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Krooniset bakteeri-infektiot (Luettu 294182 kertaa)
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Re: Krooniset bakteeri-infektiot
Vastaus #375 - 22.05.2020 - 00:21:55
 
Systematic review and meta-analysis of the association between Epstein–Barr virus, multiple sclerosis and other risk factors

https://journals.sagepub.com/doi/abs/10.1177/1352458520907901?journalCode=msja&#...
_i6

March 23, 2020

Abstract

Background:

Epstein–Barr virus (EBV) infection is thought to play a central role in the development of multiple sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk.

Objective:

To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk.

Methods:

Pubmed was searched using the terms ‘multiple sclerosis’ AND ‘Epstein Barr virus’, ‘multiple sclerosis’ AND EBV, ‘clinically isolated syndrome’ AND ‘Epstein Barr virus’ and ‘clinically isolated syndrome’ AND EBV. All abstracts were reviewed for possible inclusion.

Results:

A total of 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (attributable proportion due to interaction (AP) = 0.48, p < 1 × 10−4). Previous infectious mononucleosis (IM) was associated with increased odds ratio (OR) of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR = 2.76) but not low anti-EBV antibodies (OR = 1.16). No interaction between EBV and risk factors was found on a multiplicative scale.

Conclusion:

EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.
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Re: Krooniset bakteeri-infektiot
Vastaus #376 - 22.05.2020 - 00:24:44
 
Complete Epstein-Barr Virus Seropositivity in a Large Cohort of Patients With Early Multiple Sclerosis


https://pubmed.ncbi.nlm.nih.gov/32371533/

May 2020


Abstract

Objective: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).

Methods: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany.

Results: EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts.

Conclusion: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.
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Re: Krooniset bakteeri-infektiot
Vastaus #377 - 22.05.2020 - 00:30:02
 
Atara Pauses Enrollment in Part 2 of Immunotherapy Trial in PPMS and SPMS

https://multiplesclerosisnewstoday.com/news-posts/2020/04/03/atara-biotherapeuti...
cs-provides-update-in-context-of-covid-19-pandemic/

April 7, 2020

In response to the COVID-19 pandemic, Atara Biotherapeutics has temporarily paused patient enrollment in the second and randomized part of its ongoing Phase 1 clinical trial investigating ATA188 in people with progressive forms of multiple sclerosis (MS).

People treated in the first, open-label part of this trial, however, will continue to be monitored as defined by trial protocol, and may enter an open-label extension period to continue with this immunotherapy candidate “in an appropriate setting.”

“While this is an unprecedented time in history, Atara is working hard to ensure operational continuity to serve patients whose lives are affected by severe diseases,” Pascal Touchon, president and CEO of Atara Biotherapeutics, said in a press release.

“The COVID-19 pandemic is evolving rapidly, and we are closely monitoring it to both ensure the safety and well-being of our employees, patients and communities, as well as assess the potential impacts to our business so we can continue delivering transformative medicines to patients in critical need,” Touchon added.

Infection with the Epstein-Barr virus (EBV, a common form of the herpes virus) is known to increase the risk of MS. This virus infects B-cells (immune cells involved in antibody production), making them more likely to produce antibodies that wrongly attack myelin — the protective coating of nerve fibers that is progressively damaged in MS.

T-cells, another type of immune cell, would normally be able to recognize the infected B-cells and eliminate them, but MS patients are thought to be deficient in these cells.

Atara designed ATA188 to overcome this deficiency, providing fully functional T-cells to patients to help rid their bodies of the faulty B-cells. The T-cells are isolated from partly matched donors, and cultured in the lab in a way that makes them highly specific to EBV-infected cells.

The Phase 1 trial (NCT03283826), taking place in the U.S. and Australia, is assessing the safety and effectiveness of ATA188 in 97 patients with either primary progressive MS (PPMS) or secondary progressive disease (SPMS).

The trial is being conducted in two parts. First, about 24 patients were given one of four ATA188 doses — 5 million (5 x 106), 10 million (1 x 107), 20 million (2 x 107), or 40 million (4 x 107) cells — to determine the safest and most effective dose for future studies.

Treatment was administered in two cycles, and patients were followed for one year after initiating treatment. They could then enter an extension part and receive once-a-year ATA188 intravenous (IV) injections for up to four years.

The second part is designed to randomly assign a new group of adult patients to an established dose of ATA188, or a placebo, to continue studying this dose’s safety and effectiveness. As in the escalating part, treatment will be given in two cycles and all enrolled will be monitored for one year.

At the start of year two, those in the placebo group will receive two cycles of ATA188, and those on ATA188 will be given one cycle of AT188 and another cycle of placebo. Patients who complete the two years of treatment may then enter the open-label extension part, and be treated with ATA188 for an additional three years.

Results from the first patients included in the escalating part showed that the treatment was well-tolerated across the four dose groups, with no evidence of cytokine release syndrome (a systemic inflammatory response), graft versus host disease (a situation in which healthy cells are attacked by transplanted T-cells), or dose-limiting toxicities.

Data also demonstrated that all six patients given the 10 million cell dose experienced clinical improvement at six months. At the time, only two of six in the 5 million dose showed at least partial clinical improvement at six months, and only one of those had stable disease at one year.

