD25+Foxp3+ T cells as opposed to that of controls and resolved HBV infection. These CD4+CD25+ T cells expressed an elevated level of Foxp3 and displayed increased inhibitory activity towards both CD4+CD25− and CD8+ effector cells.http://intimm.oxfordjournals.org/content/19/2/133.full

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CD4+Foxp3 regulatory T cells mediate Toxoplasma gondii-induced T-cell suppression through an IL-2- related mechanism but independently of IL-10
We show that selective elimination of Treg cells using Foxp3 EGFP mice leads to a full recovery of CD4+ and CD8+ T-cell proliferation. After Treg-cell removal, a reduced production of IL-10 was observed, but IL-2 levels were unchanged. The numbers of IL-10-producing Treg cells also increased during infection, although the in vitro neutralization of this cytokine did not modify T-cell proliferation, suggesting that IL-10 does not mediate the Treg-mediated suppression. However, addition of rIL-2 in vitro fully restored T-cell proliferation from infected animals. Thus, we show that Treg cells mediate the T-cell suppression observed during acute T. gondii infection through an IL-2-dependent mechanism. Our results provide novel insights into the regulation of the immune response against T. gondii.


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A number of studies have shown that Tregs affect the magnitude of immunity and outcome of viral infections, especially with persistent viruses that give rise to chronic lesions (Rouse BT, 2006). Depletion of Tregs prior to infection using a monoclonal antibody against the IL-2receptor results in enhanced in vivo CD8+ and CD4+ T lymphocyte proliferation, and increased mucosa l antibody levels in response to herpes Tregs play a vital role in preventing what Khatami terms “pathogen-induced immunological chaos,” the “immune tsunami,” or cytokine storm can then lead to inflammatory disease and cancer(Khatami, 2011). Immunologists are currently trying to identify strategies to enhance regulatory T cell activation to protect against inflammatory disease such as systemic lupus erythematosis and rheumatoid arthritis. However, some viruses, including PRRSV in pigs, have exploited these cells to enhance their survival and replication in the host. Activation of regulatory T cells by viruses dampens the immune response to the virus and allows them to replicate and persist in host tissues . Understanding the mechanism of Treg activation by viruses is critical for identifying new strategies to prevent the effects on the host.http://cdn.intechopen.com/pdfs/31357/InTech-Regulatory_t_cells_and_viral_disease.pdf



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Development of virus-specific CD4+ and CD8+ regulatory T cells induced by human herpesvirus-6 infection Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus. The mechanisms by which HHV-6 establishes latency and immunosuppression in its host are not well understood. Here we characterized HHV-6-specific T cells in peripheral blood mononuclear cells (PBMCs) from HHV-6-infected donors. Our results showed that HHV-6 infection could induce both CD4+ and CD8+ HHV-6-specific regulatory T (Treg) cells. These HHV-6-specific Treg cells had potent suppressive activity and expressed high levels of Treg-associated molecules CD25, FoxP3 and GITR. Both CD4+ and CD8+ Treg cells secreted IFN-γ, IL-10, but little or no IL-2, IL-4 or TGF-β. Furthermore, HHV-6-specifc Treg cells could not only suppress naïve and HHV-6-specific CD4+ effector T cell immune responses, but also impair dendritic cell (DC) maturation and functions. In addition, the suppressive effects mediated by HHV-6-specific Treg cells were mainly through a cell-to-cell contact dependent mechanism, but not through the identified cytokines. These results suggest that HHV-6 may utilize the induction of Treg cells as a strategy to escape anti-virus immune responses and maintain the latency and immunosuppression in infected hosts.


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Human herpesvirus-6-specific interleukin 10-producing CD4+ T cells suppress the CD4+ T-cell response in infected individuals.
Human herpesvirus-6 (HHV-6) infection normally persists for the lifetime of the host and may reactivate with immunosuppression. The mechanism behind HHV-6 latent infection is still not fully understood. In this study, we observed that decreased proliferation of CD4+ T cells and PBMCs but not CD8+ T cells from HHV-6-infected individuals was stimulated with HHV-6-infected cell lysates. Moreover, HHV-6-stimulated CD4+ T cells from HHV-6-infected individuals have suppressive activity on naïve CD4+ T and CD8+ T cells from HHV-6-uninfected individuals. However, no increased proportion of CD4+ CD25+ Treg cells from HHV-6-infected individuals contributed to the suppressive activity of the HHV-6-stimulated CD4+ T cells from HHV-6-infected individuals. Transwell experiments, ELISA and anti-IL-10 antibody blocking experiment demonstrated that IL-10 may be the suppressive cytokine required for suppressive activity of CD4+ T cells from HHV-6-infected individuals. Results of intracellular interleukin (IL)-10 and IL-4 further implicated the HHV-6-specific IL-10-producing CD4+ T cells in the suppressive activity of CD4+ T cells from HHV-6-infected individuals. Results of intracellular interferon (IFN)-gamma demonstrated a decreased frequency of HHV-6-specific IFN-gamma-producing CD4+ T, but not CD8+ T cells in HHV-6-infected individuals, indicating that it was the CD4+ Th1 responses in HHV-6-infected individuals that were selectively impaired. Our findings indicated that HHV-6-specific IL-10-producing CD4+ T cells from HHV-6-infected individuals possess T regulatory type 1 cell activity: immunosuppression, high levels of IL-10 production, with a few cells expressing IFN-gamma, but none expressing IL-4. These cells may play an important role in latent HHV-6 infection.


