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Krooniset bakteeri-infektiot (Luettu 265621 kertaa)
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Re: Krooniset bakteeri-infektiot
Vastaus #360 - 06.07.2019 - 00:57:21
 
EBV infection and MS risk genes work together to facilitate MS

https://msra.org.au/news/ebv-infection-and-ms-risk-genes/

22 May, 2019

   Infection with Epstein-Barr Virus (EBV) is one of the known risk factors of developing MS but how EBV relates to MS risk is still an open question.
   New research by Australian researchers has looked at the effect of EBV infection on genetic activity in immune cells.
   Findings showed that EBV controls some MS risk genes.

What is Epstein Barr Virus (EBV)?

EBV (the virus that causes glandular fever) is a virus that belongs to the herpes virus family and it infects a type of immune cell in the blood known as a B cell. Once a person has been infected with EBV they carry the virus in their B cells for life, meaning their body has to continually control the EBV infection for the rest of their lifetime.

What do we already know about the link between EBV and MS?

Infection with EBV has long been known to be associated with the development of MS. However, while the majority of the population has been infected with the virus (only a small percent will develop recognisable symptoms), 100% of those with MS are thought to be infected.

This shows that while EBV plays a huge role in MS an EBV infection is not sufficient by itself to cause MS. So why do some people who contract EBV develop MS yet others never do? Part of the answer may lie in our genetics.

Previous research funded by MS Research Australia by Professor Michael Pender has shown that people with MS inadequately control these EBV hijacked immune cells and now Australian scientists might have uncovered an interesting interplay between the MS genetic risk factors and EBV.

A new link discovered between EBV and MS risk genes

In a new study, researchers at the Westmead Institute of Medical Research have investigated the way that EBV infection changes which genes the B cells are using and hence changes the way these cells act. Published in Genome Medicine, the researchers compared the gene activity of B cells that were infected with EBV and grown in the laboratory, and cells that had not been infected. They were particularly interested to see whether there would be any changes in the 200+ genetic elements that have already been identified as risk factors for the development of MS.

The research findings explained…

The research showed that a significant proportion of these MS risk genes were influenced by the presence of EBV. This means that:

  The infected cells used the MS risk genes differently in the presence of EBV.
   Some of these genes, in turn, controlled other genes in the cell, meaning there was a domino effect resulting in a number of changes within the cell.

   Further experiments showed that EBV may drive some of these changes at a cellular level through the binding of a molecule called EBNA2. When EBV is hijacking a cell it might try and use a number of cellular genes, and a portion of those are already known as MS risk genes.

This study indicates that the MS risk genes may be working together with EBV infection to facilitate the development of MS and that this interaction may be one way genetic changes act at a biological level to increase the risk of MS.

What do these new findings mean for the future?

A better understanding of the way that EBV infection relates to MS development is important to drive new therapeutic approaches for this disease. Professor Michael Pender’s work has led to the development of a new treatment strategy, currently in clinical trials, based on the idea that boosting a person with MS’s ability to control ongoing EBV infection could help treat MS.
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Re: Krooniset bakteeri-infektiot
Vastaus #361 - 15.07.2019 - 00:53:50
 
Are the 'viral' agents of MS, ALS and schizophrenia buried in our genome?

https://www.sciencedaily.com/releases/2019/07/190711141413.htm

July 11, 2019

What if the missing 'environmental' factor in some of our deadliest neurological diseases were really written in our genome?

Writing in Frontiers in Genetics, researchers from the University of Dusseldorf explain how viruses ended up in our DNA -- and what puts them in the frame in unsolved diseases like multiple sclerosis.

The enemy within

A whopping 8% of our DNA comes from viruses. Specifically, ones called retroviruses -- not because they're old, but because they reverse the normal process of reading DNA to write themselves into their host's genome.

Retroviruses are old though: they began merging with our earliest, primordial ancestors millions of years ago. Over the millennia, most of their remnants in our DNA -- known as human endogenous retroviruses or HERVs -- have been silenced by mutations. Others, which had evolved to fend off rival viruses, formed the prototypical immune system and to this day protect us from infection.

However, HERVs might also be the missing causative link in major 'unsolved' neurological diseases.

"HERVs have been implicated in the onset and progression of multiple sclerosis [MS], amyotrophic lateral sclerosis [ALS] and schizophrenia [SCZ]," says senior author Prof. Patrick Kuery. "Dormant HERVs can be reactivated by environmental factors such as inflammation, mutations, drugs, or infection with other viruses, so could provide a mechanism for their well-established epidemiological link to these disorders."

Role in MS

So far, the strongest evidence links HERVs to MS.

"MS is caused by direct autoimmune attacks on myelin -- the fatty coating of nerve cells -- in the brain and spinal cord," explains Kuery. "But we don't yet understand how these attacks are triggered."

A variety of studies suggest that reactivation of HERV could be just such a trigger.

"Retroviruses were first associated with MS in 1989, but only decades later was it realized that these are in fact HERVs.

"Subsequently, it was shown that levels of HERV RNA and protein -- the 'readouts' from reactivated HERV DNA -- are increased in the brain and spinal cord fluid [CSF] of sufferers, as well as in their brain tissue postmortem.

"Linking this HERV reactivation to autoimmune attacks in MS, it was found that HERV proteins can trigger an immune response against myelin, which triggers MS-like disease in mouse models."

Mechanistically, HERV proteins could trigger autoimmunity through 'molecular mimicry'.

"In addition to direct effects of HERV on myelinating cells, several groups report structural similarities between HERV and myelin oligodendrocyte glycoprotein -- a molecule displayed on the surface of myelin. This similarity could fool the immune system into damaging myelin, when it mounts an attack on HERVs."

