Post #3: isolating and suppressing a specific immune response

In my very first post, I discussed how many autoimmune disorders are treated through immune suppressant drugs which can leave a patient susceptible to many other infectious diseases and infections. It is certainly not a perfect system, and scientists are now looking at ways in which to suppress only the sector of the immune system that is generating the autoimmune response. Researchers supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) are looking at the natural methods the body uses to suppress inappropriate immune responses. Normally, when a cell dies through apoptosis, it releases chemicals that initiate a response from a type of cell called macrophages that absorb and deposit the dead cells’ antigens in the spleen into a pool of T-cells- some of the cells responsible for an immune response. Then the macrophages suppress any T-cells with the ability to bind to self-antigens to not have a negative autoimmune attack. Currently, the method being tested in mice is coupling myelin cells in subjects with multiple sclerosis (in which myelin cells cause an autoimmune response) with self-antigens that do not bind with T-cells. So far this treatment has proven to be extremely effective in halting the progression of the multiple sclerosis in mice, and the next step is clinical trials. However, cellular therapy is apparently very costly, time-consuming, and needs to be done in a high-tech facility, and thus progress with this research is going to be difficult. Still, this method of treatment is not specific to multiple sclerosis and is projected to be effective in many other autoimmune disorders and diseases like allergies, type I diabetes, and maybe even Rheumatoid arthritis

 

https://www.nibib.nih.gov/news-events/newsroom/research-breakthrough-selectively-represses-immune-system

https://study.com/academy/lesson/non-self-antigens-self-antigens-allergens.html

Post #3: The genetic heritability and make-up of MS

In order to find a method for self repairing neurons affected by the degenerative effects of multiple sclerosis, it is necessary to understand from where multiple sclerosis originates. There is limited knowledge regarding the development of multiple sclerosis specifically in terms of genetic heritability. Family based-linkage analyses have shown MS is related to genes that encode for the human leucocyte antigen (Lin, Charlesworth, Mei, & Taylor, 2012). Furthermore genome-wide association studies have identified over 60 loci related to MS in regions of the chromosome corresponding to T-cells and the immune system (Lin, 2012). These two linkage and association studies only explain 18-24% of the heritability of MS (Lin, 2012). Many theories have been created in order to make up for the lack of knowledge about the genetic heritability of MS. The first theory includes that rare and common variants of allele frequencies related to MS that account for most of its heritability have still not been found (Lin, 2012). The second theory of epigenetics suggests that environmental factors may trigger certain gene expressions related to MS (Lin, 2012). The third theory of gene-gene interactions explains how genes of the same phenotype may have an effect on how that phenotype is expressed (Lin, 2012). The fourth theory suggests structural variants in DNA that have not been thoroughly research may hold an association between the genes and complex traits related to MS (Lin, 2012). The last theory describes how pathway involvement of congregated variants of genes may lead to susceptibility of MS and other diseases (Lin, 2012). Genetic studies still lack the methods to understand the complexity of the genes associated with MS (Lin, 2012). Without knowing the exact genes associated with MS it will be difficult to create ways to modify the cell genome in order for the myelin sheath to undergo a self-reparation process. Other ways of treating MS may need to be explored since modeling the self-reparation process of the Deinococcus radiodurans bacteria maybe difficult without knowledge of the genetic makeup of MS.

Lin, R., Charlesworth, J., Mei, I. V., & Taylor, B. V. (2012, October). The Genetics of Multiple Sclerosis. Retrieved October 11, 2018, from https://pn.bmj.com/content/12/5/279.info

Post 3: Microglia and mCSF in Remyelination

This week I decided to look deeper into remyelination. As mentioned in last week’s post, patients with MS experience demyelination. Their immune system attacks the myelin sheaths on their nerve fibers, which are needed to transmit signals from the brain. Other than the death of oligodendrocytes, a cause of demyelination is the “robust immune responses mediated by microglia, which are the resident immune cells of the central nervous system.” (multiplesclerosisnewstoday) Recent studies show that microglia may actually be beneficial in promoting remyelination by promoting regeneration and clearing myelin debris.

