Elucidating the biological mechanisms underlying the association between EBV and MS in African Americans - PROJECT SUMMARY: Despite progress in treatment, multiple sclerosis (MS) continues to be a chronic progressive disease with a high personal and societal impact, and its incidence has been increasing over the past few decades, particularly in women and in African Americans. The recent discovery that the Epstein-Barr virus (EBV) is the leading cause of MS has spurred interest in the immunology of EBV infection and on the cross- reactivity of anti-EBV antibodies with autoantigens as a potential pathogenic mechanism for MS (molecular mimicry), and has raised the expectation that MS could be prevented by an EBV vaccine. Most previous investigations of the molecular mimicry hypothesis, however, have been restricted to whites of European ancestry and their results cannot therefore be generalized to Blacks, who have experienced a marked increase in MS incidence over the past few decades, have more severe MS, and are infected with EBV and other viruses at younger ages than whites. We propose therefore to conduct a longitudinal study among African Americans, using blood samples collected years before the onset of MS to determine whether EBV-induced molecular mimicry is a likely cause of MS. The study will rely on the data and serum samples prospectively collected from over 10 million individuals in active duty in the U.S. military. During the past 20 years, in collaboration with military investigators, we have reviewed the medical records of all members of this population diagnosed with MS while on active duty, confirmed the MS diagnoses according to research criteria, and obtained pre-diagnostic serum samples (up to three per person) from all cases and matched controls. At this time, we have clinical data and pre-diagnostic serum samples from 395 black individuals who developed MS and 395 controls matched by race, sex, age, dates of blood collection, and branch of the military. For the proposed project, we will include 240 black men and 240 black women. The project will rely on a set of novel platforms to profile antibody responses. Selected sera will be assessed for antibodies against the entire human virome and human proteome using the Nucleic Acid Programmable Protein Array, GlialCAM peptides, and glycosylated EBV proteins, which carry the epitopes targeted in vaccine development. In addition to the role of molecular mimicry, we will also address the following questions: i) is it possible to leverage the humoral immune response to the human virome and proteome to identify those apparently healthy individuals who will later develop MS? and ii) to which extent the humoral immunity to cytomegalovirus and other human viruses affects the risk of MS? Answer to these questions would have transcending implications for MS prevention, because only about 1 in 400 EBV infected individuals will ever develop MS. If these individuals were identified before the disease onset, it may be possible to modify their immune response to EBV with a vaccine or antiviral in a manner that reduces their MS risk. The proposed project will contribute to bridge the widening gap that exists about what we know on the causes of MS among whites and Blacks, and will strengthen our ability to identify and treat MS in its earliest stages.
