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Krooniset bakteeri-infektiot (Luettu 234860 kertaa)
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Re: Krooniset bakteeri-infektiot
Vastaus #345 - 08.09.2018 - 01:37:21
 
STAT3 can be a therapeutic target for chronic active EBV infection, a fatal disorder

https://www.sciencedaily.com/releases/2018/08/180820113117.htm

August 20, 2018
Tokyo Medical and Dental University(TMDU) study shows that ruxolitinib-induced inhibition of STAT3 activity blocks survival and reduces pro-inflammatory cytokine production in Epstein-Barr virus (EBV)-infected clonally proliferating T- or NK-cells in Chronic active Epstein-Barr virus infection.

Tokyo, Japan -- Chronic active Epstein-Barr virus infection (CAEBV) is an EBV-positive T- or NK-cell neoplasm accompanied by sustained systemic inflammation. Many studies have attempted to understand the case of CAEBV; none have provided a clear explanation, until now.

A research team, led by experts from Tokyo Medical and Dental University(TMDU), investigated the activity of STAT3, a factor that helps to control cell proliferation and survival, in EBV-infected T- or NK-cells in CAEBV. They found that STAT3 was constitutively activated in those cells, reported in Oncotarget, "STAT3 is constitutively activated in chronic active Epstein-Barr virus infection and can be a therapeutic target."

CAEBV is a disorder which has 2 aspects: an inflammatory disorder and a lymphoid neoplasm. During the course, it may progress to chemotherapy-resistant lymphoma or leukemia, or to a life-threatening disorder known as hemophagocytic lymphohistiocytosis. Despite a variety of efforts to control or cure CAEBV, the sole effective treatment has been stem cell transplantation from a HLA-matched donor. Unfortunately, some patients cannot be candidates for this therapy, and there are many side effects.

"Constitutively activated STAT3 has been observed in a variety of primary tumor cells, including other tumors associated with Epstein-Barr virus infection," says Ayoko Arai, corresponding author on the study. "We suspected that STAT3 may be similarly activated in cells from patients with CAEBV."

In the study, increased phosphorylation, an important modification of cellular proteins, was observed on STAT3 in EBV-infected T- or NK-cells from patients with CAEBV. In those same cells from health individuals, the phosphorylation was absent, suggesting that it may provide a useful drug target.

"Our analyses revealed no mutations in STAT3, so we tested whether inhibitors of STAT3 phosphorylation might modify its activity in laboratory-grown," says Erika Onozawa, lead author on the study. "We found that ruxolitinib, a drug that is currently used for treatment of myelofibrosis and polycythemia vera, could suppress the survival of the EBV-infected cells in a dose-dependent manner."

In addition to the ability of ruxolitinib to induce the death of virus-infected T- or NK-cells from patients with CAEBV, the researchers showed that it could block the production of several important inflammatory cytokines that play a role in the progression of CAEBV.

CAEBV is a neoplastic and inflammatory disease that can become extremely destructive for some patients. This study showed that STAT3 could be an important new target for treatment of this disorder, and that ruxolitinib may provide a readily available therapy that may be effectively used in clinical treatment.
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Re: Krooniset bakteeri-infektiot
Vastaus #346 - 02.10.2018 - 18:42:50
 
Multiple sclerosis and mixed microbial infections. Direct identification of fungi and bacteria in nervous tissue.

https://www.ncbi.nlm.nih.gov/pubmed/29859870

Abstract

Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system (CNS), leading to multifocal demyelination and neurodegeneration. The etiology of this incurable disease is unknown and remains a matter of intensive research. The possibility that microbial infections, such as viruses or bacteria, can trigger an autoimmune reaction in CNS tissue has been suggested. However, the recent demonstration that bacteria are present in CNS tissue points to a direct involvement of microbial infections in the etiology of MS. In the present study, we provide the first evidence of fungal infection in CNS tissue of MS patients, and demonstrate that fungal DNA from different species can be detected in the CNS. We used, nested PCR assays together with next-generation sequencing to identify the fungal species in the nervous tissue of 10 patients with MS. Strikingly, Trichosporon mucoides was found in the majority of MS patients, and particularly high levels of this fungus were found in two patients. Importantly, T. mucoides was not detected in the CNS of control subjects. We were also able to visualize fungal structures in CNS tissue sections by immunohistochemistry using specific antifungal antibodies, which also revealed the accumulation of a number of microbial cells in microfoci. Again, microbial structures were not observed in CNS sections from controls. In addition to fungi, neural tissue from MS patients was also positive for bacteria. In conclusion, our present observations point to the novel concept that MS could be caused by polymicrobial infections. Thus, mycosis of the CNS may be accompanied by opportunistic bacterial infection, promoting neuroinflammation and directly causing focal lesions, followed by demyelination and axonal injury.
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Re: Krooniset bakteeri-infektiot
Vastaus #347 - 13.11.2018 - 23:20:10
 