 

“Aiming to better understand the role of microglia in MS, scientists at Université Laval, in Canada, administered a molecule called macrophage colony-stimulating factor (mCSF) to mice receiving dietary cuprizone.” (multiplesclerosisnewstoday) The mCSF shifted the microglia to become anti-inflammatory, promoting remyelination. This research suggests that “mCSF would be an ideal target for a clinical trial in individuals diagnosed with primary and secondary progressive MS.”

https://www.frontiersin.org/articles/10.3389/fncel.2018.00178/full

Immune Response Promotes Remyelination in MS Mouse Model

Biomarkers for Rheumatoid Arthritis

The traditional means of diagnosing rheumatoid arthritis (RA) has largely relied on the manifestation of symptoms and joint damage. Furthermore, the treatment of RA generally relies on a trial and error method with different medications because many different treatments don’t work for a lot of different patients. However, a recent study from the United Kingdom has identified four biomarkers that may help diagnose RA as well as predict the effectiveness of methotrexate as a treatment method for patients (Shervington, et al 2018). Because methotrexate was original designed as a cancer treatments and essentially kills parts of the immune system in hopes that it grows back healthy, the possibility of predicting whether or not it will be an effective treatment for a patient without them having to take it is an important advancement in the RA field. Personally, the use of methotrexate and other cancer drugs as treatments for RA is something that I would like to see dissipate in the coming years and I hope that this study will be an important step in the right direction.

Shervington, L., Darekar, A., Shakh, M., Mathews, R., Shervington, A. (2018) Identifying Reliable Daignostic/Predictive Biomarkers for Rheumatoid Arthritis. Biomark Insight. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30262983

Post #3: Investigating Neurofilaments and Their Role in Identifying MS Disease Progression

Recently, a research journal entitled “Neurofilaments as Biomarkers in Neurological Disorders” published in Nature Reviews Neurology earlier this year by Michael Khalil et al. investigated neurofilaments and their role in identifying MS in patients. Included in this study was the purpose of neurofilaments, how neurofilament light chains can be used as a biomarker to identify disease progression in MS patients, and how the techniques can be used to help in the identification of effective treatments for MS and other neurological disorders.

To begin, neurofilaments, a part of the neurons, are thought to be important components in providing radial growth and overall stability in axons throughout the body. Therefore, when MS causes disease progression and axonal injuries, these neurofilaments are released into the body. Certain techniques using four different generations of immunoassays (a biochemical test that can help identify these neurofilaments) can identify the levels of these neurofilaments in both the cerebral spinal fluid (CSF) and the blood. If this is done, the concentration of these neurofilaments can be an important indicator in determining the level of disease progression for MS. The first two generations of immunoassays work for identification in CSF, although identification in blood is only reliable in the third and fourth generation immunoassays identified in the study (these immunoassays are more sensitive).

This process is an important landmark in not only identifying how severe a patient has MS, but it can also be an effective tool in future MS research. This process can be used in future clinical trials to help determine how well a MS treatment works by comparing the number of neurofilaments that are in the blood before and after treatment. This process is also much more reliable than using MRI scans which are only reliable in showing damage in white matter, while MS causes damage in both white matter and gray matter. While the first and second generation immunoassays have limitations based on low sensitivity (and therefore rely on CSF sampling), the newer third and fourth generation immunoassays have opened up opportunities in future testing and research. While not perfect, these immunoassays could help find a future treatment, if not a future cure, for MS.

As said before, the information in the above paragraphs was located in an article published in Nature Reviews Neurology entitled “Neurofilaments as Biomarkers in Neurological Disorders” by Michael Khalil et al.. The link to the article is listed below.

https://www.nature.com/articles/s41582-018-0058-z#Sec5

Post 2: A Deeper Look Into MS and Remyelination

Multiple sclerosis is an autoimmune disease that affects 2.3 million people worldwide. The immune system attacks the central nervous system, which consists of the brain and spinal cord. With MS, the immune system causes damage to the myelin that surrounds and insulates the nerve fibers. When the myelin and nerve fibers are damaged, they stop sending signals from the CNS to the brain, and the damaged areas develop scar tissue. This gives it the name multiple sclerosis – multiple scarring.

 

While MS cannot be cured, it can be treated. One of the more recent breakthroughs for this disease is remyelination – the spontaneous regeneration of the myelin that surrounds and insulates nerve fibers. Researchers at the University of Buffalo have found that drug targeting a receptor called muscarinic type 3 (M3R), found on OPC cells (the cells that make myelin), works to help remyelination. In people with MS, the activation of M3R prevents OPC cells from maturing properly. Using a drug already on the market for overactive bladders (solifenacin), scientists have successfully inhibited M3R, letting the OPC cells work to repair myelin.

