Questions regarding Multiple Sclerosis

Below are the questions that were asked to our group regarding Multiple Sclerosis. The questions are bolded with responses to each given immediately after each. Sources that were supplemental to the required article are listed at the end of the questions.


According to your interview and other data, MS appears to be more common in females. It has recently been found that women who take birth control pills may be less likely to develop MS while they're on the pill; and women are nearly three times more likely to develop the first symptoms of MS in the first six months after pregnancy than at other times (nationalmssociety.org; webmd). What does this tell you about the role of hormones in this autoimmune disease?

The findings in this question suggest that hormones that are present in high levels during pregnancy or high levels due to the pill are actually capable of preventing Multiple Sclerosis. The hormone that each is referring to is estrogen. The pill is an exogenous source of synthetic estrogen that prevents ovulation in woman. Estrogen levels naturally rise during pregnancy, and then fall in the proceeding months. It appears that when estrogen is low women are more likely to become afflicted with MS. Some studies have shown that estrogen mixed with white blood cells in a test tube actually make the WBC’s more active, producing immune substances called cytokines (www.abc.net.au). These cytokines act to keep MS away. Other studies have shown that estrogen leads to the survival and activation of autoreactive B cells (Peeva 2005). These findings are playing a significant role in furthering the research to treating MS. One article went so far as to say that the best treatment for Multiple Sclerosis is pregnancy (http://www.news-medical.net/).

In an evolutionary sense, why is it informative to study MS and its implications in mice?

Due to the orthologous nature of the developmental genes in mice and human genomes, we can study new therapies or treatments for Multiple Sclerosis in mice. Results from these studies enable researchers to interpret how effective a treatment can be. This strategy has been very successful in the past. Mouse Experimental Autoimmune Encephalomyelitis (EAE) is said to be equivalent to human Multiple Sclerosis. Thus, studying EAE in mice will allow us to learn more about MS in humans and allow us to get around some of the ethical issues surrounding experimental procedures in humans such (for example: is it ethical to try a new medication on humans? It would be more-so if it worked in a mouse that had a disease that parallels MS in humans). Many treatments for Multiple Sclerosis in humans originated from EAE research in mice, including glutamate receptor antagonists such as Riluzole (Gilgun-Sherki et al, 2003).

The paper (page 861) asserts that “[t]he rationale for autologous HSCT of MS is to regenerate an antigen-naïve immune system from the patient’s own HSCs.” Why, then, would assessing protein folding and misfolding be important to the process of HSCT of MS?

Researchers want an antigen-naïve immune system so they can start from a healthy base. The antigen-naïve immune system can defend against the effects of Multiple Sclerosis more effectively. Inflammation of the Central Nervous System decreases in this environment. This helps in studying the actual progress of the brain, more so the myelin sheath, damage because there is less tissue in the way.
Protein folding would be the next step of the process. By removing inflammation of the surrounding tissues the effects of protein folding/misfolding can be more closely scrutinized. HSCT provides this anti-inflammatory environment. Reasons or explanations for protein misfolding can be discovered and eventually remedied.

Why would this treatment regimen not be effective for patients who are suffering from the progressive, degenerative stages of MS?

As stated in the article, Hematopoietic stem cells can be acquired from euthanized animals of a different animal strain (allogeneic HSCT), from one of the same highly inbred strains (syngeneic HSCT), or from a syngeneic animal with the same stage of disease (pseudo-autologous HSCT). Any of these sources are capable of inducing remission and preventing relapse when performed during the early phases of Multiple Sclerosis. The article goes on to say, however, that hematopoietic stem cell transfer is ineffective therapy for late-stage or chronic progressive EAE. As stated in earlier questions, EAE is the mouse equivalent to MS in humans. Thus, the regimen would work better during the early stages of MS. The article even says that HSCT should be performed in the relapsing phase of MS while it is still an immune-mediated inflammatory process, rather than in it chronic progressive phase.

What would be the consequences of a regulatory gene mutation in a HSC?

As we learned in class, a mutation in any sort of gene will result in either an altered function, or a total loss of function. The book calls this change “re-purposing” or “co-opting” genes. The book goes on to say that “evolutionary change occurs when genes involved in regulatory cascades are expressed at new times or in new amounts (728). The cells being used for this new research are stem cells, meaning all subsequent cells stem from these original cells. Therefore, if the founding stem cells have a regulatory gene mutation every cell that is produced through mitosis will have the same mutation. If the mutation is on a regulatory gene then whatever that cell was originally designed for will not be accomplished. For instance, if the mutation is for the formation of a cell receptor that receptor may not develop correctly. Due to its incorrect formation, the cell would not function appropriately. In the case of this study a mutation to a regulatory gene of a hematopoietic stem cell would most likely result in failure to produce an antigen-naïve immune system. Failure to produce this type of system would render the treatment regimen suggested in this study inoperative. These cells would be basically useless in this treatment, and thus selected against all due to the mutation. The cascade of events holds true due to the one mutation in a regulatory gene.

Because there is both an environmental (page 863) and genetic component (traced to a gene cluster on Chromosome 6), is MS a qualitative or quantitative trait?

With the understanding that a quantitative trait is a “you either have it or you don’t” trait and a qualitative trait is trait that has varying degrees of severity, we believe MS to be a qualitative trait. We reached this conclusion for a couple of different reasons. First, because Multiple Sclerosis is a progressive disorder, meaning that the myelin sheaths can be more degenerated in some cases than others. Second, there are multiple types of Multiple Sclerosis that a person can be diagnosed with. They are: Benign Multiple Sclerosis, Relapsing-remitting Multiple Sclerosis, Secondary-progressive Multiple Sclerosis, Primary-progressive Multiple Sclerosis, and Malignant Multiple Sclerosis. Each of these types of the disease has different symptoms, as well as varying degrees of similar symptoms. For example, malignant multiple sclerosis is designated by a swift and relentless decline to disability which may result in death within the first few months, whereas a person afflicted with benign multiple sclerosis may show little or no effects of the disease for many years. With this in mind, it is hard to see how a person could get by with just saying, “I have multiple sclerosis,” with the intent of having the other person with whom they are talking to understand exactly what they are talking about.


Sources:

Freeman, Scott; Herron, Jon C. Evolutionary Analysis, Fourth Ed. Pearson Education, Inc.; Upper Saddle River, NJ, 2007. P. 728.

Gilgun-Sherki, Yossi; Melamed, Eldad; Offen, Daniel; Panet, Hana. Riluzole suppresses experimental autoimmune encephalomyelitis: implications for the treatment of multiple sclerosis. Laboratory of Neurosciences, Felsenstein Medical Research Center and Department of Neurology, 17 July 2003.

Peeva, Elena; Zouali, Moncef. Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes. Albert Einstein College of Medicine, Department of Medicine, Microbiology and Immunology, 5 July 2005.

http://www.abc.net.au/rn/talks/8.30/helthrpt/stories/s62050.htm

http://www.news-medical.net/?id=4375