Molecular signature of Epstein-Barr virus infection in MS brain lesions


http://nn.neurology.org/content/nnn/5/4/e466.full.pdf

Neurol Neuroimmunol Neuroinflamm. 2018

Abstract

Objective
We sought to confirm the presence and frequency of B cells and Epstein-Barr virus
(EBV) (latent and lytic phase) antigens in archived MS and non-MS brain tissue by
immunohistochemistry.

Methods
We quantified the type and location of B-cell subsets within active and chronic MS brain lesions
in relation to viral antigen expression. The presence of EBV-infected cells was further confirmed
by in situ hybridization to detect the EBV RNA transcript, EBV-encoded RNA-1 (EBER-1).

Results
We report the presence of EBV latent membrane protein 1 (LMP-1) in 93% of MS and 78% of
control brains, with a greater percentage of MS brains containing CD138+plasma cells and
LMP-1–rich populations. Notably, 78% of chronic MS lesions and 33.3% of non-MS brains
contained parenchymal CD138+plasma cells. EBV early lytic protein, EBV immediate-early
lytic gene (BZLF1), was also observed in 46% of MS, primarily in association with chronic
lesions and 44% of non-MS brain tissue. Furthermore, 85% of MS brains revealed frequent
EBER-positive cells, whereas non-MS brains seldom contained EBER-positive cells. EBV in-
fection was detectable, by immunohistochemistry and by in situ hybridization, in both MS and
non-MS brains, although latent virus was more prevalent in MS brains, while lytic virus was
restricted to chronic MS lesions.

Conclusions
Together, our observations suggest an uncharacterized link between the EBV virus life cycle and
MS pathogenesis.

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Re: Krooniset bakteeri-infektiot
Vastaus #348 - 23.11.2018 - 00:10:56
 
Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis.

https://www.ncbi.nlm.nih.gov/pubmed/30429369

JCI Insight. 2018 Nov 15

Abstract

BACKGROUND:
Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy.

METHODS:
An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro-expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses.

RESULTS:
Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher's exact test).

CONCLUSION:
EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS.

*******
Näiden kliinisten testien tarkoitus oli ainoastaan onko ATA-188 immunoterapia turvallinen. Eli on, ja seuraavaksi kliinisten testien kohteena on annostus. Toivottavasti myös eurooppalaiset osallistuisivat.
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Re: Krooniset bakteeri-infektiot
Vastaus #349 - 02.12.2018 - 19:48:44
 
About the Anti-EBV clinical trial


https://msra.org.au/news/anti-ebv-trial-results-explained-by-professor-michael-p...
ender/


A treatment to target EBV has been shown to improve symptoms in some people with progressive MS in a world-first clinical trial.

The small phase I safety trial used an ‘adoptive T cell immunotherapy’ treatment. This involves taking blood from patients, extracting their immune cells, and then ‘training’ these cells in the lab to recognise and destroy EBV. The cells are then reintroduced to the patient’s body and go to work in targeting the EBV hiding in the body.

The trial was carried out by Professor Michael Pender and Professor Rajiv Khanna and MS Research Australia is proud to have contributed to the funding of this project, as well as significantly supporting Professor Pender’s EBV research over the last decade.

In this video Professor Pender explains how the trial came about, what it involved and what the results may mean for the future.

About Professor Michael Pender

Professor Michael Pender is a neurologist and researcher from The University of Queensland and Royal Brisbane and Women’s Hospital. He has spent much of his career investigating EBV in MS with a great deal of support along the way from MS Research Australia.

