Project Grant R01AR087066

NEUROIMMUNE CONTRIBUTIONS TO LOW BACK PAIN - PROJECT SUMMARY/ABSTRACT: LOW BACK PAIN (LBP) IS EXTREMELY COMMON AND SUBSTANTIALLY DISABLING. THE POINT PREVALENCE OF LBP IS APPROXIMATELY 25%, ALTHOUGH FEMALE SEX AND ADVANCING AGE FURTHER INCREASE RISK. TREATMENTS OF MANY SORTS ARE AVAILABLE, BUT RESPONSES ARE OFTEN MODEST OR TRANSIENT. AN IMPORTANT BARRIER TO IDENTIFYING AND EFFECTIVE TREATMENTS FOR LBP IS OUR INCOMPLETE UNDERSTANDING OF CONTRIBUTORS TO ITS INTENSITY AND PERSISTENCE. OUR LONG-TERM GOAL IS, THEREFORE, TO IDENTIFY KEY MECHANISMS UNDERLYING LBP AND TO DEVELOP INNOVATIVE TREATMENTS. INJURY TO AND DEGENERATION OF INTERVERTEBRAL DISCS (IVDS) IS COMMONLY ASSOCIATED WITH LOW BACK PAIN, BUT THE MECHANISM LINKING IVD INJURY TO PAIN REMAINS ELUSIVE. RECENT FINDINGS IN A MOUSE MODEL OF LBP AND HUMAN PATIENTS DEMONSTRATE NEUROIMMUNE CONTRIBUTIONS. KEY OBSERVATIONS AFTER DISC INJURY INCLUDE REGIONAL LYMPH NODE GERMINAL CENTER RESPONSES, IGM (EARLY) AND IGG (LATER) DEPOSITION IN SPINAL CORD AS WELL AS IVD TISSUE, NEUROINFLAMMATION AND THE REPRODUCTION OF PAIN AFTER INTRATHECAL OR SYSTEMIC ADMINISTRATION OF IGM/IGG ISOLATED FROM IVD INJURED MICE AND PATIENTS. INTRIGUINGLY, DOGS WITH PAINFUL IVD DISEASE ALSO PRODUCE PRONOCICEPTIVE ANTIBODIES PROVIDING A TRANSLATIONALLY POWERFUL INTERMEDIATE SPECIES FOR THE STUDY OF LBP. PAIN MAY ARISE FROM THE BINDING OF FRACTION CRYSTALLIZABLE (FC) CONSTANT REGIONS OF THESE ANTIBODIES TO FC RECEPTORS (FCRS) EXPRESSED ON SENSORY NEURONS, GLIA, AND ADDITIONAL IMMUNE CELLS WITH SUBSEQUENT NEURONAL ACTIVATION AND GENERATION OF PAIN MEDIATORS. OUR MAIN OBJECTIVE IS TO DEFINE THE ROLES, REGULATION AND MECHANISMS OF ADAPTIVE IMMUNE CONTRIBUTIONS TO LOW BACK PAIN. OUR CENTRAL HYPOTHESIS IS THAT IVD INJURY CAUSES B CELL ACTIVATION, THE FORMATION OF AUTOANTIBODIES AND THE STIMULATION FCRS THAT SUPPORT NEUROINFLAMMATION, SUBACUTE AND CHRONIC PAIN, FUNCTIONAL LOSS AND NEUROPSYCHOLOGICAL SEQUELAE. NEUROIMMUNOLOGICAL MECHANISMS MAY REGULATE THE ACTIVATION OF B CELLS AFTER IVD INJURY AND MEDIATE RESPONSES TO THE RESULTING AUTOANTIBODIES. THREE INNOVATIVE AND COMPREHENSIVE AIMS WERE DESIGNED TO RIGOROUSLY ADDRESS OUR NOVEL HYPOTHESIS, 1) TO IDENTIFY KEY MODULATORS OF AUTOIMMUNOLOGICAL IVD-RELATED PAIN AND ADVERSE OUTCOMES INCLUDING AGE, SEX AND SPECIES. WE WILL EXAMINE THE AGE AND SEX DEPENDENCE OF IGM AND IGG MEDIATED CONTRIBUTIONS ALONG WITH NEUROINFLAMMATORY AND IMMUNOLOGICAL RESPONSES. STUDIES WILL BE EXTENDED TO CANINES AND HUMANS WITH IVD- RELATED BACK PAIN. 2) TO IDENTIFY THE SPECIFIC IMMUNOLOGICAL CELL TYPES AND MECHANISMS REGULATING PAIN-RELATED AUTOANTIBODY FORMATION AFTER IVD INJURY. OUR STUDIES WILL IDENTIFY THE PARTICIPATING B CELL SUBTYPES AND REGULATION BY THE CHOLINERGIC ANTI-INFLAMMATORY SYSTEM, PD-1 SIGNALING AND DOWNSTREAM JAK/STAT ACTIVATION. THE IVD INJURY-ASSOCIATED B CELL RECEPTOR REPERTOIRE AFTER IVD INJURY WILL BE ESTABLISHED. 3) TO DELINEATE THE ROLES OF FC RECEPTORS IN SUPPORTING AND RESOLVING PAIN, NEUROINFLAMMATORY CHANGES AND MEDIATOR PRODUCTION RESULTING FROM IVD INJURY. THE THIRD AIM WILL DEFINE THE ROLES OF INDIVIDUAL IGM/IGG FCRS AND PRECLINICALLY TEST CANDIDATE BIOLOGIC FCR TARGETED DRUGS USING MATERIALS FROM MICE, CANINES AND HUMANS WITH IVD INJURIES AND BACK PAIN.