Finding the Cause of MS

Overview

Our approach to discovering the cause of MS is based on the finding that over 90% of MS patients have antibodies (oligoclonal bands) in cerebrospinal fluid (CSF). These antibodies are not randomly present. They are produced within the brain and spinal cord, and are closely related to each other, suggesting that they have a common target (that is what oligoclonal means). These oligoclonal antibodies (OCBs) are important to study because in every condition in which OCBs are found, such as in measles, they are targeted toward the cause of the illness. Thus our assumption is that if we find out what these oligoclonal antibodies in MS are targeting, it will be the cause of MS or at the very least the key target protein (antigen). This assumption is also based on certain immunological dogma. When the immune system is “activated” and reacting to a specific target, the body produces select antibodies that are clones of each other to enable a highly specific and effective response. This phenomenon is called clonal expansion and a persistent clonal response is highly suggestive of purposeful targeted amplification of the immune system.

Strategy

We set out to first isolate clonally expanded and persistent B-cells from patients with MS, mass produce them in the lab to allow detailed experimentation without repeated spinal taps and determine their reactivity against all plausible targets. Jerry Lin and his research assistants have accomplished the following in the past 6 years: 1) Using FACS analysis have reliably isolated B-cells; 2) Using recombinant technology and sequencing have been able to determine which B-cells are clonally expanded and, if spinal tap is repeated at a later time in the same patient, detect clonally expanded B-cells that persist; 3) Have isolated, sequenced and cloned single antibody producing cells from selected MS patients and a disease control (patient with HTLV-1 myelopathy).

In September of 2011, while investigating a patient with early Primary Progressive MS (PPMS), Lin and associates made an unexpected discovery. They found that a single isolated B-cell clone derived from the patient’s CSF reacted with a protein X. Over the ensuing months, we established the identity of this protein and determined that it was derived from an environmental agent hitherto unassociated with MS or any other disease. Furthermore, we found protein X interacted with an intermediary agent and resulted in greatly activating the immune production of antibodies.

Over the past few months we have purified protein X and have established an assay for testing other patients with MS. Thus far we have found that approximately 75% of all MS patients tested have CSF reactivity to protein X. We are currently recruiting non-MS subjects as controls to determine whether or not these findings are specific for MS.

Implications for MS Patients

The identification of protein X and the environmental agent has been a critical breakthrough in discovering the initial trigger of the autoimmune response seen in MS. In the next year we should be able to verify and publish these findings revealing the identity of the environmental agent and protein X. Scientific acceptance of this investigation will have enormous implications for the future direction of MS research as it pertains to vaccination design (prevention) and treating both newly diagnosed cases of MS and those patients with established disease. We will be applying for a patent upon completion of our initial studies.