Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system. Antibodies directed against the myelin, the insulating sheath that surrounds neurons in the central nervous system and nerve cells throughout the body, may play an important in the pathophysiology of MS. If myelin is damaged, neuronal transmission can be disrupted and communications between the brain and other parts of the body fail. Although much research has been focused on identifying the targets (auto-antigens) of these antibodies on myelin, the picture remains largely incomplete. Dr. Elledge and his team at Brigham and Women's Hospital have developed Phage Immunoprecipitation Sequencing (PhIP-Seq), a new, powerful technology that combines synthetic biology with recent advances in DNA sequencing, to determine the proteins that are being targeted by a patient's own antibodies. Phage (viral particles that infect bacteria) may be manipulated to display on their capsid proteins any single desired sequence. Dr. Elledge applied parallel DNA synthesis technology to encode the entire set of human proteins (the "proteome") on the surface of phage viral particles. An essential property of these particles is that they encapsulate the DNA encoding their "displayed" protein. This proteomic "library" is utilized to sift through and specifically identify proteins from a patient's serum that may interact and bind to form stable complexes. The complexes are then precipitated on protein magnetic beads and are subjected to next-generation sequencing, which allows the identification of the human DNA sequence within the phage. The identified DNA sequence corresponds to candidate proteins or possible auto-antigens of the MS inflammatory response.
Dr. Elledge received a Fiscal Year 2009 Multiple Sclerosis Research Program Metric Development and Validation Award to utilize PhIP-Seq analysis to determine the autoantibody profiles of MS patients versus age/sex-matched controls and identify novel MS-specific autoantigens. Identifying MS-specific auto-antigens will shed new light on disease etiology and elucidate new targets for tolerance induction therapy.
2011 Multiple Sclerosis Research Highlights