Saturday, December 14, 2013

Can a virus stabilize Multiple Sclerosis?

Multiple Sclerosis (MS) is a neurodegenerative disease in which the neurons in the central nervous system (CNS; brain and spinal cord) cannot communicate effectively. The root of the disease is the degradation of the sheath of fat that surrounds some CNS neurons (myelin) - thus disrupting the effectiveness with which the neurons can survive and signal to each other. This destruction of the neurons is largely thought to be a result of the body attacking itself (an autoimmune disease), and not originating from an outside bacteria or virus; this hypothesis is largely the result of mice models that show that injecting components of this myelin sheath into a mouse will make the mouse exhibit MS-like symptoms.
Ref: http://health.howstuffworks.com/diseases-conditions/musculoskeletal/multiple-sclerosis1.htm

Although it seems as if this disease's cause is well-known and can be modeled well in animals, effective therapies to MS have proven hard to develop - one reason for this is that MS is different in almost every patient as to when it is symptomatic or not. This variation is so great that MS is characterized into many types of the disease such as relapse-remitting MS (RRMS) which the patient experiences many symptoms for months and then relapses into a largely symptom free condition, only to repeat in the future. Further, secondary progressing MS (SPMS) is a type of the disease - when symptomatic - declines at a devastating rate. There are more types, such as some that do not relapse and a continual decline is observed. It has been hypothesized that the Epstein-Barr virus (EBV; commonly known to cause mononucleosis) has some influence on this stability of disease - although results have not been very conclusive. This variability in the disease, as you can assume, confounds scientists researching therapies and potential cures to this devastating disease.

In hopes of elucidating why this variability is so great in this disease and if EPV has a role in disease stability, Annunziata et al in Italy investigated the role of EPV-positive B cells in disease severity. By extracting B cells from patients with MS, they examined the spectrum of antibodies that were produced by the MS patients of varying disease type. Initially, they identified 7 monoclonal antibodies (mAbs) that were found to bind a specific epitope (105-120) in one of the components of myelin that surround the neurons, MBP (myelin-basic protein). They chose this epitope of MBP because these mAbs were detected in the more 'stable' MS patients - and hoped to find something unique in these patients' body responses to the disease. Further testing included myelin-reactive T cells from MS to be evaluated in environments of the mAbs. Interestingly enough, only 3 mAbs showed dose-dependent inhibitory effects to the T cells - which are thought to contribute to the damaging environment in MS.

With the researchers identifying 3 mAbs that could help mitigate the damaging autoimmune T cell response in MS, they looked to see what these mAbs can bind to - other than the MBP fatty sheath component. Similar to the T cell experiment they ran above, they submitted MS patients' monocytes to environments of mAb 1-3. They discovered that mAb 1 was effective in inhibiting proliferation of monocytes. Further immunoprecipitation testing protocols identified potential binding structures as TNF-alpha Receptor or Fc-gamma Receptor 1 (aka CD64). Computer programs were run to compare MBP's 105-120 domain to specific epitopes of the two receptors listed above, and they found that there is near sequence homology with the 220-228 CD64 peptide. (Unfortunately, the authors did not further pursue the TNF-alpha receptor affinity to mAB 1 - a missed opportunity I believe as although sequence homology was not evident, inhibition of this receptor could contribute to decreased damaging TNF-alpha cytokines in MS.)

The authors too the next step to investigate at what level and what type of Ab is this mAb 1 present in MS patients. They found that mAb is found in high concentrations in MS patients in the IgM form (not in the more common IgG form) and that increased levels of IgM mAb 1 were evident in more stable patients. Further testing showed, as expected, that damaging cytokines like IL-1beta and IL-12 were downregulated when monocytes were in a mAb 1-rich environment. Perhaps more significantly, the immunosuppressive cytokine IL-10 was heavily upregulated (by 413%!) in these environments. This suggests that this mAb 1 (hereafter anti-CD64) could mediate the stability seen in some MS patients when compared to others, and even suggest a possible means to therapy for this disease.

Overall, these results are very encouraging for the MS community as these researchers have not only better-characterized the environment in MS patients that contribute to disease stability, they also show that they can inhibit monocyte and T cells activity in culture. The latter finding is promising for a potential anti-CD64 MS therapy. Further research must be conducted to investigate the effect anti-CD64 has on microglia - the resident monocyte in the CNS - to better understand if anti-CD64 therapy would be effective. This paper also supports the theory that the EBV contributes to disease stability in MS, yet did not investigate any specific role the virus plays in cells of the MS patient other than indirect mAb results. In the future, look for researchers to more intently examine the differences in EBV infected B cells and those not infected, as this could illuminate how B cells contribute to disease progression in MS. Overall, exciting work coming out of Italy in regards to MS and hopefully the mechanisms surrounding inhibition of the Fc gamma receptor can elucidate how anti-CD64 can be used in future MS therapies.

     Annunziata P, Cioni C, Cantalupo L, Genova GD, Savellini GG, and Cusi G. Immunosuppressive monoclonal antibody to CD64 from patients with long-term stable Multiple Sclerosis. Journal of Neuroimmunology 256 (2013) 62-70.

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