These treated patients were a near equal mix of adults with SPMS and PPMS, the company reported.

In the coming months, Atara plans to present six-month data from all four dose groups, as well as one-year data from the first three groups, the company said in the release.

Atara added that it will continue to monitor the COVID-19 pandemic, and assess the impact and timing of potential changes to its operations, and to clinical and preclinical studies.
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Re: Krooniset bakteeri-infektiot
Vastaus #378 - 16.07.2020 - 21:40:16
 
1st Progressive MS Patient Enrolls in Phase 1b Study of Cell Therapy ATA188

https://multiplesclerosisnewstoday.com/news-posts/2020/06/19/first-progressive-m...
s-patient-enrolls-atara-biotherapeutics-phase-1b-study-t-cell-therapy-ata188/

June 19, 2020

Atara Biotherapeutics has enrolled a first patient in a clinical trial testing ATA188, its off-the-shelf T-cell immunotherapy for people with progressive forms of multiple sclerosis (MS).

The Phase 1b trial (NCT03283826) follows promising safety and tolerability results from its open-label Phase 1a part, including a sustained lessening in disability among treated patients with primary progressive MS and secondary progressive MS.

This study’s placebo-controlled second part will assess ATA188’s safety, as well as its potential efficacy via measures of changes in patient disability, MRI imaging, and physical and cognitive function.

“The initiation of this [Phase 1b] study, including first-patient-enrolled, is an important step in further assessing the potential of ATA188 in progressive MS, a complex disease of high unmet medical need where disability continues to progress despite approved treatment options,” AJ Joshi, senior vice president and chief medical officer of Atara Biotherapeutics, said in a press release.

ATA188 is a cell-based therapy designed to counter the harmful effects of Epstein-Barr virus (EBV, a common type of herpes virus). Multiple avenues of research increasingly point toward EBV infection as a likely cause of MS. EBV can cause another class of immune cell, called B-cells, to produce antibodies against the myelin sheath of nerve cells.

Loss of myelin underlies the symptoms and progression of MS. By insulating nerve cells, myelin enables them to efficiently transmit the electrical impulses needed for tasks such as coordinating movement.

In the EBV hypothesis of MS, the body’s T-cells — which normally recognize and destroy foreign molecules like viruses — fail to clear infected B-cells. ATA188 provides patients with T-cells designed to selectively target EBV-infected B-cells.

The ongoing double-blind and randomized Phase 1b study will assess the safety and efficacy of ATA188 versus a placebo in up to 97 people. Its primary endpoints are the therapy’s safety and tolerability, as measured by the incidence of adverse events, and the change from baseline (study’s start) in immunoglobulin G (IgG) index, a measure of immune system health.

Secondary outcomes include changes from baseline in several standard disability measures, including the expanded disability status scale (EDSS) and timed 25 foot walk (T25FW; time taken to safely walk 25 feet), as well as measures of neurological health assessed by MRI. These will consist of changes from baseline in cervical spinal cord volume and whole brain volume, and the occurrence of new or enlarging brain lesions.

Other measures include cognition and outpatient ambulatory activity, patient-reported fatigue, and visual acuity.

Participants will be given two cycles of ATA188, or a placebo, by intravenous (IV) infusion, and the trial’s primary goals will be measured at 12 months. After this, all will receive active treatment with an additional 12 months of followup. Patients who complete these two years of treatment will be eligible to enter into a three-year, open-label (no placebo group) extension study.

The trial is recruiting adults with progressive MS at sites in the United States and Australia. More information can be found here.

Phase 1a data showed that ATA188 is safe and well-tolerated, and induces a sustained reduction in disability in a dose-dependent manner. The 20 million cells dose (the third highest dose tested) was chosen for the Phase 1b trial.

“Based on the promising results of safety and sustained disability improvements seen to date in the Phase 1a study, we look forward to continuing enrollment … with the goal of developing a transformative therapy for patients that could halt or reverse the progression of this severe disease,” Joshi said.
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Re: Krooniset bakteeri-infektiot
Vastaus #379 - 16.07.2020 - 21:48:53
 
Bacteria–Host Interactions in Multiple Sclerosis

https://www.frontiersin.org/articles/10.3389/fmicb.2018.02966/full

Front. Microbiol., 04 December 2018

Multiple sclerosis (MS) is caused by a complex interaction of genetic and environmental factors. Numerous causative factors have been identified that play a role in MS, including exposure to bacteria. Mycobacteria, Chlamydia pneumoniae, Helicobacter pylori, and other bacteria have been proposed as risk factors for MS with different mechanisms of action. Conversely, some pathogens may have a protective effect on its etiology. In terms of acquired immunity, molecular mimicry has been hypothesized as the mechanism by which bacterial structures such as DNA, the cell wall, and intracytoplasmic components can activate autoreactive T cells or produce autoantibodies in certain host genetic backgrounds of susceptible individuals. In innate immunity, Toll-like receptors play an essential role in combating invading bacteria, and their activation leads to the release of cytokines or chemokines that mediate effective adaptive immune responses. These receptors may also be involved in central nervous system autoimmunity, and their contribution depends on the infection site and on the pathogen. We have reviewed the current knowledge of the influence of bacteria on MS development, emphasizing the potential mechanisms of action by which bacteria affect MS initiation and/or progression.