Experimental proof in humans

Similar experiments have linked HERVs to the peripheral demyelinating disease CIDP, as well as more distinct disease processes like progressive loss of motor neurons in ALS (Lou Gehrig's disease).

In schizophrenia, a complex neurodevelopmental disorder, the link to HERVs is more circumstantial.

"HERV proteins have been reported to increase expression of schizophrenia-linked genes in cultured human brain cells," reports Kuery. "However, studies on schizophrenia sufferers show inconsistent changes in HERV expression in blood, CSF and postmortem brain tissue compared to healthy controls."

Whether or not HERVs contribute to these and other unexplained neurological conditions requires further investigation. An important step will be to test the effects of HERV-neutralizing antibodies in humans.

"Of note, in relapsing MS patients a phase 2b clinical trial using HERV protein-neutralizing antibody Temelimab has been conducted. We're now waiting to see if the treatment showed beneficial effects on remyelination or attenuated neurodegeneration," Kuery concludes.
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Re: Krooniset bakteeri-infektiot
Vastaus #362 - 15.07.2019 - 01:01:10
 
Epstein-Barr Virus and miRNAs: Partners in Crime in the Pathogenesis of Multiple Sclerosis?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456696/

2019 Apr 3

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression post transcriptionally. In healthy individuals, miRNAs contribute to maintaining gene expression homeostasis. However, the level of miRNAs expressed is markedly altered in different diseases, including multiple sclerosis (MS). The impact of such changes is being investigated, and thought to shape the immune system into the inflammatory autoimmune phenotype. Much is yet to be learned about the contribution of miRNAs in the molecular pathology of MS. Epstein-Barr virus (EBV) infection is a major risk factor for the development of MS. EBV encodes more than 40 miRNAs, most of which have been studied in the context of EBV associated cancers. These viral miRNAs regulate genes involved in cell apoptosis, antigen presentation and recognition, as well as B cell transformation. If EBV infection contributes to the pathology of MS, it is plausible that EBV miRNAs may be involved. Unfortunately, there are limited studies addressing how EBV miRNAs are involved in the pathogenesis of MS. This review summarizes what has been reported regarding cellular and viral miRNA profiles in MS and proposes possible interactions between the two in the development of MS.

***********
Conclusion

Of the environmental factors, substantial amount of data indicates that EBV is directly or indirectly involved in the pathogenesis of MS. Moreover, cellular, exosomal, plasma and erythrocyte miRNAs profiles indicate that these profiles are disrupted in MS patients, compared to healthy controls. Although a large number of studies have investigated the significance of EBV encoded miRNAs in altering the levels of viral and cellular genes in EBV associated malignancies, much less is known in the context of MS. On the one hand, the disrupted homeostasis of cellular miRNAs in MS appears to serve the ongoing inflammation linked to the disease, whilst on the other hand, they may aid in supporting the survival of EBV infected cells by positively influencing viral miRNAs that function in evading anti-EBV immune response. Dysregulated cellular miRNAs may also pave the way for CNS infiltration by inflammatory cells and EBV infected cells. It is reasonable to think that EBV miRNAs in MS CNS can also impact CNS resident cells, particularly those involved with MS pathology. Thus, investigating the targets and role of EBV miRNAs in MS, mainly in peripheral blood, CSF, brain, and CNS draining lymph nodes, could shed light on disease mechanism not yet explored.



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Re: Krooniset bakteeri-infektiot
Vastaus #363 - 02.08.2019 - 00:31:19
 

Neuronal loss or dysfunction in patients with early Lyme neuroborreliosis: a proton magnetic resonance spectroscopy study of the brain.


https://europepmc.org/abstract/med/31076877

10 May 2019

Abstract
BACKGROUND:We hypothesized that since Borrelia burgdorferi causes systemic inflammation and infects the brain, it may lead to alterations in cerebral metabolism, as measured by 1H-magnetic resonance spectroscopy (1H-MRS). The purpose of our study was to determine whether 1H-MRS could detect brain metabolite alterations in patients with early Lyme neuroborreliosis (LNB) in normal-appearing brain tissue on the conventional magnetic resonance imaging (MRI).

METHODS:Twenty-six patients diagnosed with early LNB and twenty-six healthy volunteers as a control group have been involved in the study. All of them underwent routine MRI protocol using 3.0-T MRI scanner. 1H-MRS examinations were performed with repetition time (TR) = 2000 ms, and echo time (TE) = 135 ms. Single voxels were positioned in the anterior and posterior parts of the right and left frontal lobes.

RESULTS:We found a statistically significant decrease of the N-acetylaspartate/creatine ratio within the anterior part of the right and left frontal lobes (p ≤ 0.001 and p = 0.001 respectively) and in the posterior part of the right and left frontal lobes (p ≤ 0.001 and 0.031) in the patients with LNB.

CONCLUSION:A significant reduction in NAA/Cr ratio in comparison with the controls suggests the presence of diffuse neuronal loss in patients with early LNB.

******
Tutkimus koski alkuvaiheesa olevaa borrelioosia. Mutta myöhemmässä vaiheessa jos on plakkeja aivoissa? Syy voi olla MS-taudin tai borrelioosin. Vain asiantunteva radiologi pystyy erottamaan kumpi on kumpi. Näin minulle kertoi neurologi, joskaan ei Suomessa.

