13 Responses

  1. M. Ilic
    M. Ilic at | | Reply

    The inactivation of FAS in the role of autoimmunity, specifically generation of self-binding antibodies produced by B cells is a sound explanation. A mutation in a pathway that regulates apoptosis can be the cause of many diseases, not only autoimmune ones. As we have found through research, inactivation of regulators in cell cycle as well as apoptosis is also the cause for the proliferation of cancer cells and eventually, malignant tumor formation.
    The discovery of the role of mutations in pathways as identifiers of many diseases is a milestone but now the challenge lies upon finding a way to compensate for the mutation so that the individual can live unaffected.

  2. J.Wilson
    J.Wilson at | | Reply

    I have personal experience with this topic. At the age of 18 I was diagnosed with type 1 diabetes. Now while the exact cause of type 1 diabetes is not known, many researchers and scientist have associated it as an autoimmune disorder. In many of the young children and adults I believe it is because their immune systems have not fully developed, which possibly makes it easier for the deactivation of the FAS, that leads to autoimmunity. In my case, I came down with a very bad case of strep throat that lasted for a couple of weeks. After going to the hospital it was later found that my glucose levels were high and I was in fact diabetic. My body had fought the infection but in doing so also shut down my spleen. While the body is fighting off a viral infection, I am certain that the interaction between the viral pathogens, the B cells that leads to the mutation of the FAS. While looking at patient data, maybe it should be observed as to the conditions, age, previous illnesses, and family health history, as to provide certain clues.

    1. S M K
      S M K at | | Reply

      I also have personal experience with this topic. My mother was diagnosed with Multiple Sclerosis (MS) four years ago. Like type 1 diabetes, the exact cause of it is still not known, but many scientists believe it to also be caused my an immune-mediated disease. MS is caused when T cells target proteins in the CNS, which causes inflammation that is harmful to the myelin sheets. According to Cell death induced by the Fas/Fas ligand pathway and its role in pathology FAS also signals apoptosis in T cells. There have been a vast number of studies done that show that added stress can weaken the immune system, and many people who suffer from MS also suffer from depression and anxiety. So, my hypothesis is that stress and anxiety somehow mute FAS, causing an increase in rogue T cells that cause inflammation in the CNS that leads to the damage of the myelin sheets.

  3. M. Brydson
    M. Brydson at | | Reply

    If B cells were discovered to be “Rogue;” and plays a role in triggering autoimmune diseases, therefore T cells should also be considered a part of this logic. Similar to B cells receptors (BCR), T cells also express receptors on its cell surface known as TCRs (T-cell receptors). According to Lauren M. Sompayrac author of “How the Immune System Works,” states “Autoimmune disease result when the breakdown in the mechanism meant to preserve tolerance of self is severe enough to cause a pathological condition.”

    Sompayrac further goes on to state that they are conditions for which autoimmune diseases occur. Firstly, as a result of the polygyny of MHC molecules that are inherited by the individual. Secondly, the individual must produce T and B cells which have receptors that recognize self-antigens. Thirdly, there must be an environmental event that leads to the breakdown of the tolerance mechanism which are designed to eliminate self-reactive lymphocyte. Such an environmental factor would be in the case of Mr. Wilson who had strep throat prior to his diagnosis with diabetes.

    Despite the immature population of B cells undergo a series of phases of processing to select for cells that do not express “self-reactive or autoreactive” receptors autoimmune diseases can still result due to binding of antibodies to cell-surface receptors. Negative selection acts to rid the body of B cells and T cells that bind self-antigens. Since “Rogue B cells” are now a critical factor in autoimmune diseases, then the possibility of there being ‘Rogue T cells’ can not be ruled out.

    According to Paul Waring and Arno Müllbacher, authors of “Cell death induced by the Fas/Fas ligand pathway and its role in pathology,” state that the interaction between Fas by FasL lead to “activation-induced cell death (ACID). This induction serves two functions. There is an alteration in clonal T cell proliferation and the deactivation of peripheral T cells that escape screening through negative selection in the thymus. Not only is the mutation of Fas and FasL a likely possibility for immune dysfunction but maybe its “up-regulation” due to stimulation by antibodies.

    1. Anuj Patel
      Anuj Patel at | | Reply

      The concept of T cells triggering autoimmune diseases has already been established and is not something new to be looked into. Initially, autoimmunity used to be considered as T cell mediated. We are now shifting to now narrowly looking at it as T cell mediated but into the mechanisms of the B cell as this post is doing.

      Any alteration to the FasL on T cells would be moot if there is no binding site for the B cell since it lacks an Fas receptor as this post is presenting. We need to look into a) preventing the proliferation of the Fas lacking B cells or b) if proliferated, inactivating such B cells. Thankfully, we already have research looking into that as the linked paper will point too. By depleting B cells, we can “flush out” the autoimmune B cells. Another way is increases Act1, a molecule that regulates BAFF-R and CD-40 signaling in B cells. Non-deficient mice with Act1 were shown to prevent production of autoantibodies, essentially rendering an autoimmune Fas lacking B cell powerless.

  4. S.dayman
    S.dayman at | | Reply

    I have personal experience with this topic as well. I’ve suffered with severe eczema since I was just a few months old. Daily, topical steroid creams have helped but long-term steroid use is not ideal as it can cause atrophy of the skin.

    Are any clinical applications being investigated to eliminate rogue B cells? If antibodies could be produced to attack the mutated FAS receptor, perhaps these rogue B cells could be eliminated. There was one study done, Fas receptor-mediated apoptosis: a clinical application, which investigated the use of anti-FAS antibodies to induce apoptosis in cancer cells. Unfortunately the treatment was not successful as it caused severe liver damage.