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In humans, a P. falciparum-mediated (Malaria) conversion of CD4(+)CD25(-) T cells into CD25+Foxp3+CD4+ T cells has been described. Induction of Foxp3 cells in vitro required TGF-β1 and IL-10, and these cells show the typical suppressor phenotype (CTLA-4(+), CD127(low), CD39(+), ICOS(+), TNFRII(+)) [104]. In accordance, an increase in systemic IL-10 and TGF-β that correlates with up-regulation of CD4+CD25+Foxp3+ has been observed in humans infected with P. falciparum and P. vivax [105, 106].



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By selectively altering the numbers of these cells either by targeted depletion with monoclonal antibody or adoptive transfer of highly enriched naïve CD25+ cells prior to infection, we show that Tregs impairs efficient parasite control and impacts on production of disease-exacerbating proinflammatory cytokines. Collectively, our findings suggest that Tregs contribute to enhanced susceptibility to experimental T. congolense infection in mice.
http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001761
 
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I have some corrections to make. There was some misunderstanding on the text posted on Asssem.org

I was told by Clara today, that the second "study" and the text published in Spanish on Asssem.org was " patients putting together their test results" and "expressing their thoughts" . "It is not a topic" and "cannot be published, cannot be circulated".

I therefore delete some comments I made. They are based on a misunderstanding the text posted on asssem.org are test results presented by Dr. Blanco.

The slide presentation by Dr. Blanco is the correct information.
 
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From Anushka on me cfs forums.

I tried my level best to get the promised video of the presentation by Dr. Blanco to no avail, - but we got the slides. (It seems they are all overwhelmed with work). I guess we have to wait for Dr. Blanco's presentation at the ME conference in London to get a better understanding what Dr. Blanco and his team are planning to do.

I looked a bit at previous research done by the same team - it looks very interesting.

Here a link to IrsiCaixa research page.

http://www.irsicaixa.es/en/recerca/az_publicacions?page=9 on the

Please keep spreading the word and keep donating to this study. I think they are a good team and their study could provide further important clues to the immune abnormalities found in patients with ME CFS.

Based on results from the slides by Dr. Blanco some quick info :

About increased Tregs and how they affect other cells I think I don't have to write here anymore. The lower proliferation of Tregs is topic I will look at later.

CD38 is surface expressed by various cells of both hematopoietic and non-hematopoietic lineages. In the T cell compartment, CD38 is expressed by a significant fraction of human thymocytes, mainly at the double-positive stage.

CD38 is also present in many tissues other than haematopoietic cells, including normal prostatic epithelial cells, pancreatic islet cells and the brain, where it is detected in perikarya and dendrites of many neurons, such as the cerebellar Purkinje cells, in rat astrocytes and in perivascular autonomic nerve terminals. Other CD38+ cells include smooth and striated muscle cells, renal tubules, retinal gangliar cells and cornea (Malavasi et al., 2008).

CD38 produces an enzyme which regulates the release of oxytocin within the central nervous system.

The CD38 has been connected to HIV infection, leukemias, myelomas, solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.

Flow cytometric detection of CD38 expression can be conveniently performed in most clinical laboratories and may prove a valuable adjunct in the current staging system for predicting the clinical outcome in B-CLL patients.

The loss of CD38 function is associated with impaired immune responses.


CD5
The T cell-associated antigen CD5 has been shown to play an important role in the regulation of T cell activation.

CD5 is a good immuno-histochemical marker for T-cells, although not as sensitive as CD3. About 76% of T-cell neoplasms are reported to express CD5, and it is also found in chronic lymphocytic leukemia, hairy cell leukemia, and mantle cell lymphoma cells.

More info on CD5 and Lymphomas http://e-immunohistochemistry.info/web/Cd_5.htm

CD5 is also expressed on subsets of B cells associated with autoantibody production, and CD5+ B cells are present in increased numbers in patients with rheumatoid arthritis and systemic lupus erythematosis.

Recent data indicate that the cell surface glycoprotein CD5 functions as a negative regulator of T cell receptor (TCR)-mediated signaling.

What intrigues me the most is the topic of reduced CD8 effector cells. It ties into topic of memory cells (Scheibenbogen paper), T cell exhaustion, reduced IL-15 (and IL-7) and chronic viral infections - and might even explain why transfer factor work.

Here just some essentials on CD8

CD8(+) T cells contribute to resistance against intracellular infections with certain viral, protozoan, and bacterial pathogens. Although they are known primarily for their capacity to kill infected cells, CD8(+) T cells elaborate a variety of effector mechanisms with the potential to defend against infection.

Dramatic cellular changes occur as T cells transition through the three characteristic phases of an antiviral response, initial activation and expansion, the death phase, and the formation of memory T cells. .

Each of these three phases of the T-cell response is accompanied by extensive transcriptional and functional changes that result in naïve T cells expanding and gaining effector functions, survival of 5 to 10% of the effectors through the death phase, and the gradual acquisition of memory properties by the surviving virus-specific T cells.

I found a beautifully clear, easy to read mini review which has so much good information in it that I don't really now what to pick out. I think you just have to read the full paper. Memory CD8 T-Cell Differentiation during Viral Infection E. John Wherry and Rafi Ahmed*

I linked it to my thread because it ties in to what I posted preciously and I am connecting dots again. http://www.mecfsforums.com/index.php/topic,16077.msg161224.html#msg161224