*********
Katso video, jossa Dr Pender selittää kliinisen kokeen tuloksia.
Vaikka kukaan ei sano sitä, on tämä paras uutinen vuosiin.
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Re: Krooniset bakteeri-infektiot
Vastaus #350 - 02.12.2018 - 19:58:30
 

Anti-EBV trial shows promise in progressive MS

https://msra.org.au/news/anti-ebv-trial-shows-promise-in-progressive-ms/


20 November, 2018

   A treatment called ‘adoptive T cell immunotherapy’ – which targets the Epstein Barr virus (EBV) – was shown to be safe in a group of 10 patients with primary and secondary MS in a small phase I (safety) trial
   EBV infects B cells of the immune system and is a known risk factor for developing MS
   The treatment takes the patient’s own T cells from the immune system and primes them to recognise and kill EBV-infected B cells
   Seven of the 10 patients showed clinical improvements including some reduction in disability and improvements in fatigue
   Larger studies are now underway to test the safety and effectiveness of the treatment

Overview

A treatment to target EBV has been shown to improve symptoms in some people with progressive MS in a world-first clinical trial.

The small phase I safety trial used an ‘adoptive T cell immunotherapy’ treatment. This involves taking blood from patients, extracting their immune cells, and then ‘training’ these cells in the lab to recognise and destroy EBV. The cells are then reintroduced to the patient’s body and go to work in targeting the EBV hiding in the body.

The trial was carried out by Professor Michael Pender and Professor Rajiv Khanna and MS Research Australia is proud to have contributed to the funding of this project, as well as significantly supporting Professor Pender’s EBV research over the last decade.

What is EBV and its relationship with MS?

EBV is a virus which infects a subset of white blood cells in the body called B cells. Most people won’t know they have had it as it is a common childhood illness with non-specific symptoms, although in adolescents it can cause the more serious glandular fever (infectious mononucleosis).

Once a person becomes infected with EBV, they carry the virus in their B cells for the rest of their life, mostly without any symptoms or problems. The infected cells are usually kept under control by other cells of the immune system called T cells which recognise and kill virus-infected cells.

While we know that EBV is a risk factor for the development of MS, there has been intense research to understand exactly how the virus contributes to MS and how we might tackle it to prevent or treat MS.

How did this EBV trial come about?

Professor Michael Pender, a neurologist and researcher from The University of Queensland and Royal Brisbane and Women’s Hospital has spent much of his career investigating EBV in MS with a great deal of support along the way from MS Research Australia.

Previous studies by Professor Pender’s research group have shown that people with MS have a reduced number of T cells capable of killing EBV-infected B cells, compared with people who do not have MS. This led to the idea that boosting a person’s ability to kill EBV-infected cells might help treat MS.

In recent years Professor Pender has teamed up with Professor Rajiv Khanna from QIMR Berghofer Medical Research Institute to test a novel treatment that targets EBV infected cells in the body.

Professor Khanna had developed a technique where the T cells could be removed from a patient, grown in the laboratory and primed to recognise and destroy EBV infected cells. The T cells are then returned to the patient where they act like heat-seeking missiles to kill the problem cells. He has primarily been testing the type of treatment called ‘adoptive T cell immunotherapy’ on certain cancers that are associated with EBV.

After initially treating just one patient with secondary progressive MS with some success (reported in 2014), the pair set up a phase I clinical trial to test the safety of the therapy in a small group of five people with primary progressive MS and five with secondary progressive MS.

What did the trial involve?

13 people with progressive MS were enrolled into the study. The scientists were able to collect the EBV-targeting T cells from 11 of 13 people and grow them in the laboratory.

One patient had to drop out of the trial before being treated due to an unrelated health condition, leaving 10 patients still in the trial. 5 with primary progressive MS and 5 with secondary progressive MS. The T cells were primed against EBV and then infused back into their body in four doses.

The participants were then monitored for a period of 27 weeks with a range of tests including MRI scans, the EDSS neurological disability scoring system, fatigue, quality of life and thinking and memory skills.

Were there any improvements in MS symptoms?

This very small study was first and foremost designed to identify any safety issues with the treatment, however, it did appear to have some positive effects.

Seven of the 10 participants showed a clinical improvement on the tests of neurological disability. Of the three that did not improve, two remained stable and one experienced worsening of disability.

Overall for the whole group, fatigue was significantly improved across the 27 week period, this being a prominent feature in five of the seven patients who showed neurological improvements.

Thinking and memory skills, while not improved, did not worsen over the period of the study.

In general, the treatment did not appear to prevent the appearance of new or active lesions in the MRI scans of some of the participants, but these people were still among those who did show neurological improvement.

Were there any side-effects?