    1. B P 9 4
      B P 9 4 at | | Reply

      I have severe eczema as well, so after reading about this finding, I read up on how it correlates with our atopic dermatitis (AD). There are recent findings that a human monoclonal antibody, dupilumab, inhibits the activity of the interleukins, IL-4 and IL-13, which are linked to AD (Beck 2014); these cytokines are secreted by the T-helper lympocytes, actors of the adaptive immune system. Although dupliumab is found to provide some relief, I wonder if a more effective treatment or even a cure could come about if future studies were done linking the FAS activity in the germinal centers of the lymph nodes and the secretion of these cytokines?

      Beck LA et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med 2014 Jul 10; 371:130. (http://dx.doi.org/10.1056/NEJMoa1314768) – See more at: http://www.jwatch.org/na35019/2014/07/09/il-4-and-il-13-biologic-inhibitor-atopic-dermatitis#sthash.NCpaUeEx.dpuf

    2. Eugene Lee
      Eugene Lee at | | Reply

      So would the antibodies be produced constantly so that Rogue B Cells that have the mutated FAS receptor be dealt with constantly? Because whatever mutation is already causing the abnormal amount of Rogue B Cells would still exist, so while the currently existing and active Rogue B Cells are removed, in a few weeks would the effects of more Rogue B Cells not continue on as the body just produces more? Of course this is still all new information so much more research has to be done, but I feel unless it taken care of in a more direct manner of stopping the production of the Rogue B Cells instead of just keeping them at bay. It would just be a temporary solution that would need constant treatment.

  5. M. Coole
    M. Coole at | | Reply

    The inhibition of Fas is a valid explanation for the triggering of autoimmune diseases, but there could be more factors involved in creating the rogue B cells and preventing apoptosis from occurring. There has been research about a decoy protein within the TNF family. DcR3 competes with Fas for the binding site, FasL. If Fas cannot bind, then apoptosis cannot occur, so the cells will not die. The failed binding can lead to various autoimmune diseases and cancers from being destroyed by the cytotoxic cells.

  6. A. Bhansali
    A. Bhansali at | | Reply

    This article provides a compelling and accurate view of the foundation of auto-immune diseases and more importantly, brings to light another very intriguing cause of harmful self-antigen binding antibodies. I believe that the FAS receptor being mutated into not functioning would cause a terrible problem in destruction of these “rogue B cells”, as many have already stated, but also that the understanding of these malfunctioning receptors allows scientists and researchers another avenue for treatment of auto-immune diseases as a whole. Although mutated FAS receptors are just one piece of the entire puzzle that is auto-immune disease, being able to positively correlate a study done in mice to the actual human species is a miracle in and of itself. It is my opinion that being able to track down new sources of an issue, regardless of how detrimental those sources may be, is a large step forward in the solution and finalization of that issue. Specifically, by allowing researchers another avenue for treatment and discovery of auto-immune disease sources via the evaluation of these harmful self antibodies and their producers, it is possible that a greater understanding of how the bodies “rogue B cells” interact with each other and, as another commenter noted, potentially “rogue T cells” interact with each other, that medicine may be able to treat a large slew of auto-immune diseases history has previously been unable to understand or deal with.

  7. D I
    D I at | | Reply

    Upon infection by a pathogen, the process of B lymphocytes maturation is initiated and only a few B cells that carry a receptor for that certain pathogen are selected to contribute a defense mechanism in the immune response, then these cells proliferate and differentiate to produce a large number of effector cells against that pathogen. In the case of autoimmune disorder, these premature groups of lymphocytes carry receptors for self-antigens are selected for and the body would start attacking healthy cells instead of the infected cells. Autoimmune disease has been investigated to understand the trigger of it to emerge, but only a few broad notions are concluded such as chemical irritants, genetics, or an infectious agent. So this article shed some light on FAS receptor being one of the triggers for autoimmune disease, but it did not clarify what have caused the FAS death receptor to be inactivated in the first place. So I came across this research article and it turns out that T lymphocytes are the cells that express the FAS ligand so that FAS receptor can bind to it and cause apoptosis to maintain the equilibrium of T cells production during immune response. When the FAS ligand/FAS receptor binding does not occur, the FAS receptor will not be activated, therefore T lymphocytes play a role in disrupting the activation pathway of FAS death receptor and ultimately causing the formation of rogue B cells.

  8. Hitoyou
    Hitoyou at | | Reply

    I would be interested to see if Omalizumab, a humanized antibody also known as Xolair, would be of any therapeutic use in the treatment of ALPS and Lupus. A study from 2012 showed that there was little correlation between the use of Omalizumab and the development of malignant cancers.

  9. Csom1
    Csom1 at | | Reply

    Within the body there is a constant balance of life and death. For lymphocytes, regulation is needed to ensure that the right cells are living and the malfunctioning cells are put to death. Apoptosis is the preferred method to dispose of cells that will bind to self-antigens and cause these autoimmune diseases. In the Journal of Clinical Investigation, the article “Death receptors couple to both cell proliferation and apoptosis” explains that death receptors such as the FAS receptor found on the surface of B-cells may play a role in its survivability. The mutation of these receptors may have actually allowed these “renegade” cells to grow as it has done for T cells, fibroblasts, hepatocytes and certain tumors according to the article mentioned before. A possible next step towards a solution might be to find a ligand for the mutated form of the FAS receptors in hopes that we can stimulate programmed cell death of these rogue cells.


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