************

Conclusion

In 1890, Robert Koch formulated postulates for determining that a particular bacterium is the cause of a specific disease. According to these criteria, the causative organism must be found and isolated in every case of the disease and absent in the healthy subjects. Despite the importance of these postulates in the development of microbiology, there are many limitations associated with them, and with the advent of new molecular and genetic techniques in the fields of microbiology and medicine, these criteria of causation have been revised several times. Nevertheless, these criteria for infectious disease causality are still considered of contemporary relevance and might still have some use.

To date, none of the bacteria related to MS have fulfilled Koch’s postulates, and a causative relationship between a specific bacterium or vaccination with a live attenuated organism and MS has yet to be established. Current data suggest that multiple infections along with non-infectious environmental factors might trigger the development of MS in a certain genetic background. It is possible that a single bacterium need not be responsible for MS, but different pathogens may initiate events that trigger a common immune-pathologic pathway. In addition, an infectious pathogen may not be causative, but it may still influence the development and progression of MS, having a protective role or exacerbating disease manifestation during immunological maturation.

Interestingly, the existence of an abnormal immunological mechanism has been shown to operate in the pre-disease stage of MS, which in turn favors the phenomenon of epitope spreading (Achiron et al., 2010). Considering that the time interval between a bacterial infection and MS initiation may not be immediate and that a long period between the two events may be needed, bacteria could be one of several environmental factors responsible for the activation of this apoptotic process in a time-dependent mechanism.

Another issue is that most pathogens related to MS, with few exceptions, seem to be highly prevalent in the general population; however, the increase of MS incidence is not ubiquitous and depends on various environmental and/or genetic factors such as latitude, ethnicity, and development of the country.

Future research should concentrate on combining data obtained from animal models and epidemiological studies, in order to better explain specific aspects of host–pathogen interactions and, consequently, define the role of bacteria in the etiology and pathogenesis of MS.


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Re: Krooniset bakteeri-infektiot
Vastaus #380 - 16.07.2020 - 21:55:04
 
Is Multiple Sclerosis an Autoimmune Disease?

https://www.hindawi.com/journals/ad/2012/969657/

16 May 2012

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with varied clinical presentations and heterogeneous histopathological features. The underlying immunological abnormalities in MS lead to various neurological and autoimmune manifestations. There is strong evidence that MS is, at least in part, an immune-mediated disease. There is less evidence that MS is a classical autoimmune disease, even though many authors state this in the description of the disease. We show the evidence that both supports and refutes the autoimmune hypothesis. In addition, we present an alternate hypothesis based on virus infection to explain the pathogenesis of MS.
*************

10. Conclusions

In MS, for an oligodendrocyte to be injured by inflammatory cells, it must express MHC class I or class II genes. CD8+ T cells can then engage a novel protein that is expressed in the context of class I MHC. CD8+ T cells would then secrete perforin, granzyme, or other factors that may directly injure or kill the oligodendrocyte resulting in demyelination. Antibodies, through molecular mimicry, may recognize autoantigens of the CNS and can also injure the oligodendrocyte by binding to the surface of the cell and, in association with complement, may induce direct injury to myelin or the oligodendrocytes. This partially leads us to the autoimmune hypothesis. In addition, the B cells may also present virus antigens in the context of class II MHC molecules. The oligodendrocyte or microglia itself may also express class II MHC. This presentation of the viral antigen must be processed, which allows the CD4+ T cells to be engaged with class II MHC to induce injury, the common mechanism of injury presumed to be present in experimental autoimmune encephalomyelitis. The oligodendrocyte may die as a consequence of direct and persistent virus infection. These mechanisms of injury may be independent or occur concurrently in each brain. All of these mechanisms lead to demyelination that the host may correct by transient remyelination. Ultimately, the demyelination process overtakes remyelination resulting in axonal damage, thus leading to permanent neurologic deficits. At the present time, there is no clear evidence that these patterns of injury relate to various stages of the disease course and do not correlate with the clinical subtypes of relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, or primary progressive multiple sclerosis, although this is yet to be determined.

Many of the observed findings have subsequently led investigators to false conclusions regarding MS pathogenesis. Immune cells are present in the MS plaque, and the immune system is important in the pathogenesis of the disease because a number of immunomodulatory and immunosuppressive therapies do decrease relapses and the number of gadolinium-enhancing lesions in MS brain. However, the long-term consequences of immunosuppression on disease course are unknown because most published clinical trials end after two years of observation, an insufficient period of time to address the long-term consequences of these treatments. It is increasingly evident that CD8+ T cells and their effector molecules may directly affect the disease process. Unfortunately, despite years of documentation of involvement of CD8+ T cells in MS lesions, scant experimentation has been performed on this aspect of the immune response. This is probably due to the bias of the experimental model, EAE, in which CD8+ T cells play only a regulatory role whereas CD4+ T cells play a major effector role in disease pathogenesis. Once we move away from the experimental model and begin to investigate MS in humans, it becomes apparent that the MHC class II CD4+ T-cell immune response yields less important critical data of the MHC class I CD8+ T-cell immune response. The most important diagnostic test for MS continues to be the presence of increased CSF IgG and the presence of specific oligoclonal bands in the CSF but not in the serum. Therefore, it is critical to identify the specificity of these bands. Ultimately, it may be proven that CSF oligoclonal IgG bands play a neuroprotective rather than a pathologic role [137–140].


