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Krooniset bakteeri-infektiot (Luettu 266058 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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