Project Grant F30AI202590

METABOLIC REGULATION OF THE GERMINAL CENTER MICROENVIRONMENT - PROJECT SUMMARY AUTOIMMUNE DISEASES ARE DEBILITATING CONDITIONS THAT CAUSE SIGNIFICANT MORBIDITY AND MORTALITY, DISPROPORTIONATELY AFFECTING YOUNG TO MIDDLE-AGED WOMEN. THESE CONDITIONS ARE DRIVEN BY PATHOGENIC AUTOANTIBODIES PRODUCED THROUGH DYSREGULATED GERMINAL CENTER (GC) RESPONSES. UNDER PHYSIOLOGIC CONDITIONS, GCS PRODUCE HIGH AFFINITY ANTIBODIES THAT RECOGNIZE AND NEUTRALIZE PATHOGENS. MOST RESEARCH INVESTIGATING DYSREGULATED GC RESPONSES IN AUTOIMMUNITY HAS FOCUSED ON B AND T CELL CONTRIBUTIONS. HOWEVER, THE ROLE OF THE GC MICROENVIRONMENT IN REGULATING GC REACTIONS REMAINS LARGELY UNKNOWN. FOLLICULAR DENDRITIC CELLS (FDCS) ARE CRITICAL STROMAL CELLS THAT ORGANIZE GCS. FDCS HAVE TRADITIONALLY BEEN VIEWED AS STATIC CELLS THAT RETAIN ANTIGEN LONG-TERM AND FACILITATE SELECTION OF HIGH-AFFINITY B CELLS. HOWEVER, RECENT FINDINGS REVEAL DYNAMIC FEATURES OF FDCS, AS THEY EXPAND AND UNDERGO MORPHOLOGICAL CHANGES DURING GC REACTIONS. THE METABOLIC REPROGRAMMING ADAPTED FOR THEIR FUNCTIONAL CHANGES DURING HEALTHY AND DYSREGULATED GC RESPONSES IS UNKNOWN. THE HYPOTHESIS OF THIS PROJECT IS THAT FDCS UNDERGO DIFFERENTIAL DYNAMIC METABOLIC REPROGRAMMING DURING GC REACTIONS AND REGULATE THE AVAILABILITY OF KEY NUTRIENTS AND METABOLIC BYPRODUCTS IN THE GC MICROENVIRONMENT, THEREBY INFLUENCING GC B CELL EXPANSION, SELECTION, AND AFFINITY MATURATION. AIM 1 WILL ELUCIDATE FDC-INTRINSIC METABOLIC AND KINETIC REPROGRAMMING IN HEALTHY AND DYSREGULATED GERMINAL CENTER RESPONSES. AIM 2 WILL EXPLORE THE METABOLIC CROSSTALK BETWEEN B CELLS AND FDCS AND ITS IMPACT ON GC REACTIONS. THE PROPOSED RESEARCH WILL REVEAL NOVEL MECHANISMS BY WHICH FDCS SUPPORT GC FUNCTION IN HEALTH AND DISEASE AND WILL ESTABLISH FDCS AS ACTIVE METABOLIC GATEKEEPERS RATHER THAN PASSIVE STRUCTURAL SCAFFOLDS. THESE FINDINGS WILL INFORM TARGETED THERAPEUTIC STRATEGIES TO TREAT ANTIBODY-MEDIATED AUTOIMMUNITY BY MODULATING THE GC METABOLIC MICROENVIRONMENT. COMBINED WITH AN INTENSIVE TRAINING PLAN AND STRONG MENTORSHIP, THIS PROJECT WILL SERVE AS A CRITICAL TRAINING PLATFORM TO FOSTER THE DEVELOPMENT OF THE KNOWLEDGE, SKILLS, AND INDEPENDENCE REQUIRED FOR SUCCESS AS A PHYSICIAN-SCIENTIST IN RHEUMATOLOGY AND IMMUNOLOGY.