Published February 4, 2019
John D. Kriesel, Preetida Bhetariya, Zheng-Ming Wang, David Renner, Cheryl Palmer & Kael F. Fischer
Scientific Reports volume 9, Article number: 1387 (2019)
Abstract:
Multiple sclerosis (MS) is an autoimmune disease characterized by multiple lesions in the brain and spinal cord. We used RNA sequencing to identify microbial sequences and characterize human gene expression patterns in 30 human brain biopsy specimens. RNAs which aligned to known microbial taxa, were significantly enriched in 10 of 12 primary demyelination (MS) brain specimens compared to a group of 15 epilepsy controls, leading to a list of 29 MS microbial candidate genera from 11 different phyla. Most of the candidate MS microbes are anaerobic bacteria. While there were some shared candidates, each of the 10 MS samples with significant microbial RNA enrichment had a distinct set microbial candidates. The fraction of microbial sequencing reads was greater for the MS group (128.8 PPM) compared to the controls (77.4 PPM, p = 0.016). Bacterial peptidoglycan was demonstrated in brain tissue sections from several MS subjects. Human gene expression analysis showed increased expression of inflammation-related pathways in the MS group. This data shows that demyelinating brain lesions are associated with the presence of microbial RNA sequences and bacterial antigen. This suggests that MS is triggered by the presence of a diverse set of microbes within a lesion.
Introduction:
MS is a chronic demyelinating disease of unknown cause, which affects the brain and spinal cord of about 400,000 individuals in the U.S. A number of infections of the central nervous system (CNS) can lead to demyelination, including distemper (dogs), measles (SSPE, humans), JC virus (humans), and influenza (humans)1. Microbes, particularly viruses, have long been suspected as causative agents of MS, based on the epidemiology of the disease including geographic patterns, isolated outbreaks, and migration studies 2,3,4,5.
Acute tumefactive MS is an acute tumor-like variant where some patients with demyelinating disease present with large acute lesions, often associated with edema and/or ring enhancement on imaging studies 6,7. This type of inflammatory demyelinating disease is also called pseudotumoral MS, transitional sclerosis, diffuse myelinoclastic sclerosis, and Marburg variant MS. The initial description by Kepes6 suggested that only a few such patients would go on to develop MS. However, a more recent, much larger study of 168 patients with biopsy-confirmed CNS inflammatory demyelinating disease showed that the majority of such patients (79%) go on to develop clinically definite MS7. Clinically isolated syndrome (CIS) refers to a single attack compatible with MS, such as optic neuritis. Sixty to 80 percent of patients with a CIS and magnetic resonance imaging (MRI) lesions go on to develop MS, while approximately 20–40 percent have a self-limited process 8,9,10.
The pathology of MS is well summarized by Lucchinetti 11: “The pathologic hallmark of multiple sclerosis (MS) is multiple focal areas of myelin loss within the CNS called plaques or lesions…. Acute active MS lesions are hypercellular demyelinated plaques massively infiltrated by macrophages evenly distributed throughout the lesion forming the classic ‘sea of macrophages.’ These macrophages contain myelin debris, an indication that they have taken up and degraded the remnants of the destroyed myelin sheaths (i.e., active demyelination)”.
Given these factors, including known infectious causes of demyelination and the macrophage-dominated pathology of MS plaques, we considered the possibility that microbes within brain parenchyma might trigger the onset of MS, or the worsening of existing MS disease. In the present study, we hypothesized that the microbial sequence content of primary demyelination brain samples would differ from that in a set of controls. An IRB protocol was written and approved for the collection and analysis of leftover CSF and formalin-fixed paraffin-embedded (FFPE) brain tissue. The feasibility of RNA extractions and deep sequencing from such tissues was demonstrated. This present study involved neuropathology, metatranscriptomics, infectious diseases, and clinical neurology within our institution.
Results:
click here to continue reading
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John D. Kriesel, Preetida Bhetariya, Zheng-Ming Wang, David Renner, Cheryl Palmer & Kael F. Fischer
Scientific Reports volume 9, Article number: 1387 (2019)
Abstract:
Multiple sclerosis (MS) is an autoimmune disease characterized by multiple lesions in the brain and spinal cord. We used RNA sequencing to identify microbial sequences and characterize human gene expression patterns in 30 human brain biopsy specimens. RNAs which aligned to known microbial taxa, were significantly enriched in 10 of 12 primary demyelination (MS) brain specimens compared to a group of 15 epilepsy controls, leading to a list of 29 MS microbial candidate genera from 11 different phyla. Most of the candidate MS microbes are anaerobic bacteria. While there were some shared candidates, each of the 10 MS samples with significant microbial RNA enrichment had a distinct set microbial candidates. The fraction of microbial sequencing reads was greater for the MS group (128.8 PPM) compared to the controls (77.4 PPM, p = 0.016). Bacterial peptidoglycan was demonstrated in brain tissue sections from several MS subjects. Human gene expression analysis showed increased expression of inflammation-related pathways in the MS group. This data shows that demyelinating brain lesions are associated with the presence of microbial RNA sequences and bacterial antigen. This suggests that MS is triggered by the presence of a diverse set of microbes within a lesion.
Introduction:
MS is a chronic demyelinating disease of unknown cause, which affects the brain and spinal cord of about 400,000 individuals in the U.S. A number of infections of the central nervous system (CNS) can lead to demyelination, including distemper (dogs), measles (SSPE, humans), JC virus (humans), and influenza (humans)1. Microbes, particularly viruses, have long been suspected as causative agents of MS, based on the epidemiology of the disease including geographic patterns, isolated outbreaks, and migration studies 2,3,4,5.
Acute tumefactive MS is an acute tumor-like variant where some patients with demyelinating disease present with large acute lesions, often associated with edema and/or ring enhancement on imaging studies 6,7. This type of inflammatory demyelinating disease is also called pseudotumoral MS, transitional sclerosis, diffuse myelinoclastic sclerosis, and Marburg variant MS. The initial description by Kepes6 suggested that only a few such patients would go on to develop MS. However, a more recent, much larger study of 168 patients with biopsy-confirmed CNS inflammatory demyelinating disease showed that the majority of such patients (79%) go on to develop clinically definite MS7. Clinically isolated syndrome (CIS) refers to a single attack compatible with MS, such as optic neuritis. Sixty to 80 percent of patients with a CIS and magnetic resonance imaging (MRI) lesions go on to develop MS, while approximately 20–40 percent have a self-limited process 8,9,10.
The pathology of MS is well summarized by Lucchinetti 11: “The pathologic hallmark of multiple sclerosis (MS) is multiple focal areas of myelin loss within the CNS called plaques or lesions…. Acute active MS lesions are hypercellular demyelinated plaques massively infiltrated by macrophages evenly distributed throughout the lesion forming the classic ‘sea of macrophages.’ These macrophages contain myelin debris, an indication that they have taken up and degraded the remnants of the destroyed myelin sheaths (i.e., active demyelination)”.
Given these factors, including known infectious causes of demyelination and the macrophage-dominated pathology of MS plaques, we considered the possibility that microbes within brain parenchyma might trigger the onset of MS, or the worsening of existing MS disease. In the present study, we hypothesized that the microbial sequence content of primary demyelination brain samples would differ from that in a set of controls. An IRB protocol was written and approved for the collection and analysis of leftover CSF and formalin-fixed paraffin-embedded (FFPE) brain tissue. The feasibility of RNA extractions and deep sequencing from such tissues was demonstrated. This present study involved neuropathology, metatranscriptomics, infectious diseases, and clinical neurology within our institution.
Results:
click here to continue reading
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Article Provided by: #MSViewsandNews
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