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Re: Krooniset bakteeri-infektiot
Vastaus #364 - 13.08.2019 - 00:10:19
 
How do ancient viruses cause MS and other neurological diseases?

https://www.medicalnewstoday.com/articles/325718.php?type=medical-news

Ancient viruses have left behind traces in our DNA. Researchers believe these contribute to neurological conditions. Could inhibiting our viral passengers pave the way for future treatments?

Ancient viruses link to neurological conditions
What links neurological conditions and ancient viruses?

Transposable elements, which scientists also call transposons or jumping genes, are stretches of DNA that harbor the ability to move around our genome.

Scientists can trace back one type of transposon — human endogenous retroviruses (HERVs) — to ancient retroviruses that inserted themselves into the human genome millions of years ago. HERVs make up about 8% of our DNA.

Some HERVs hold crucial functions during processes such as embryonic development. But most HERVs lie dormant, silenced by DNA modifications.

Yet, in a recent review article in Frontiers in Genetics, researchers from Heinrich Heine University in Dusseldorf, Germany, detail how some HERVs may be reactivated and wreak havoc in our brain and central nervous system.

HERVs in neurological diseases

Back in 1989, Hervé Perron, then at the University of Grenoble in France, was the first to identify the presence of viral particles in cell cultures isolated from the cerebrospinal fluid (CSF) of a person with multiple sclerosis (MS). He later discovered that these originated from a transposon called HERV-W.

Activation of this dormant HERV results in an immune reaction. HERV-W envelope (ENV) RNA and protein are present at increasing levels in the serum and CFS of people with MS, but only rarely in those without the condition.

"Linking this HERV reactivation to autoimmune attacks in MS, it was found that HERV proteins can trigger an immune response against myelin, which triggers MS-like disease in mouse models," explains Patrick Kuery, a professor of neurodegeneration and senior review author.

Several triggers can reactivate HERVs. One of them is infection with common viruses, such as the Epstein-Barr virus that causes infectious mononucleosis, and other members of the herpes virus family.

How childhood viral infections may later drive multiple sclerosis

Viral infections during childhood leave lasting marks in the brains of people with MS.
Research also suggests that immune system mediators and environmental factors, such as diet and drugs, can switch HERVs back on, although there is limited evidence at this point.

MS is not the only neurological disease where scientists suspect HERV involvement. A number of studies have implicated reactivation of HERV-K in amyotrophic lateral sclerosis (ALS), a form of motor neuron disease.

When it comes to schizophrenia, the case is less clear.

"HERV proteins have been reported to increase expression of schizophrenia-linked genes in cultured human brain cells," explains Kuery. "However, studies on schizophrenia [patients] show inconsistent changes in HERV expression in blood, CSF, and postmortem brain tissue compared to healthy controls."

Can deactivating HERV improve MS?

In MS, the immune system attacks myelin, the protective layer that coats many neurons in the central nervous system.

Repairing this myelin damage by allowing the cells in the CNS to remyelinate neurons may prove an effective strategy to treat MS.

Since identifying HERV-W in MS patients, Perron co-founded the pharmaceutical company GeNeuro and developed a monoclonal antibody called GNbAC1 that targets the HERV-W ENV protein. Scientists are currently testing the antibody in clinical trials.

In a recent paper published in Proceedings of the National Academy of Sciences of the United States, Kuery, Perron, and colleagues dug deeper into the mechanism that links HERV-W to MS.

The team found cells that contained the HERV-W ENV protein in close proximity to neurons in brain tissue of MS patients, particularly in areas that contained chronic and acute MS lesions.

Dr. Tobias Derfuss, a professor in clinical neuroimmunology at the University of Basel in Switzerland, was a principal investigator of one of the clinical trials investigating the use of GNbAC1 in MS and a member of the steering committee for a further trial.

Writing in Therapeutic Advances in Neurological Disorders, Dr. Derfuss comments: "This treatment approach of GNbAC1 and the concept of a HERV-associated pathophysiology in MS remain controversial."

He explains that the results of the clinical trials investigating GNbAC1 for the treatment of MS indicate that the antibody does not prevent the immune system from attacking myelin, meaning it does not prevent MS.

The antibody may, on the other hand, kickstart remyelination.

   "Pharmacodynamic and imaging data do not reveal any immunomodulatory effects of GNbAC1. MRI changes during a phase IIb study with GNbAC1 are compatible with remyelination."

MS is a complex disease, and scientists do not fully understand the biology of HERVs. A HERV-modifying therapeutic may prove to be a promising treatment for people living with MS, but its true potential remains to be seen.
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Re: Krooniset bakteeri-infektiot
Vastaus #365 - 20.09.2019 - 13:50:01
 

Preliminary safety and efficacy of ATA188, a pre-manufactured, unrelated donor (off-the-shelf, allogeneic) Epstein-Barr virus-targeted T-cell immunotherapy for patients with progressive forms of multiple sclerosis


https://onlinelibrary.ectrims-congress.eu/ectrims/2019/stockholm/278696/michael.
pender.preliminary.safety.and.efficacy.of.ata188.a.pre-manufactured.html?f=listi
ng%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Dbar-or


Introduction: Evidence suggests Epstein-Barr virus (EBV) infection is associated with multiple sclerosis pathogenesis. In patients (pt) with progressive forms of MS (pMS), autologous EBV-specific T cells may prevent progression and improve symptoms (Pender, et al. JCI Insight. 2018).

Objectives: To evaluate ATA188, an off-the-shelf, allogeneic, EBV-targeted T cell immunotherapy comprised of HLA-matched, in vitro-expanded, cytotoxic T lymphocytes in a first-in-human, multicenter, 2-part study in adults with pMS (NCT03283826). Preliminary data are reported.