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Re: Krooniset bakteeri-infektiot
Vastaus #381 - 13.11.2020 - 19:01:04
 
Trigger identified that likely unleashes autoimmune disease

https://www.sciencedaily.com/releases/2015/05/150512164526.htm

May 12, 2015

Australian researchers believe they have discovered a group of cells that trigger autoimmune disease, as well as the molecular 'trigger guard' that normally holds them in check.

Dubbed 'rogue germinal centre B cells', these previously undetected cells are renegade versions of the germinal centre B cells that make the 'high affinity' antibodies required for long-term immunity.

When we develop an infection, or are vaccinated, we create antibodies that attack invading microbes. When we develop an autoimmune disease, we create antibodies that attack ourselves.

During a normal immune response, B cells that encounter foreign 'antigen' (such as a virus or bacteria) migrate to germinal centres, transient microstructures that form in lymph nodes and tonsils. Once inside, B cells mutate their antibody genes randomly until they produce an antibody with high affinity to the invader.

At that point, successful B cells transform into small antibody factories known as 'plasma cells', which multiply and flood the system with new antibodies.

Unfortunately, the urgency and speed at which B cells mutate, as well as the random nature of the process, sometimes creates B cells with high affinity 'autoantibodies' that happen to match 'self'. Such cells must be inactivated in order to avoid autoimmune disease.

The process by which autoantibody-producing B cells are prevented from developing in the germinal centre remains unknown. The FAS molecule, a 'death receptor' present at high levels on these cells, has been a prime suspect in their control.

A research team led by Danyal Butt, Dr Tyani Chan and Professor Robert Brink, from Sydney's Garvan Institute of Medical Research, now demonstrates that FAS has a very important, but entirely unexpected, role in preventing autoantibody production.

FAS mutations were found to enable the development of a subclass of 'rogue germinal centre B cells', with antibody genes that in no way recognise foreign antigen. These rogue cells produce large numbers of plasma cells that in turn produce unexpected and damaging antibodies, including autoantibodies. The findings are published in the journal Immunity.

"In very simple terms, we believe FAS prevents rogue germinal centre B cells from developing, and we suspect that is its primary role," said Professor Brink.

"When we removed FAS from a mouse model, we saw the appearance of rogue cells in the germinal centre, and the plasma cells they produced, and neither obeyed any of the normal rules.

"A disproportionately large number of plasma cells were formed by these rogue cells, producing antibodies you wouldn't expect to see, very high numbers of IgE antibodies in particular.

"Instead of getting better at binding foreign antigen, rogue cells got worse -- the opposite of what is supposed to happen in the germinal centre!

"Most significantly, many of the antibodies derived from rogue cells turned out to be autoantibodies."

Patients with a mutation in FAS develop an autoimmune disease known as Autoimmune Lymphoproliferative Syndrome (ALPS) in which the body cannot control the number of immune cells (lymphocytes). This results in enlargement of the lymph nodes, liver and spleen.

Through collaborators at the National Institutes of Health in the US, Brink and colleagues gained access to a database containing disease information from the largest cohort of ALPS patients in the world. They found that over 25% of ALPS patients have abnormally high levels of IgE in the blood.

Professor Brink believes that the patient data provides "provocative evidence" that his group's findings about FAS and rogue germinal centre B cells in mice also apply to humans.

"High levels of IgE antibodies are being found in other autoimmune diseases, such as lupus, and IgE is becoming increasingly associated with severe disease," he said.

"The fact that these rogue cells produce both autoantibodies and IgE antibodies, provides a compelling association with the more severe forms of autoimmunity.

"We do not yet know how rogue B cells arise -- mutation of FAS is certainly one way, but there are likely to be others. Defining these mechanisms promises to advance our understanding of the genesis of autoimmune disease and will point the way towards new diagnosis and treatment strategies."
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Vastaus #382 - 13.11.2020 - 19:08:13
 
Multiple sclerosis as the flip side of immune fitness

https://www.sciencedaily.com/releases/2020/10/201022112554.htm

October 22, 2020

About half of the people with multiple sclerosis have the HLA-DR15 gene variant. A study led by the University of Zurich has now shown how this genetic predisposition contributes to the development of the autoimmune disease multiple sclerosis in combination with environmental factors. The decisive factor is the shaping of a repertoire of immune cells which -- although they are effective in fighting off pathogens such as Epstein-Barr virus -- also attack brain tissue.

Multiple sclerosis is an autoimmune disease that damages the brain and the spinal cord and often severely limits a person's quality of life. It affects about 2.5 million people worldwide, most of them young adults. The cause of the disease is a complex interaction between genetic factors and environmental influences such as smoking or infections.