None of the 10 people experienced any serious side effects as a result of the treatment. Just one patient experienced a minor side effect of an alteration to their sense of taste. This was thought to be due to one of the chemicals used in the preparation of the cells.

What do the results tell us?

The results of the trial firstly show that it is possible to collect and identify the EBV-targeting T cells from the majority of people with progressive MS and grow them in the laboratory.

They also tell us that the treatment appears safe. The findings have been published in the scientific journal JCI Insight. It is a potentially encouraging results for people living with primary and secondary progressive MS. However, it is important to be mindful that this was a very small study that was first and foremost designed to identify any safety issues with the treatment. It is too small, and not designed with the gold-standard placebo controlled, blinded, design to identify whether the treatment was truly effective.

However, the clinical signs of improvement noted in this study are encouraging. In particular, one important observation was that the strength of the EBV-targeting response noted in the preparation of the cells in the laboratory prior to treatment did seem to match with the clinical outcomes. The six participants with a strong reaction to EBV showed clinical improvement, whereas only one of the four participants with a weak reaction to EBV showed clinical improvement of symptoms but not disability.

What’s next?

Professor Khanna is now collaborating with biotechnology company Atara Biotherapeutics to conduct a bigger, randomised controlled (double blind) trial of another ‘off-the-shelf’ version of this treatment – you can learn more about this trial here.

This phase I trial was funded through a grant to Professor Rajiv Khanna and Professor Michael Pender in a partnership between MS Research Australia and MS Queensland and other philanthropic support to QIMR Berghofer Medical Research Institute.

*****************
Ilmoitin aikaisemmin, että tulokset olivat ATA-188 tutkmuksesta, mutta olivat adoptive immunotherapy tutkimuksesta, joka perustuu potilaan omiin soluihin.
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Re: Krooniset bakteeri-infektiot
Vastaus #351 - 06.01.2019 - 00:38:44
 
Fungi cause brain infection and impair memory in mice

https://www.sciencedaily.com/releases/2019/01/190104104006.htm

January 4, 2019

Fungal infections are emerging as a major medical challenge, and a team led by researchers at Baylor College of Medicine has developed a mouse model to study the short-term consequences of fungal infection in the brain.

The researchers report in the journal Nature Communications the unexpected finding that the common yeast Candida albicans, a type of fungus, can cross the blood-brain barrier and trigger an inflammatory response that results in the formation of granuloma-type structures and temporary mild memory impairments in mice. Interestingly, the granulomas share features with plaques found in Alzheimer's disease, supporting future studies on the long-term neurological consequences of sustained C. albicans infection.

"An increasing number of clinical observations by us and other groups indicates that fungi are becoming a more common cause of upper airway allergic diseases such as asthma, as well as other conditions such as sepsis, a potentially life-threatening disease caused by the body's response to an infection," said corresponding author Dr. David B. Corry, professor of medicine-immunology, allergy and rheumatology and Fulbright Endowed Chair in Pathology at Baylor College of Medicine.

Importantly, explains Corry, fungal infections causing airway allergic diseases and sepsis have been associated with increased risk for dementia later.

"These observations led us to investigate the possibility that fungus might produce a brain infection and, if so, the consequences of having that kind of infection," said Corry, who also is a member of the Dan L Duncan Comprehensive Cancer Center.

The researchers began their investigation by developing a mouse model of a low-grade fungus infection with the common yeast C. albicans that would not cause severe disease, but might carry implications for brain function. They tested several doses and finally settled on one dose of 25,000 yeasts.

They injected C. albicans into the blood stream of mice and were surprised to discover that the yeast can cross the blood-brain barrier, a robust protective mechanism the brain employs to exclude all kinds of large and small molecules, as well as a number of microorganisms that can potentially damage the brain.

"We thought that yeast would not enter the brain, but it does," Corry said. "In the brain, the yeast triggered the activity of microglia, a resident type of immune cell. The cells became very active 'eating and digesting' the yeast. They also produced a number of molecules that mediated an inflammatory response leading to the capture of the yeasts inside a granule-type structure inside the brain. We called it fungus-induced glial granuloma, or FIGG."

Corry and his colleagues also tested the animals' memory in both yeast-infected and non-infected mice. They found that infected mice had impaired spatial memory, which reversed when the infection cleared.