Methods: Eligible pt (age 18‒< 66) are EBV-seropositive with pMS and an Expanded Disability Status Scale (EDSS) score of 3‒7. Cohorts (cht) 1‒4 (6‒9 pt/cht) receive escalating doses of ATA188.
1° endpoints: safety and identification of the recommended phase 2 dose (RP2D) of ATA188. Efficacy criteria: EDSS, MS Impact Scale-29, Fatigue Severity Scale, and 12-Item MS Walking Scale scores; timed 25-foot walk; 9-hole Peg Test; and visual acuity. A responder (R) has sustained ≥ minimal clinically significant (MCS) improvement from BL in 2 consecutive evaluations on ≥2 efficacy criteria; a partial responder (PR) has ≥ MCS improvement from baseline (BL) in any 1 evaluation on ≥2 efficacy criteria; and a non-responder (NR) has ≥ MCS decline from BL in any 1 evaluation on ≥2 efficacy criteria (if both criteria are met, pt is NR). Plasma inflammatory biomarkers (IL-2, IL-1β, TNF-α, IL-6) are monitored throughout treatment.

Results: As of 27 May 2019, 19 pt (53% male; median age, 56 years) have enrolled (6 in each of cht 1‒3; 1 in cht 4) and received ≥1 dose of ATA188. Treatment-emergent AEs (TEAE) occurred in 63% (12/19) pt and treatment-related AEs (TRAE) in 37% (7/19) pt; 1 pt (cht 2) had a grade ≥ 3 TEAE, and 1 (cht 4) had a serious TRAE. No dose-limiting toxicities or fatal TEAE have been reported. Efficacy data are available for cht 1 and 2: cht 1, 1 R, 1 PR, and 4 NR at 6 months and 1 R, 0 PR, and 1 NR at 12 months; cht 2, 2 R, 4 PR, and 0 NR at 6 months. On measures of disability, 3/6 showed improvement and 3/6 showed decline in cht 1; 4/6 showed improvement and 1/6 showed decline in cht 2. Inflammatory cytokines remained at or near baseline.

Conclusion: Preliminary data indicate ATA188 is well tolerated and improves efficacy measures in adults with pMS, even at lower doses. These results support continuing part 1 to identify RP2D for part 2, (randomized, double-blind, placebo-controlled portion).
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Re: Krooniset bakteeri-infektiot
Vastaus #366 - 20.09.2019 - 13:56:30
 
Sama, mutta ymmärrettävässä muodossa. Ja tämä on siis ATA188 tutkimusta:


Epstein-Barr virus–specific T cell therapy for progressive multiple sclerosis


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302936/

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.

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Re: Krooniset bakteeri-infektiot
Vastaus #367 - 29.09.2019 - 16:15:21
 
Genomic map implicates broad immune cell involvement in multiple sclerosis

https://www.sciencedaily.com/releases/2019/09/190926141655.htm

September 26, 2019
The International Multiple Sclerosis Genetic Consortium (IMSGC) reports the results of its latest study, "Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility," in the journal Science today: the highly productive collaborative group presents a new milestone in its efforts to understand the genetic basis of multiple sclerosis (MS). In a study of 115,803 individuals, the authors have identified 233 sites or loci in the human genome that contribute to the onset of MS. This is the largest study to date in MS and is based on the generous contribution of genetic material from 47,429 MS patients and 68,374 healthy individuals. The study's results confirm earlier results and offer a rich new perspective on the molecular events that lead some individuals to develop MS: it appears that dysfunction of many different immune cell types, both in the peripheral blood and the brain, contribute to triggering a cascade of events that ultimately leads to brain inflammation and neurodegeneration.

Dr. Philip De Jager, who directs the Multiple Sclerosis Center and the Center for Translational & Computational Neuroimmunology at Columbia University Irving Medical Center in New York City, and the principal investigator of the study says that "the study has created a detailed genetic map of MS, identifying over two hundred regions of the human genome that influence a large number of different immune cells, highlighting the fact that this disease is not caused by a single immune cell type but rather by a broad dysfunction of the immune system." MS has an initial inflammatory component and a secondary neurodegenerative component, so the investigative team looked closely at available data from human brain to assess whether changes in brain cells contribute to the onset of MS. Until now, it appeared that immune cells found in blood that come from the bone marrow played a critical role; the new study confirms this but also implicates microglia, the immune cells that live in the human brain. However, there is little evidence that other brain cells such as neurons that carry electrical signals in the brain are implicated in triggering MS.

Dr. Nikolaos Patsopoulos, Director of Systems Biology and Computational Science Program at the Ann Romney Center for Neurologic Diseases of Brigham & Women's Hospital and Harvard Medical School in Boston, says that "our study explains approximately half of the heritability of MS, establishing MS as one of the well-characterized common diseases in terms of their genetic architecture." He adds that "this study highlights the complexity of the genetic contribution to MS susceptibility by identifying several regions of the genome with multiple genetic variants that play a small role. Further, we report the first ever association of genetic variant in chromosome X with MS, a disease that affects mainly young women. This study more than doubled our knowledge of MS genetics, however our findings suggest that there is more work to be done to fully understand how the human genome is involved in MS."

Dr. Tomas Olson, an author on the study from the Karolinska Institute in Stockholm, Sweden says that "this collaborative effort integrated multiple streams of North American and European funding to establish an important foundation for future projects that will uncover the sequence of events leading from health to MS. These genetic variants are not sufficient to cause MS; they interact with a host of environmental factors, making it more likely that a viral infection or other exposure triggers an autoimmune reaction against the brain and spinal cord."