Genetic variation and viruses as risk factors

For almost 50 years now, it has been known that a gene variant called HLA-DR15 is strongly associated with multiple sclerosis (MS). This gene variant is responsible for up to 60 percent of genetic risk. If carriers of this common gene (about a quarter of the healthy population is HLA-DR15 positive) are also infected with the Epstein-Barr virus and have a symptomatic course of infection called Pfeiffer's disease (also known as glandular fever or infectious mononucleosis), the risk of MS increases 15-fold.

UZH Professor Roland Martin, Head of the Department of Neuroimmunology and MS Research at the University Hospital Zurich, says: "There are therefore clear indications that the interaction between HLA-DR15 and infectious agents such as Epstein-Barr virus is significant for the development of the disease, even though the exact mechanisms behind this have not been understood until now."

An interdisciplinary, international study led by Martin has now shown that the immune cells of people with HLA-DR15 recognize certain microbes -- such as the Epstein-Barr virus -- very effectively, but that this "fitness" can also lead to an undesired immune reaction against the person's own brain tissue.

Individual training for immune cells

The gene products of HLA-DR15 control how the adaptive immune system shapes an immune repertoire that allows the body to recognize and fight pathogens. One of the locations of HLA-DR15 molecules is on the surface of white blood cells. There, they present protein fragments from bacteria, viruses and body cells to the T lymphocytes of the immune system.

The T lymphocytes -- which later control the immune response -- learn to distinguish between foreign proteins and the body's own tissue. This individual training of immune cells takes place first in the thymus and then in the blood. Since there are many more possible pathogens than T lymphocytes, each T lymphocyte must be able to respond to many different antigens and probably also many different pathogens.

Identifying the fragments presented

The researchers first investigated which fragments HLA-DR15 captured and presented to the immune cells. To do this, they used two novel antibodies that recognize the two variants of HLA-DR15 that occur in MS patients with a very high level of specificity. They found that the HLA-DR15 molecules in the thymus mainly present fragments of themselves. This is new information that was not previously known.

The T lymphocytes that have been trained in this way then migrate into the blood. There, they also learn to recognize fragments of the Epstein-Barr virus if the carrier of the genetic variant becomes infected with it. The fragments from the virus have a much stronger activating effect than the HLA-DR15 fragments.

As a result, the T lymphocytes not only keep virus-infected cells in check, but can also migrate to the brain and react with the body's own proteins that trigger an autoimmune reaction in the case of MS. Nearly 100 percent of people with MS are infected with the Epstein-Barr virus. It is the greatest environmental risk factor for MS. The researchers also often found a reaction to fragments of the intestinal bacterium Akkermansia muciniphila, which occurs in abnormally high numbers in MS patients.

Good immune defenses come with a risk of MS

Summarizing, Martin states that "The most important genetic risk factor for MS therefore shapes a repertoire of T lymphocytes that responds very well to certain infectious agents such as Epstein-Barr virus and intestinal bacteria." However, as the experiments have shown, this group of T lymphocytes also reacts to proteins found in the brain by way of a kind of cross-reactivity. "The disadvantage of this fitness is therefore that those affected also become susceptible to an immune response against their own brain tissue, which can lead to multiple sclerosis."

Therefore, these results have for the first time illustrated how the combination of genetic predisposition and certain environmental factors can trigger an autoimmune disease. "Our work has shed light on mechanisms that are likely to play a role in a number of other autoimmune diseases," says Martin. "In addition to improving our understanding of underlying causes of the disease, this could also lead to the development of new treatments."
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Re: Krooniset bakteeri-infektiot
Vastaus #383 - 29.11.2020 - 22:30:14
 
Prevalence of a history of prior varicella/herpes zoster infection in multiple sclerosis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725504/

J Neurovirol. 2017

Abstract

Varicella zoster virus (VZV) infection has been implicated in multiple sclerosis (MS), but direct causal involvement has been disputed. Nevertheless, knowledge of VZV exposure is important, given the risk of serious complications of first exposure while undergoing immunosuppressive treatment, in particular with fingolimod. We distributed questionnaires to MS clinic patients, requesting information about history of chickenpox, sibling/household/occupational exposure, history of zoster (shingles), and disease-modifying treatment. A random, proportionally representative sample of 51 patients that included patients with positive, negative, and unknown chickenpox history were selected for determination of VZV IgG by ELISA. Of 1206 distributed questionnaires, 605 were returned (50% response rate). Of these, 86% reported history of chickenpox, 5.6% gave negative history, and 8.5% did not know. Of 594 who answered the zoster question, 78% gave a negative response, 4% did not know, and 104 (17%) answered yes. Of these, 83 reported 1 episode; 12 had 2; 5 had 3; and 1 each reported 5, 6, and 15 episodes. Of 51 patients tested for VZV IgG (44 “yes,” 4 “no,” and 3 “I don’t know” answers to the question of whether they had chickenpox), 48 were seropositive; the 3 seronegative all had reported having had chickenpox. The high rate of MS patients reporting prior chickenpox infection is comparable with previous reports. A substantial proportion of MS patients, estimated to be higher than an age-matched general population, report single or multiple episodes of zoster. These data are useful for consideration of immunosuppressive treatments and/or VZV and zoster vaccination.