The mice cleared the yeast infection in about 10 days; however, the microglia remained active and the FIGGs persisted well past this point, out to at least day 21. Intriguingly, as the FIGGs formed, amyloid precursor proteins accumulated within the periphery and amyloid beta molecules built up around yeast cells captured at the center of FIGGs. These amyloid molecules are typically found in plaques that are the trademark of Alzheimer's disease.

"These findings suggest that the role fungi play in human illness potentially goes well beyond allergic airway disease or sepsis," Corry said. "The results prompted us to consider the possibility that in some cases, fungi also could be involved in the development of chronic neurodegenerative disorders, such as Alzheimer's, Parkinson's and multiple sclerosis. We are currently exploring this possibility."

"For these reasons, if we better understand how our immune system deals with this kind of constant threat and what are the weaknesses in our immunological armor that occur with aging that allow fungal disease to take root, then we would likely increases the possibility of finding ways to fight back, " Corry said.
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Re: Krooniset bakteeri-infektiot
Vastaus #352 - 27.01.2019 - 13:28:31
 
Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192109

February 2, 2018

Abstract
Multiple sclerosis (MS) is a chronic neuroinflammatory condition of the central nervous system (CNS). It is a major cause of neurological disability in young adults, particularly women. What triggers the destruction of myelin sheaths covering nerve fibres is unknown. Both genetic and infectious agents have been implicated. Of the infectious agents, Epstein-Barr virus (EBV), a common herpesvirus, has the strongest epidemiological and serological evidence. However, the presence of EBV in the CNS and demonstration of the underlying mechanism(s) linking EBV to the pathogenesis of MS remain to be elucidated. We aimed at understanding the contribution of EBV infection in the pathology of MS.
We examined 1055 specimens (440 DNA samples and 615 brain tissues) from 101 MS and 21 non-MS cases for the presence of EBV using PCR and EBER-in situ hybridization (EBER-ISH). EBV was detected by PCR and/or EBER-ISH in 91/101 (90%) of MS cases compared to only 5/21 (24%) of non-MS cases with other neuropathologies. None of the samples were PCR positive for other common herpesviruses (HSV-1, CMV, HHV-6). By quantitative PCR, EBV viral load in MS brain was mainly low to moderate in most cases. However, in 18/101 (18%) of MS cases, widespread but scattered presence of EBV infected cells was noted in the affected tissues by EBER-ISH. Immunohistochemical analysis of EBV gene expression in the 18 heavily infected cases, revealed that the EBV latent protein EBNA1, and to a lesser extent the early lytic protein BZLF1 were expressed. Furthermore, using double-staining we show for the first time that astrocytes and microglia, in addition to B-cells can also be infected. To the best of our knowledge, this is the most comprehensive study demonstrating that EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS pathogenesis. Further studies are required to address the mechanism of EBV involvement in MS pathology.

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Re: Krooniset bakteeri-infektiot
Vastaus #353 - 02.03.2019 - 00:20:47
 
Revisiting the old link between infection and autoimmune disease with commensals and T helper 17 cells

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797425/

2018 Feb 3
Abstract

Genetic composition and major histocompatibility complex polymorphisms unequivocally predispose to autoimmune disease, but environmental factors also play a critical role in precipitating disease in susceptible individuals. Notorious among these has been microbial infection. Older studies describing associations between microbial infection and autoimmune disease are now followed by new studies demonstrating correlations between susceptibility to autoimmune disease and commensal colonization of the intestinal tract. T helper 17 (TH17) cells have gained a prominent role in autoimmune disease, and notably, their development within the intestine has been linked to colonization with specific commensal bacteria. Here, we consider current views on how microbes, TH17 cells, and autoimmunity are connected. We speculate on how the intricate relationships among commensal, pathogen, and the host might ultimately determine susceptibility to autoimmune disease.
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Re: Krooniset bakteeri-infektiot
Vastaus #354 - 02.03.2019 - 00:33:38
 
When good cells go bad: Regulating the MS-causing properties of Th17 cells

https://www.sciencedaily.com/releases/2019/02/190213093144.htm

February 13, 2019
Inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis (MS) are a major healthcare burden worldwide and are life-altering conditions for afflicted patients. Yet, while much is known about the mechanisms of disease, in most cases there are very few effective treatment options.

However, a recent study published in Nature Communications provides hope for autoimmune disease sufferers. Led by researchers from Osaka University, the study team found that genome organizer protein Satb1 triggers a shift in immune cells, inducing tissue inflammation and autoimmunity. This breakthrough could lead to new treatments targeting the source of inflammation.