Dr. Adrian Ivinson, Chief Operating Officer of the UK Dementia Research Institute who is also an author of this study adds that "this study reflects the combined, collaborative efforts of the international MS Genetics community to advance our understanding of MS disease mechanisms and the continuing support of the National MS Society in the completion of this project, the development of young investigators and support for basic research in MS. It is an excellent example for the success of collaborative team-oriented science in medicine."

This study is an important milestone in identifying which genetic variants play a role in triggering MS, but it unfortunately does not clarify why some MS patients have a more severe course than others. The IMSGC is pursuing that question in other projects. The results of this project will impact most the development of clinical algorithms to manage individuals at risk of developing MS and the development of treatments for preventing MS. All current treatments aim to stop the inflammation after it has already started, so the study of MS genetics has opened a unique perspective on the earliest events that lead to the disease and that can now be targeted by drug-development efforts.

The Columbia University Multiple Sclerosis Center provides compassionate care for MS patients, and we engage with our our patients to perform both basic research that brings new insights into our understanding of the disease and clinical research that brings the latest technologies and medications with which to improve our management of each patient. This is study is an example of Columbia's leadership of international collaborations in the field of MS and of the emerging foundation for Precision Medicine in MS.

******
Geenit eivät aiheuta MS:ää vaan ympäristö ja virukset. No, tulipahan sekin nyt varmistettua.
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Re: Krooniset bakteeri-infektiot
Vastaus #368 - 19.11.2019 - 02:49:34
 
Epstein-Barr virus-specific CD8 T cells selectively infiltrate the multiple sclerosis brain and interact locally with virus infected cells: clue for a virus-driven immunopathological mechanism

https://jvi.asm.org/content/early/2019/09/26/JVI.00980-19.abstract

Copyright © 2019 Serafini et al.

ABSTRACT

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus strongly associated with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). Yet, the mechanisms linking EBV infection to MS pathology are uncertain. Neuropathological and immunological studies suggest that a persistent EBV infection in the CNS could stimulate a CD8 T-cell response aimed at clearing the virus but inadvertently causing CNS injury. Inasmuch as in situ demonstration of EBV-specific CD8 T cells and their effector function is missing, we searched for EBV-specific CD8 T cells in MS brain tissue using the pentamer technique.

Postmortem brain samples from 12 donors with progressive MS and known HLA class I genotype were analyzed. Brain sections were stained with HLA-matched pentamers coupled with immunogenic peptides from EBV-encoded proteins, control virus (cytomegalovirus, influenza A virus) proteins and myelin basic protein. CD8 T cells recognizing proteins expressed in the latent and lytic phases of the EBV life cycle were visualized in white matter lesions and/or meninges of 11/12 MS donors. The fraction (median value) of CD8 T cells recognizing individual EBV epitopes ranged from 0.5 to 2.5% of CNS-infiltrating CD8 T cells. Cytomegalovirus-specific CD8 T cells were detected at a lower frequency (≤0.3%) in brain sections from 4/12 MS donors. CNS-infiltrating EBV-specific CD8 T cells were CD107a-positive, suggesting a cytotoxic phenotype, and stuck to EBV infected cells.

Together with local EBV dysregulation, selective enrichment of EBV-specific CD8 T cells in the MS brain supports the notion that skewed immune responses toward EBV may contribute to inflammation causing CNS injury.

IMPORTANCE
EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas. The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology. Infectious mononucleosis increases the risk of developing MS and immune reactivity toward EBV is higher in persons with MS indicating inadequate control of the virus. Previous studies have suggested that persistent EBV infection in the CNS might stimulate an immunopathological response causing bystander neural cell damage. To verify this, we need to identify the immune “culprits” responsible for the detrimental antiviral response in the CNS. In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus infected cells. This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.

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Re: Krooniset bakteeri-infektiot
Vastaus #369 - 27.11.2019 - 11:08:15
 

MS linked to variant of common herpes virus


https://www.sciencedaily.com/releases/2019/11/191126075238.htm

November 26, 2019

Researchers at Karolinska Institutet have developed a new method to separate between two different types of a common herpes virus (HHV-6) that has been linked to multiple sclerosis. By analyzing antibodies in the blood against the most divergent proteins of herpesvirus 6A and 6B, the researchers were able to show that MS-patients carry the herpesvirus 6A to a greater extent than healthy individuals. The findings, published in Frontiers in Immunology, point to a role for HHV-6A in the development of MS.

Multiple sclerosis, MS, is an autoimmune disease that affects the central nervous system. The cause of the disease is unclear, but one plausible explanation is a virus tricks the immune system to attack the body's own tissue. Human Herpesvirus 6 (HHV-6) has previously been associated with MS, but in those studies it wasn't possible to distinguish between 6A and 6B. Through virus isolation from ill individuals, researchers have been able to show that HHV-6B can cause mild conditions such as roseola in children, but it has been unclear if HHV-6A is the cause of any disease.

According to estimates, as many as 80 percent of all children are infected with the HHV-6 virus before 2 years of age, and many also carry protection in the form of antibodies against this particular virus for the rest of their lives. But since it hasn't been possible to tell the two variants apart post-infection, it has been difficult to say whether HHV-6A or B is a risk factor for MS.

In this study, however, the researchers were able to distinguish between the A and B virus by analyzing antibodies in the blood against the proteins -- immediate early protein 1A and 1B (IE1A and IE1B) -- that diverge the most between the two viruses.

