Project Grant R21AI193282

DEEP PHENOTYPING OF DR15-RESTRICTED CD4+ T CELLS SPECIFIC FOR EPSTEIN-BARR VIRUS EPITOPES IN THE SPINAL FLUID AND BLOOD OF PEOPLE WITH MULTIPLE SCLEROSIS - PROJECT SUMMARY/ABSTRACT MULTIPLE SCLEROSIS (MS) IS A DEBILITATING AUTOIMMUNE DISEASE THAT AFFECTS MILLIONS OF PATIENTS WORLDWIDE. WHILE THE EXACT CAUSE REMAINS UNKNOWN, TWO MAJOR RISK FACTORS HAVE BEEN IDENTIFIED: INFECTION WITH EPSTEIN-BARR VIRUS (EBV) AND PRESENCE OF THE HLA-DR15 GENETIC VARIANT. THIS PROJECT AIMS TO UNDERSTAND HOW THESE RISK FACTORS INTERACT TO POTENTIALLY CAUSE MS. OUR RESEARCH FOCUSES ON SPECIFIC IMMUNE CELLS CALLED CD4 T CELLS THAT RECOGNIZE SPECIFIC EBV PROTEINS IN INDIVIDUALS WITH THE HLA-DR15 GENE VARIANT. WE HYPOTHESIZE THAT THESE CELLS BEHAVE DIFFERENTLY IN MS PATIENTS COMPARED TO INDIVIDUALS WITHOUT MS, POTENTIALLY DRIVING THE DISEASE PROCESS. WE PROPOSE THREE MAIN OBJECTIVES: 1. DETERMINE IF EBV-SPECIFIC CD4 T CELLS ARE MORE ABUNDANT IN THE CEREBROSPINAL FLUID THAN IN THE BLOOD OF MS PATIENTS COMPARED TO INDIVIDUALS WITHOUT MS. 2. COMPARE THE GENE EXPRESSION PATTERNS OF EBV-SPECIFIC CD4 T CELLS IN THE BLOOD AND CEREBROSPINAL FLUID BETWEEN MS PATIENTS AND INDIVIDUALS WITHOUT MS. 3. ASSESS TO WHAT EXTENT EBV-SPECIFIC CD4 T CELLS IN PATIENTS' BLOOD AND CEREBROSPINAL FLUID PREDICT CLINICAL BIOMARKERS OF DISEASE ACTIVITY. TO ACHIEVE THESE GOALS, WE WILL USE ADVANCED TECHNIQUES, INCLUDING CELL SORTING, GENE SEQUENCING, AND PROTEIN ANALYSIS, TO STUDY EBV-SPECIFIC CD4 T CELLS FROM BLOOD AND CEREBROSPINAL FLUID SAMPLES OF MS PATIENTS AND CONTROLS. THIS RESEARCH IS SIGNIFICANT BECAUSE IT COULD REVEAL HOW EBV INFECTION LEADS TO MS IN GENETICALLY SUSCEPTIBLE INDIVIDUALS. UNDERSTANDING THIS PROCESS COULD LEAD TO NEW WAYS TO DIAGNOSE, MONITOR, AND TREAT MS. IT MAY ALSO HELP IDENTIFY INDIVIDUALS AT HIGH RISK OF DEVELOPING MS BEFORE SYMPTOMS APPEAR, POTENTIALLY ALLOWING FOR EARLY INTERVENTION. THE PUBLIC HEALTH IMPACT OF THIS RESEARCH COULD BE SUBSTANTIAL. MS AFFECTS YOUNG ADULTS IN THEIR PRIME WORKING YEARS, CAUSING SIGNIFICANT DISABILITY AND ECONOMIC BURDEN. BY UNCOVERING THE MECHANISMS LINKING EBV TO MS, THIS PROJECT COULD CONTRIBUTE TO THE DEVELOPMENT OF MORE EFFECTIVE TREATMENTS OR EVEN PREVENTIVE STRATEGIES, ULTIMATELY IMPROVING THE LIVES OF MILLIONS AFFECTED BY THIS DISEASE.