Interleukin 17-producing T-helper (Th17) cells are a recently-identified class of immune cells that play a major role in protecting us against invading pathogens. But, despite their name, Th17 cells aren't always so helpful. In fact, studies have shown that excessive inflammation induced by Th17 cells is actually one of the underlying causes of many inflammatory and autoimmune disorders.

But what causes Th17 cells to cross the line from helpful to harmful?

To answer this question, the researchers examined genome organizer protein Satb1. "We have known for some time that Satb1 is indispensable for the development of T-cells in the thymus. However, how it is involved in the regulation of pathogenic processes of Th17 cells in inflamed tissues had not been examined," explains lead author Keiko Yasuda.

Using a mouse model of MS,
the researchers deleted the Satb1 gene in Th17 cells and found that the disease no longer developed in the mutant mice. Key to this mechanism was the lack of expression of a protein called granulocyte-macrophage colony-stimulating factor (GM-CSF) by the Satb1-defective Th17 cells. GM-CSF is a pathogenic cytokine that causes localized tissue inflammation in MS and other inflammatory autoimmune diseases. Importantly, Satb1 was also found to enhance the expression of the GM-CSF gene, confirming its role in promoting inflammation in diseased individuals.

But as well as promoting inflammation, Satb1 also seems to block the expression of a protein specially designed to suppress T-cell inflammatory activity and prevent autoimmune diseases. This protein, programmed cell death protein 1, was more highly expressed in Satb1-deficient Th17 cells compared with normal Th17 cells, indicating that Satb1 normally inhibits protein expression.

As explained by study corresponding author Shimon Sakaguchi, these findings are something to get excited about: "Our results suggest that manipulating Satb1 gene expression in Th17 cells could form the basis of novel treatments for various autoimmune diseases caused by Th17 cells. If we can prevent the pathogenic processes of Th17 cells, we may be able to alleviate or even eliminate disease symptoms."

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Re: Krooniset bakteeri-infektiot
Vastaus #355 - 18.05.2019 - 23:11:51
 
Multiple sclerosis: Discovery of a mechanism responsible for chronic inflammation

https://www.sciencedaily.com/releases/2019/05/190510091354.htm

May 10, 2019
Multiple sclerosis (MS) is an autoimmune disease. The defense system that usually protects patients from external aggression turns on its own cells and attacks them for reasons that are not yet known. Scientists from the Institut Pasteur have shown that ancient viruses are involved in the acute inflammatory defense response that may contribute to the disease.

Multiple sclerosis (MS) is an incurable inflammatory autoimmune disease that leads to irreversible damage to the brain and spinal cord. This disease is also associated with the reactivation of ancient viruses, which were inserted in our DNA during the evolution of humankind. It was therefore long thought that multiple sclerosis was due to a viral infection.

"Our study shows that reactivation of ancient viruses does not correspond to an infectious phenomenon, but to a defense response of the body when faced with an acute inflammatory phenomenon" explains Christian Muchardt, Head of the Epigenetic Regulation Unit at the Institut Pasteur.

Viral sequences were neutralized during evolution and no longer represent a source of infection. But these sequences are a source of external DNA containing information about virus behavior. Cells have therefore been able to control these sequences to detect infections as quickly as possible and turn on their defense genes during an attack.

These viral sequences are, above all, used to control defense genes in stem cells. They lie dormant in adult cells and it is the more traditional sequences that become active. By examining samples from patients with MS, the scientists observed that regulatory sequences of viral origin emerged from their dormant state and were responsible for abnormal expression of several pro-inflammatory genes.

To conclude, in multiple sclerosis, activation of viral sequences does not correspond to an infectious phenomenon but to the unexpected use of regulatory sequences, leading to chronic excessive inflammation.

"The discovery of this mechanism, linked to epigenetic phenomena, may one day pave the way for management of MS using small molecules that inhibit chromatin modification enzymes" sums up Christian Muchardt.


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Re: Krooniset bakteeri-infektiot
Vastaus #356 - 18.05.2019 - 23:17:49
 
Atara Biotherapeutics Study Links Epstein-Barr Virus Infection with MS

https://multiplesclerosisnewstoday.com/2018/06/19/atara-biotherapeutics-study-li...
nks-epstein-barr-virus-infection-with-ms/

Analysis of post-mortem brain samples from multiple sclerosis (MS) patients and healthy individuals (without neurologic disease) showed that while signs of Epstein-Barr virus (EBV) infection are present in both groups of brains, EBV-positive immune cells were more prevalent and densely populated in the MS brain.