"This is a big breakthrough for both the MS and herpes virus research," says Anna Fogdell-Hahn, associate professor at the Department of Clinical Neuroscience at Karolinska Institutet and one of the study's senior authors. "For one, it supports the theory that HHV-6A could be a contributing factor to the development of MS. On top of that, we are now able, with this new method, to find out how common these two different types of HHV-6 are, something we haven't been able to do previously."

The researchers compared antibody levels in blood samples of some 8,700 MS-patients against more than 7,200 healthy people whose gender, date of birth, date of blood sample and other factors matched those with MS. They concluded that people with MS had a 55 percent higher risk of carrying antibodies against the HHV-6A protein than the control group. In a sub-group of almost 500 people, whose blood samples were drawn before the onset of the disease, the risk of developing MS in the future was more than doubled if they had a 6A viral infection. The younger the people were when the virus was first discovered in the blood, the higher the risk was of developing MS in the future. HHV-6B, on the other hand, was not positively associated with MS. Instead MS-patients had lower levels of antibodies toward IE1B than those without MS.

Antibodies toward Epstein-Barr virus (EBV), another herpes virus that is also associated with MS, were analyzed with the same method and the researchers were able to show that individuals affected with both viruses had an even greater risk of MS. This indicates that several virus infections could be acting jointly to increase the risk of MS.

"Both HHV-6A and 6B can infect our braincells, but they do it in slightly different ways. Therefore, it is now interesting to go forward and attempt to map out exactly how the viruses could affect the onset of MS," says Anna Fogdell-Hahn.

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Re: Krooniset bakteeri-infektiot
Vastaus #370 - 31.12.2019 - 00:45:59
 
Levels of Infection-fighting Antibodies Low in Blood of People with MS, Study Finds

https://multiplesclerosisnewstoday.com/news-posts/2019/10/23/reduced-serum-immun...
oglobulin-g-concentrations-in-multiple-sclerosis-prevalence-and-association-with
-disease-modifying-therapy-and-disease-course/

October 29, 2019
People with multiple sclerosis (MS) tend to have low levels in their blood serum of certain antibodies that can protect against infection, regardless of whether they are using a disease-targeted therapy or not, a study reports.

These levels were not so low as to risk infection on their own, but were lower-than-normal across all MS subtypes and particularly low in people with secondary progressive disease (SPMS).


“Reduced serum immunoglobulin G concentrations in multiple sclerosis: prevalence and association with disease-modifying therapy and disease course,” the study was published in the journal Therapeutic Advances in Neurological Disorders.

Antibodies (also known as immunoglobulins, or Ig) are an essential component of the immune system that help fight infection. Because many MS therapies work by decreasing the activity of the immune system, it is possible that treated patients have abnormally low levels of certain kinds of antibodies and, as a result, become more prone to infection.

A team led by researchers at Bern University Hospital, University of Bern, Switzerland, set out to examine the link between antibodies, targeted therapies, and disease characteristics in people with MS.

To do this, they analyzed data from two European MS cohorts — a Bern University Hospital group (Switzerland), and a Eginition University Hospital group (Greece) — totaling 327 patients.

They found that 15.3% of the MS patients had lower-than-normal (less than 700 mg/dL) levels of a type of antibody called immunoglobulin G (IgG)
, the most common type of antibody the body produces. These low levels were seen in a significantly higher percentage of MS patients than in a control group of people with head and neck pain (3.5%).

Other antibody types — namely IgA and IgM — trended toward being lower in the MS groups, but the differences were not statistically significant.

Interestingly, low IgG levels were found even in MS patients who were not being actively treated — about 8.1% of untreated MS patients had IgG levels below the 700 mg/dL threshold. According to the team, these patients “were 2.3 times more likely to have IgG concentrations below 700 mg/dL compared with the control patients.”

People with MS who were being treated with rituximab (Rituxan), corticosteroids, Tysabri (natalizumab), and Gilenya (fingolimod) had significantly lower IgG levels, on average, than those who were not being treated, which is in line with the fact that these therapies work by decreasing immune system activity.

The researchers also found that people with secondary progressive MS had significantly lower IgG levels (average of 750 mg/dL) than those with primary progressive MS (PPMS; average of 940 mg/dL) or relapsing-remitting MS (RRMS; average of 950 mg/dL). This difference held even when looking only at serum levels of untreated SPMS and PPMS patients.

“When considering only RRMS and SPMS patients without disease-modifying treatment (n = 179 and n = 8, respectively), the significant difference in IgG concentrations remained present despite the small sample size in the SPMS group,” they wrote.

“Altogether, our study demonstrated high prevalence rates of reduced serum IgG concentrations in MS patients with and without disease-modifying treatments,” they concluded.

However, “the significance of lower IgG concentrations at the levels noted is unclear, considering that infections or interference with antibody production generally occur when IgG levels are much lower, at or below 400 mg/dl,” they aded.

Nonetheless, the researchers believe that monitoring IgG levels, particularly in MS patients on treatments that target the immune system, could be helpful in avoiding dangerously low antibody levels (generally considered to be at or below 400 mg/dL) that could predispose these people to infections.
*******

Ainakin itseni suhteen tämä pitää paikkansa - IgG on pysytellyt juuri ja juuri minimirajan yläpuolella vuosikausia ja IgM ja IgA ovat erittäin alhaisia. Ilman immuunisupressiivista lääkitystä..
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Re: Krooniset bakteeri-infektiot
Vastaus #371 - 31.12.2019 - 00:54:04
 
Tutkijoilta ehdotus mekanismiksi, jolla virusinfektio aiheuttaa autoimmuunitaudin

https://www.jyu.fi/fi/ajankohtaista/arkisto/2019/05/tutkijoilta-ehdotus-mekanism...