 

This recent research establishes that once M3R is blocked, remyelination becomes possible. It also helps us understand the role of receptors in autoimmune diseases like MS.

https://www.nationalmssociety.org/Treating-MS

https://medicalxpress.com/news/2018-07-drug-remyelination-ms.html

Post #2: Self Reparation and Remyelination

Currently, our research of treatment of autoimmune diseases focuses on multiple sclerosis. One of the most detrimental effects of MS involves the demyelination of the myelin sheath of neurons (Podbielska, 2013). The destruction of the myelin sheath affects transmitting speed and the action potential of neurons which can severely impact mental capabilities (2013). The destruction of the myelin sheath usually results from certain proteins, paranodal and juxtaparanodal proteins, congregating on the myelin sheath and creating lesions (2013). Without the protection of the myelin sheath, the axon is vulnerable to damage from consequent electrical firing of the neurons (2013). Normally, neurons are able to repair their myelin sheath by the process of remyelination. But often the neuron’s of people who suffer from MS fail to induce this process (2013). Understanding what components of remyelination lead to the repair of the myelin sheath may offer insight into treatment for MS.

In last weeks post I researched how Deinococcus radiodurans could repair their shattered genome after undergoing extreme amounts of radiation. This week I researched more on the genome of the Deinoccocus radiodurans. Its genome comprises of chromosome I, chromosome II, a megaplasmid, and a plasmid. Chromosome II contains information regarding “amino acid utilization, cell envelope formation, and transporters” (Dassarma, 2006). Understanding how the expression of these genes leads to the full self-reparation of the Deinoccocus radiodurans bacterium and its genome could aid in understanding the generation of remyelination in neurons. Rates of remyelination decrease throughout the progression of MS (Podbielska, 2013). It involves creating new myelin sheaths over damaged demyelinated sheaths (2013). By studying the sequences of the Deinoccous radiodurans’ genome, there may be a way to genetically imitate the genes that code for self reparation in the genome of neurons.  

Podbielska, M., Banik, N. L., Kurowska, E., & Hogan, E. L. (2013). Myelin Recovery in Multiple Sclerosis: The Challenge of Remyelination. Brain Sciences, 3(3), 1282–1324. http://doi.org/10.3390/brainsci3031282

White, O., Eisen, J. A., Heidelberg, J. F., Hickey, E. K., Peterson, J. D., Dodson, R. J., … Fraser, C. M. (1999). Genome Sequence of the Radioresistant Bacterium Deinococcus radiodurans R1. Science (New York, N.Y.), 286(5444), 1571–1577.

post #2: what is actually going down on the neurons

Multiple Sclerosis (MS) is an autoimmune disorder that causes the body’s immune system to attack the central nervous system (CNS). This immune response diminishes the myelin sheaths that surround axons and also damages the nerve fibers underneath the myelin. This attack results in lesions of the axons and eventually results in a lack of insulation for nerve signals. Without these myelin sheaths, the nerve signaling is either slowed or completely blocked. The signals cannot reach the brain quickly or effectively and basic motor function or signaling pathways become greatly compromised. If one were to think of wires that connect to a phone or computer: if the rubber insulating the wire was not there, the charge could disperse to other surrounding objects and make the ending result much weaker or non-existent.

 

However, this comparison is not completely analogous to multiple sclerosis as the main purpose of the myelin sheaths is not actually to provide insulation for incoming and outgoing nerve signals. Instead the myelin sheaths allow for the neurons to perform saltatory conduction to speed up the slower process of an action potential. In between each myelin sheath is a regulated space of bare neuron that exists only at a length of a few microliters. These spaces between the myelin are called the Nodes of Ranvier (NORs) and are essential to rapid signal transmission. Therefore, the myelin sheaths work in conjunction with the NORs in order to execute saltatory conduction. The word “saltatory” comes from the Latin word “to jump” or “to hop” and describes the process of the sodium and potassium ion charge transferring from one node to the next, thus exponentially increasing the speed of the action potential by decreasing the area through which the charge is conducted.