*********
Tämä herpes virus aiheuttaa vesirokon ja vyöruusun.
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Re: Krooniset bakteeri-infektiot
Vastaus #384 - 29.11.2020 - 22:46:26
 
Varicella Zoster Virus and Relapsing Remitting Multiple Sclerosis

https://www.hindawi.com/journals/msi/2011/214763/

30 Mar 2011

Abstract

Multiple sclerosis (MS) is an immune-mediated disorder; however, little is known about the triggering factors of the abnormal immune response. Different viruses from the herpes family have been mentioned as potential participants. Here, we review the evidences that support the association of varicella zoster virus (VZV) with MS. Epidemiological studies from geographical areas, where incidence of MS has increased in recent decades, pointed out a high frequency of varicella and zoster in the clinical antecedents of MS patients, and also laboratory investigations have found large quantities of DNA from VZV in leucocytes and cerebrospinal fluid of MS patients restricted to the ephemeral period of MS relapse, followed by disappearance of the virus during remission. The above observations and the peculiar features of VZV, mainly characterized by its neurotropism and long periods of latency followed by viral reactivation, support the idea on the participation of VZV in the etiology of MS. However, as with reports from studies with other viruses, particularly Epstein Barr virus, conflicting results on confirmatory studies about the presence of viral gene products in brain tissue indicate the need for further research on the potential participation of VZV in the etiology of MS.

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Herpes viruses hold very intriguing properties, among them is the capacity to remain latent in their host for long periods, even decades, and their ability to induce recurrent infections. Some herpes viruses are neurotrophic, particularly those from the subgroup alpha-herpes viruses, like herpes simplex virus and, most remarkably, varicella zoster virus (VZV) [18]. By means of the above properties these viruses remain within the nervous system from their hosts for decades producing periodic exacerbations; in the case of herpes simplex 1 the typical labial blisters, in the case of VZV the initial infection as chickenpox during childhood and late reactivations as zoster in older individuals.
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In this sense, global epidemiological studies have indicated that varicella is almost universal in cold and temperate countries from the northern hemisphere, whereas its incidence decreases drastically in tropical countries below the parallel 40, where Mexico is located [29]; in these areas the incidence of varicella during infancy is about fifty percent or lower. Coincidentally, the epidemiology of MS is similar to that of varicella, high in the northern hemisphere sharply decreasing towards tropical areas [30]. Our initial study demonstrated that the antecedent of varicella in MS patients was far more frequent than that in matched controls and in the general population [25, 31]; moreover, the mean age of infection in MS patients (8 years of age) was significantly older than in controls (5 years of age). The above unexpected findings prompted us to study the possible presence of VZV in MS patients: the initial study searched for DNA from VZV in peripheral mononuclear blood cells (PBMC) from 82 MS patients [32]; results showed that only 13 (16%) were positive by polymerase chain reaction (PCR) to one or various genes specific for VZV. However, when reviewing retrospectively the clinical charts from the few positive cases, to our surprise in all of them the blood samples had been taken within the first week of an acute relapse of MS, from this cohort only 2 patients with this particular condition were negative; thus, 11 MS patients studied during relapse (82%) were positive for VZV DNA. In contrast, all MS patients who were on remission at the time of the test were negative [32]. With these findings we hypothesized that the presence of VZV-DNA in PBMC, restricted to the initial days of an acute relapse, could signify either an epiphenomenon of virus reactivation due to the immune disturbances classically associated with episodes of MS exacerbation or that the VZV was primary involved in the etiopathogenesis of MS [32]. Subsequent studies have indicated that the latter explanation is indeed more feasible than the former. When PBMC from neurological patients with inflammatory, tumoral, or autoimmune ailments, as well as immunosuppressed patients were tested for VZV antigens, the results were all negative, identically to those obtained in healthy controls [33], thus showing that the abnormal activation or suppression of the immune response is not commonly associated with an epiphenomenon of VZV activation. It was also observed by real/time PCR that the amount of VZV found in PBMC from MS patients during relapse was high during the first week of the acute relapse but became gradually minor on clinical remission, until its disappearance in samples taken 2 months later [32–34]. These variations were observed in patients studied at various times during the cycle remission/relapse of MS. In these studies no similar phenomenon was seen when other herpes viruses were searched such as herpes simplex 1 and 2, Epstein Barr virus, human herpes virus 6, and cytomegalovirus [33, 35].
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VZV has the ability to remain latent in its host for long periods, which may extend several decades. If a subject suffers from varicella at 4 years of age and herpes zoster at 84 years of age, the virus remained viable, but in latency for an astonishing 80 years it is apparent that no other known viral disease infection reaches these extremes of latency, of which we know so little.
Also, the fact that both, varicella and zoster, are totally different diseases caused by the same infectious agent is intriguing and gives support to the concept of multiple viral pathogenicity [40], where the same virus can produce various diseases according to the age and susceptibility of the subject. Thus, it might be postulated that VZV produces varicella, a systemic disease at early ages of the host; it also produces zoster, a local disease of the peripheral nervous system in the elderly, and we speculate, based on our findings, that it could also produce MS, a local disease of the central nervous system during adulthood.