The study reporting those findings, “Molecular signature of Epstein-Barr virus infection in MS brain lesions,” was published in the journal Neurology: Neuroimmunology & Neuroinflammation, the official journal of the American Academy of Neurology.

EBV infection is estimated to affect about 95% of adults worldwide, and previous studies have suggested a potential causal link between EBV infection and the risk for MS. These studies reported that MS patients had higher levels of antibodies against EBV than non-MS individuals, but follow-up studies have failed to find the same results.

Now, researchers analyzed autopsied brain samples from a MS brain tissue bank and from healthy, non-MS samples (controls).

They detected signs for the presence of EBV in 93% of MS brain samples, but also in the controls, although to a less extent (78%).
******

EBV infects immune B-cells, and the results showed that 85% of MS brain samples contained a higher percentage of B-cells positive for EBV-encoded RNA. In contrast, almost none of these cells were found in brain samples from controls.

“The Neurology publication extends the growing body of evidence linking EBV infection and MS using a well-characterized MS brain tissue bank,” Chris Haqq, MD, PhD, said in a press release. Haqq is executive vice president of research and development and chief scientific officer of Atara Biotherapeutics.

“We observed that EBV is present in both MS and control brains, with EBV-infected B-cells and plasma cells more prevalent and localized to MS brain lesions,” Haqq said.

Within immune B-cells, EBV switches between latent and lytic forms. The latent form is a way for the virus to evade the host’s immune system, whereas the lytic form corresponds to a state in which the virus replicates more actively. EBV infection was detectable in both MS and non-MS brains. although latent virus was more prevalent in MS brains, and lytic virus was restricted to chronic MS lesions.

“Taken together, our results that are derived from a well-characterized MS brain tissue bank support previous studies demonstrating the presence of EBV in the MS brain,” the team concluded.

“These findings advance the understanding of EBV’s potential role in MS pathogenesis and provide support for targeting EBV-infected immune cells associated with chronic MS lesions as a potential treatment for this severe autoimmune disorder,” Haqq said.

Atara is developing two therapies, ATA188 and ATA190, to eliminate EBV-infected  B-cells in the central nervous system that can induce autoimmune responses and potentially contribute to MS development. Early results suggest these therapies can induce clinical improvements in MS symptoms.
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Re: Krooniset bakteeri-infektiot
Vastaus #357 - 21.05.2019 - 13:02:07
 
Humoral response to EBV is associated with cortical atrophy and lesion burden in patients with MS

https://nn.neurology.org/content/3/1/e190

January 7, 2016
Abstract

Objective: Because dysregulated Epstein-Barr virus (EBV)-infected B cells may induce meningeal inflammation, which contributes to cortical pathology in multiple sclerosis (MS), we investigated associations between antibody responses to EBV and development of cortical pathology in MS.

Methods: We included 539 patients with MS (369 with relapsing-remitting MS, 135 with secondary progressive MS, and 35 with primary progressive MS), 66 patients with clinically isolated syndrome (CIS), 63 patients with other neurologic diseases (OND), and 178 age- and sex-matched healthy controls (HC). All participants were scanned on 3T MRI. Serum samples were analyzed for IgG antibodies against EBV viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1), and their quartiles were determined on the whole study sample. Differences between the study groups were assessed using analysis of covariance adjusted for multiple comparisons.

Results: More than 30% of patients with MS and CIS presented with the highest quartile of anti-EBV-VCA and -EBNA-1 status compared to ≤10% of HC (p < 0.001). The figures were 9 (14.3%) and 7 (12.3%) for patients with OND. Patients with MS with the highest quartile of anti-EBV-VCA showed significantly increased T2 lesion volume (p = 0.001), T1 lesion number (p = 0.002), and T1 lesion volume (p = 0.04) and decreased gray matter (p = 0.041) and cortical (p = 0.043) volumes compared to patients with MS with lower quartiles. No significant differences of MRI outcomes in patients with CIS, patients with OND, and HC with lower or highest quartiles of anti-EBV-VCA and -EBNA-1 were detected.

Conclusions: Humoral response to anti-EBV-VCA and -EBNA-1 is associated with more advanced cortical atrophy, accumulation of chronic T1 black holes, and focal white matter lesions in patients with MS.
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