Jyväskylän yliopiston tutkimusryhmä on löytänyt uuden mahdollisen mekanismin virusinfektion ja autoimmuunisairauksien välille. Yliopistonlehtori Leona Gilbertin tutkimusryhmä sai näyttöä mekanismista hiirillä tehdyissä kokeissa. Kokeissa havaittiin virusinfektion aikana tapahtuvan solu- ja kudosvaurion olevan yhteydessä autoimmuunireaktioon eli elimistön oman immuunijärjestelmän hyökkäykseen elimistön omaa DNA:ta vastaan. Tutkimusartikkeli julkaistiin The Journal of infectious diseases -tiedejulkaisussa toukokuussa.
Tutkijoilta ehdotus mekanismiksi, jolla virusinfektio aiheuttaa autoimmuunitaudin.

Autoimmuunisairauksissa immuunijärjestelmä hyökkää kehon omia soluja vastaan sen sijaa, että se tuhoaisi bakteereita tai viruksia. Siksi ne voivat olla kuntoa heikentäviä ja vaikeasti hoidettavia.
Sairauksien synnyn tarkka mekanismi ei ole tiedossa. Hiljattain eräitä yleisiä bakteeri- ja virusinfektioita on yhdistetty autoimmuunisairauksiin.
Myös ihmisen parvovirus B19 on yhdistetty esimerkiksi nivelreuman kaltaiseen autoimmuunisairauteen. Parvovirus B19 on hyvin yleinen virus, jonka aiheuttama infektio voi olla oireeton tai aiheuttaa flunssan kaltaisia oireita.
”Ihmisen parvovirus B19 NS1-proteiinin tiedetään aiheuttavan apoptoottista solukuolemaa. Solukuolemaa esiintyy tavallisestikin terveissä soluissa ja se poistaa vanhoja ja vaurioituneita soluja elimistöstä. Kuitenkin mikrobi-infektion aikaan patogeeni voi aiheuttaa liiallisen määrän solukuolemia ja se kuormittaa immuunijärjestelmää”, sanoo Leona Gilbert.

Parvovirusinfektiossa muodostuvat apoptoottiset kappaleet aiheuttivat hiirissä immuunivasteen omaa DNA:ta vastaan

Leona Gilbertin ryhmän mukaan virusinfektion seurauksena muodostuneet apoptoottiset kappaleet, joissa on mukana sekä viruksen NS1-proteiinia että isäntäsolun rakenteita, saivat aikaan autoimmuunireaktion. Autoimmuunireaktio johti solu- ja kudosvaurioihin hiirien aivoissa, sydämessä, munuaisessa ja maksassa.
”Oma immuunijärjestelmämme hyökkää omaa DNA:tamme vastaan, mikä puolestaan aiheuttaa enemmän ja enemmän tuhoa soluissa, mikä taas johtaa kudosvaurioihin tärkeimmissä elimissä. Lisäksi hiirimalli osoitti, että eläimessä syntyi immuunivaste sen omaa DNA:ta kohtaan, mikä on systeemisen lupus erythematosus -taudin erityispiirre”, sanoo Gilbert.
Tutkijoiden mukaan tulokset ilmaisevat, että  virusinfektioissa nopea hoitaminen on tärkeää, jotta tauti ei etene krooniseksi autoimmuunisairaudeksi.
”Toivomme tuloksiamme käytettävän tulevaisuudessa uusien antiviraalisten hoitomuotojen kehittämiseen, jotta viruksista aiheutuvia autoimmuunisairauksia voidaan ehkäistä ja hoitaa”, Gilbert sanoo.

Artikkeli: Puttaraksa, K., H. Pirttinen, K. Karvonen, J. Nykky, S. J. Naides, and L. Gilbert. "Parvovirus B19V Non-structural Protein NS1 Induces dsDNA Autoantibodies and End Organ Damage in Non-autoimmune Mice." The Journal of infectious diseases, Volume 219, Issue 9, 1 May 2019, Pages 1418–1429

Linkki artikkeliin:  https://doi.org/10.1093/infdis/jiy614


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Re: Krooniset bakteeri-infektiot
Vastaus #372 - 13.02.2020 - 14:18:51
 
Multiple sclerosis: an example of pathogenic viral interaction?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330019/

2017 Feb 28

A hypothesis is formulated on viral interaction between HHV-6A and EBV as a pathogenic mechanism in Multiple Sclerosis (MS). Evidence of molecular and genetic mechanisms suggests a link between HHV-6A infection and EBV activation in the brain of MS patients leading to intrathecal B-cell transformation. Consequent T-cell immune response against the EBV-infected cells is postulated as a pathogenic basis for inflammatory lesion formation in the brain of susceptible individuals. A further link between HHV-6A and EBV involves their induction of expression of the human endogenous retrovirus HERV-K18-encoded superantigen. Such virally induced T-cell responses might secondarily also lead to local autoimmune phenomena. Finally, research recommendations are formulated for substantiating the hypothesis on several levels: epidemiologically, genetically, and viral expression in the brain.

Conclusion

A link is postulated between HHV-6A and EBV in the aetio-pathogenesis of MS.

In summary, the tenet is that infection with the neurotropic HHV-6A leads to transformation of latently EBV-infected B-cells in the CNS. Both viruses will elicit a T-cell response, either specific towards HHV-6A and EBV, or non-specific as a response to the HERV-K18-encoded superantigen. Such viral induced T-cell responses might secondarily also lead to autoimmune phenomena. Evidence for mechanisms for induction of autoimmunity by viral infections has recently been reviewed [56].