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Re: Krooniset bakteeri-infektiot
Vastaus #385 - 06.03.2021 - 19:55:26
 
Unbiased examination of genome-wide human endogenous retrovirus transcripts in MS brain lesions

https://journals.sagepub.com/doi/abs/10.1177/1352458520987269?journalCode=msja&a...;


January 19, 2021

Abstract

Background:
Human endogenous retrovirus (HERV) expression in multiple sclerosis (MS) brain lesions may contribute to chronic inflammation, but expression of genome-wide HERVs in different MS lesions is unknown.

Objective:
We examined the HERV expression landscape in different MS lesions compared to control brains.

Methods:
Transcripts from 71 MS brain samples and 25 control WM were obtained by next-generation RNA sequencing and mapped against HERV transcripts across the human genome. Differential expression of mapped HERV-W and HERV-H reads between MS lesion types and controls was analysed.

Results:
Out of 6.38 billion high-quality paired end reads, 174 million reads (2.73%) mapped to HERV transcripts. There was no difference in HERVs expression level between MS and control brains, but HERV-W transcripts were significantly reduced in chronic active lesions. Of the four HERV-W transcripts exclusively present in MS, ERV3633503 located on chromosome 7q21.13 close to the MS genetic risk locus had the highest number of reads. In the HERV-H family, 75% of transcripts located to nearby 7q21-22 were overrepresented in MS, and ERV3643914 was expressed more than 16 times in MS compared to control brains.

Conclusion:
Novel HERV-W and HERV-H transcripts located at chromosome 7 regions were uniquely expressed in MS lesions, indicating their potential role in brain lesion evolution.
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Re: Krooniset bakteeri-infektiot
Vastaus #386 - 06.03.2021 - 19:59:05
 
Research suggests development of antiviral therapies to treat multiple sclerosis

https://www.sciencedaily.com/releases/2021/01/210115155326.htm

January 22, 2021
Scientists have uncovered new clues implicating a type of herpes virus as the cause of a central nervous system disease in monkeys that's similar to multiple sclerosis in people.

The findings, published in the Annals of Clinical and Translational Neurology, expand on previous work to understand the cause of the disease and potentially develop antiviral therapies. The work was led by scientists at Oregon Health & Science University.

"This gives us a better understanding of the model," said Scott Wong, Ph.D., senior author of the study and a scientist at the OHSU Vaccine and Gene Therapy Institute and the Oregon National Primate Research Center. "It draws more parallels to MS in people."

The new study reveals the presence of two kinds of T cells, a type of white blood cell that's a critical part of the body's immune system. In this case, scientists determined the T cells were associated with an immune response involving the loss of myelin, the protective sheath that covers nerve fibers.

Myelin and nerve fibers become damaged in multiple sclerosis, which slows or blocks electrical signals required for us to see, move our muscles, feel sensations and think.

"We found that some of the T cell epitopes targeting myelin in these animals are identical to those found in humans with MS," Wong said.

By linking these specific T cells to the loss of myelin, scientists say the new study opens the possibility of developing an antiviral therapy that could be especially useful for newly diagnosed cases of multiple sclerosis.

"If we found a unique virus that we believed was causing MS, then you could in theory come up with a vaccine against that virus," said co-author Dennis Bourdette, M.D., professor emeritus and former chair of neurology in the OHSU School of Medicine.

The work builds on a chance discovery in the colony of Japanese macaques at the primate center.

In 2011, scientists at OHSU published research identifying a group of monkeys at the primate center with a naturally occurring disease known as Japanese macaque encephalomyelitis. Since then, scientists have been working to understand the cause and progression of the disease in the macaques with an eye toward applying possible therapies in people.

The latest study points toward developing strategies to combat the disease leveraging the body's immune response.

"If we can understand how it's doing it, we may be able to test vaccine strategies," Wong said. "I'm not sure we can prevent virus infection, but we may be able to prevent virus-associated disease."

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Re: Krooniset bakteeri-infektiot
Vastaus #387 - 06.03.2021 - 20:05:14
 
Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(19)30294-1

December 17, 2019

Highlights
- Clinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients.
- B cell-tropic viruses may trigger aberrant immune responses in MS in genetically susceptible individuals owing, in part, to a failure in viral surveillance and clearance.
- The most compelling data supporting an etiologic role for viral involvement in MS have emerged for Epstein–Barr virus (EBV).
- Targeting mechanisms by which EBV is thought to participate in MS pathogenesis provides an opportunity for new drug development in MS.

New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein–Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention.

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Re: Krooniset bakteeri-infektiot
Vastaus #388 - 06.03.2021 - 20:14:41
 
T cells depressed

https://www.sciencedaily.com/releases/2021/02/210212101839.htm

February 12, 2021

T lymphocytes, or T cells, are an important component of our immune system. They can recognize foreign proteins, so-called antigens, as peptide fragments -- for instance, those derived from viruses or cancer cells. In principle, they could, but usually do not, attack our own ('self') proteins. "That is why it is important for the organism to tightly control the activities of T cells," says Dr. Reinhard Obst, head of a research group at the Institute for Immunology at LMU's Biomedical Center that studies the activation of T cells. The project contributed to the Collaborative Research Center 1054 that explores the plasticity of cell fate decisions in the immune system.