 

Action potential is a binary electrical process that occurs in the membrane of our neurons. At what is called resting potential, our neurons are polarized so that they are negatively charged within the membrane and the extracellular space is positively charged. Embedded in the membrane are potassium ion channels and sodium ion channels that open for K+ ions to slowly flow out while Na+ slowly flows in when given a small type of stimulus. This flow of ions causes the depolarization of the membrane and the decrease of the resting concentration gradient, and if the stimulus is significant enough to depolarize the membrane past the threshold, then an action potential will occur. When an action potential occurs, Na+ ions flow rapidly into the membrane while K+ ions flow rapidly out.

 

Saltatory conduction increases the rate of nerve transmission through action potential from 5 meters/second (11mph) to 150 meters/second (330mph).

 

The main problem with having this new multitude of unmyelinated nerve fibers (otherwise known as unmedullated) suddenly in the central nervous system lies in the fact that unmyelinated axons are used primarily for sensory nerve signals. These neurons are either unmyelinated or sparsely myelinated, as they travel at much slower speeds and create duller signals. This specific type of nerve structure, the peripheral postganglionic autonomic fibers, has a great deal to do with how our body feels pain. Everyone has stubbed a toe in the past, and the feeling we get at first is a quick shooting pain that then dulls down to a bearable throbbing. Those quick shooting pains are the doing of medullated axons called A delta fibers that send pain signals quickly to the brain, and the slow and dull pulsing pain accounts for the unmedullated fibers named C fibers. Unmyelinated axons are also much smaller and travel shorter distances.

 

The main goal that researchers are currently working towards is enabling the body to rebuild the diminished myelin and repair the lesions done on the axons and nerve fibers. The primary research being conducted lies in stimulating brain cells and nerve tissue to repair what’s damaged. However, a big issue of MS is that the axons do in fact repair themselves to some extent, but biologists do not understand what prevents full reparations in the CNS.

http://www.webmd.com/multiple-sclerosis/features/advances-ms-research-treatment

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801692/

http://www.ncbi.nlm.nih.gov/pubmed/10723060

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC387409/

post #2 More on promoting remyelination in multiple sclerosis

In my last post, I discussed a treatment for multiple sclerosis that promotes axon remyelenation that was in the first stages of clinical trials. A more recent article discusses multiple treatments that have some remyelnating properties that are currently furhter along in the clinical trial process, as well as others that are currently in the development phases (Kremer, et al 2018). While most of the treatments the article discusses were not intended to treat multiple sclerosis by promoting remyelination, they have found that some of these treatments that were meant to treat other things may be used to treat multiple sclerosis as well (Kremer, et al 2018). Possible remyelination in multiple sclerosis is an exciting and hopeful new treatment method because it could possibly reverse the damage from previous attacks or relapses and combat future bouts as they occur.

Kremer, D., Akkermann, R., Küry, P., Dutta, R. (2018). Current advancements in promoting remyelination in multiple sclerosis. Sage Journals. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30270725

Post #2: Converting Astrocytes into Myelinating Cells In Vivo for Possible MS Treatment

Multiple sclerosis, or MS, is a disease that is characterized by the degradation of the myelin sheaths in the central nervous system (CNS). As one of the autoimmune diseases that our group has chosen to focus on, this autoimmune disease results in the interruption of nerve signals in the body, creating many cognitive and physical impairments upon the individual affected. This disease currently is very difficult to combat, and many patients lose a lot of their function over the course of many years. A recent study done by Maryam Ghasemi-Kasman, Leila Zare, Hossein Baharvand, and Mohammad Javan explored the ability to convert astrocytes within the CNS into oligodendroglia in vivo in order to combat the myelin destruction associated with this disease.

According to the study, when the degradation of myelin occurs, astrocytes appear in higher numbers at the injury site. These astrocytes change the inflammatory response in the body, creating a situation where the myelin cannot repair itself and therefore helps in the progression of nerve damage. The study completed by the four researchers above found that forcing the expression of the miR-302/367 cluster in astrocytes can create a situation where the astrocytes will turn into oligodendroglia, or nerve cells that naturally repair the myelin within the CNS. This study was completed using mice subjects, and after the above process was completed the study found an increase in neurological function within the mice and saw increased myelination via staining techniques. This conclusion shows a possibility for remyelination within the human body, which eventually could lead to the slowing if not the reversal of MS and other neurogenerative diseases.

The above information was found on the SCOPUS database. This study was published in the Journal of Tissue Engineering and Regenerative Medicine in 2018. The DOI for the scientific journal is below.

10.1002/term.2276