The hypothesis could be tested on several levels:

   Epidemiological level: The prevalence of genetic subtypes of EBV (EBNA2) and HHV-6A and its subtypes are not known. Establishing the prevalence of co-infection with the two viruses is crucial to estimate the likelihood of their combined effects in MS.

   Level of genetic associations to MS: The relations between MHC2TA as well as EBNA2 polymorphisms with MS suggest a link between active replication of HHV-6A, regulated by MHC2TA, and HHV-6A-induced EBNA2 expression in EBV-infected cells. A crucial test would be to look for genetic interaction between all three polymorphisms, MHC2TA, EBNA2, and HERV-K18 in the risk for MS.

   Molecular level: Both, findings for HHV-6A and EBV expression in MS lesions are not unanimous. Studies looking for co-expression of the two viruses in brain tissue of MS patients using the MALDI-TOF MS technology [57] and/or multiplex detection of herpes viruses in CSF by PCR [58] might clarify the issue.
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Re: Krooniset bakteeri-infektiot
Vastaus #373 - 13.02.2020 - 14:31:33
 
EBV and MS: Major cause, minor contribution or red-herring?

https://www.msard-journal.com/article/S2211-0348(17)30133-5/fulltext

August 2017
Abstract

Multiple Sclerosis (MS) is a chronic neurological disease with genetic and environmental risk factors. Epstein Barr-Virus (EBV) has been closely associated with MS but with a significant amount of conflicting evidence. Some of the evidence for EBV involvement in MS includes: almost 100% of MS patients showing past EBV infection, an association with Infectious Mononucleosis (acute EBV infection), higher titres of EBV antibodies associated with an increased risk of MS development, and an overall altered immune response to EBV found in peripheral blood and the CNS of MS patients. However, evidence for EBV presence in the CSF and T cell responses to EBV in MS have been particularly conflicting. Several hypotheses have been proposed for direct and indirect EBV involvement in MS such as 1) Molecular Mimicry 2) Mistaken Self 3) Bystander Damage and 4) Autoreactive B cells infected with EBV. More recently, an association between EBV and human endogenous retrovirus in MS has been shown, which may provide an alternative pathogenetic target for MS treatment. However, if EBV is not the major contributor to MS and is instead one of several viral or infectious agents able to elicit a similar altered immune response, MS development may be the result of a failure of viral clearance in general. This review aims to evaluate the evidence for the currently discussed theories of EBV involvement in MS pathogenesis.

********
Conclusion

There is an undeniable association between EBV and MS, with evidence that includes higher EBNA-1 titres (Sundqvist et al., 2012, Sundstrom et al., 2009) and an increased incidence of IM (Nielsen et al., 2007) in MS patients. Another consistent feature of MS is the finding that nearly 100% of MS patients have been shown to be infected with EBV, with one report indicating 100% seroconversion prior to MS onset, suggesting EBV infection is a pre-requisite to MS (Levin et al., 2010). Nonetheless, the presence of EBV DNA in the CNS (Peferoen et al., 2010), and an altered EBV reactive CD8+ T Cell response (Pender et al., 2009a, Lindsey and Hatfield, 2010, Cepok et al., 2005, Lünemann et al., 2008, Gronen et al., 2006, Angelini et al., 2013, Jilek et al., 2008, Jilek et al., 2012) in MS patients has been inconsistent. Thus, none of the evidence so far has unequivocally implicated EBV involvement in MS pathogenesis. Therefore, the question whether EBV is a causative factor or simply associated with an altered immune system in MS remains to be answered.

Given the conflicting evidence about EBV involvement in MS there are two further plausible contributions of EBV involvement into MS. If EBV is truly a pre-requisite and/ or the main contributor of MS pathogenesis, then the fact that most of the world's population are infected by EBV yet only a small proportion go on to develop MS (or other EBV related diseases), needs to be addressed. Genetic risks for MS, such as the presence of the HLA allele DRB15*01 and absence of A*02, have been shown to be increased in combination with EBV infection (Sundqvist et al., 2012), but this still does not account for 100% of MS cases. It would be interesting to know if individuals with the major genetic risk factors for MS, in the absence of EBV infection, developed MS.

One possibility that addresses the issue of why some individuals who are infected with EBV are asymptomatic, while others might develop MS or lymphomas, is the notion that differential random integration of EBV in host cells may drive different disease pathologies. EBV integration may cause particular methylation changes resulting in subtle or more discrete expression level changes in regions yet to be identified as risk factors for MS. EBV has already been shown to integrate into random locations (Santpere et al., 2014, Takakuwa et al., 2004) and cause methylation changes in vitro in B cell lines (Hernando et al., 2013). This could also account for the inconsistent findings of EBV within the CNS, since detection of viral load of EBV DNA relies upon a conserved sequence of the EBV genome (Gulley and Tang, 2010), which may be disrupted in the process of integration.

Another possibility, since the presence of EBV has not been unequivocally shown in the CNS, the involvement of EBV mediation outside the CNS, by means of molecular mimicry, is still a plausible contributor to MS development or disease progression. However, if molecular mimicry is a key player in MS pathogenesis, then EBV is not the only pathogen that needs to be considered, since other pathogens such as the influenza virus and LCMV can elicit a similar response against MBP as EBV. Thus, there may be a failure of viral clearance in general in MS patients that could provide new therapeutic targets. Whether this is caused by a combination of pathogens augmenting the hosts’ immune system and/or a genetic pre-disposition is worthy of further investigation.
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Re: Krooniset bakteeri-infektiot
Vastaus #374 - 13.02.2020 - 14:57:08
 
Bacteria–Host Interactions in Multiple Sclerosis

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

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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