When viruses gain access to our tissues, T cells are activated to eliminate the pathogens. However, if T cells are exposed to their target antigens for too long, they can lose their functionality and become 'exhausted.' They no longer secrete pro-inflammatory messenger molecules, and therefore cannot contribute much to an immune response. On the one hand, it makes sense to keep these cells under control, so as to avoid collateral damage to the organism. On the other, T cell exhaustion makes it difficult to fight chronic diseases, such as those caused by HIV, hepatitis viruses and cancer cells. Understanding immune responses to chronically persisting threats like these is thus one of modern medicine's great challenges. "This is where T cell exhaustion plays a central role." the LMU researcher says.

A new model to study T cell exhaustion

Several years ago, Obst developed an animal model which has now yielded important insights. He focused on T helper cells, which express the CD4 marker molecule and make up the largest subset of T cells. Each of these cells recognizes a defined protein fragment as an antigen.

To control the timing and the amount of the specific antigen expressed in this model system, the LMU scientists used a trick. Their transgenic mice were exposed to different doses of the antibiotic doxycycline, which controls the synthesis of the antigen, via their drinking water. Different amounts of antigen are thus being presented to the T cells in these animals, which avoids the need for experimental infection. "In this way, we are able to regulate the amount of antigen produced," Obst explains. "Our goal was to find out how the corresponding T helper cells respond.

The results showed that the effects were dose dependent: In the presence of high antigen doses, the T cells underwent apoptosis, meaning they died by programmed cell death. At an intermediate dose, however, the T cells survived but quickly lost their functionality. "We demonstrated this state of exhaustion by regulating the amount of antigen that the cells encountered," the LMU researcher explains. At a low dose, it took several weeks before the cells showed signs of exhaustion. When in further experiments the antigen was subsequently removed, the cells were able to partially recover from their exhausted state. Such dynamic adjustments convinced the researchers that T-helper cells are capable of a surprising degree of plasticity.

Supporting the T cells' fight against chronic infections and cancer

Obst and his colleagues believe that their findings could have therapeutic implications. The data indicate that a number of transcription factors (proteins that control gene expression) and signaling pathways regulate the different states of exhaustion.

Two years ago, several groups showed that one of these transcription factors, named Tox, contributes significantly to the exhaustion of T killer cells, another T cell subset. When the Tox gene was deleted, the T-killer cells were less readily exhausted in a chronic infection and could more effectively fight a chronically persisting virus. However, they also attacked the host animals' organs and died sooner. The new findings suggest that there are several mechanisms in place to adjust T helper cells dynamically to different antigen loads.

Obst now hopes to identify molecules that inhibit transcription factors or signaling pathways which contribute to T cell exhaustion. This could provide a possible strategy to support T cells' fight against chronic infections and cancer and boost our natural defences against such diseases.
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Re: Krooniset bakteeri-infektiot
Vastaus #389 - 30.04.2021 - 22:57:16
 
New links between B cells and EBV infections in women with MS

https://msra.org.au/news/bcells-ebv-infections-women-ms/

13 April, 2021

April, 2021

-MS Research Australia has funded laboratory research showing how B cells are uniquely altered in women with MS.
- The study looked at different B cell types and Epstein-Barr Virus (EBV), (the virus associated with glandular fever) infection in people with and without MS.
- The study found that a specific receptor on the surface of particular B cell types is reduced in women with MS, which could influence both autoimmune responses and infections such as EBV.

Recent MS treatments have focused on depleting a type of white blood cell (called B cells), to halt MS relapses and disease progression. These new therapies, such as ocrelizumab (Ocrevus) and ofatumumab (Kesimpta) have directly improved outcomes for people living with MS. These therapies are able to reduce MS relapses by decreasing B cell numbers in the body. Even though we know that B cells are critical to the development of MS, the exact mechanisms by which they do this are not clearly understood.

B cells, MS, and the EBV connection


When a pathogen (such as a virus or bacteria) enters the body, it is “presented” to naïve B cells, which are B cells before they have met an antigen (the pathogen). This stimulates the production of antibodies to defend the individual from the infection. But in MS, where the immune system inappropriately attacks the brain and spinal cord, deposits of antibodies are found in and around areas of damage in the brain. Exactly how these antibodies are produced, their association with B cells, and how they contribute to the damage in the brain in MS is not yet known.

The molecular mechanisms linking EBV and MS are not fully understood; however we do know that EBV chronically infects B cells and causes them to both multiply and be resistant to the natural cell death that would normally occur. B cells are very powerful cells in the immune system and are normally kept under tight control by the body. However, EBV infected B cells might be more resistant to these normal control measures. One theory of how MS develops suggests that if autoimmune B cells (B cells targeting the brain) are infected by EBV, they become resistant to the body’s control systems, and continue to multiply and attack the brain, leading to the development of MS.
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What does this mean for people with MS?

Women are almost three times more likely to develop MS than men. The CD32b molecule is known to prevent autoimmune disease in laboratory models. The discovery that the CD32b molecule is reduced in women who have CIS and MS, opens new avenues to understanding the autoimmune process in MS more generally. Discovering unique differences in the immune system of women with MS may also help us to understand why women are more susceptible to developing MS. As EBV is an important risk factor for MS and possibly a driver of the MS disease process, further work is also warranted to understand how the CD32b molecule is related to the control of EBV infection in MS, particularly early in the disease process.
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