Chronic low back pain (LBP) and osteoarthritic (OA) joint pain are the most common causes of chronic disabling pain and despite extensive investigation the pathophysiology of these conditions remains undefined and there is considerable controversy regarding their clinical management. Clearly current hypotheses for the progression of tissue injury to painful disability have not, short of removing the painful joint from the body, generated effective and safe treatments. Our recent studies in the mouse tibia fracture model of complex regional pain syndrome (CRPS) demonstrated that all CRPS patients expressed IgM autoantibodies with pronociceptive passive transfer effects after intraplantar injection into the injured hindlimb or intrathecal injection into muMT fracture mice lacking B cells and immunoglobulin, and these pronociceptive CRPS IgM effects were mediated by C5a complement signaling and inflammatory cytokine release. Tibia fracture in mice caused an increase of C5a receptor (C5aR) expressing macrophages in the fracture limb dermis and C5aR expressing microglia in the corresponding spinal cord segments, and these activated immune cells release pronociceptive inflammatory cytokines in response to C5a signaling. Moreover, after fracture in mice, exaggerated neuropeptide and sympathetic adrenergic signaling stimulated pronociceptive IgM antibody accumulation in the skin and spinal cord. These observations are potentially paradigm shifting. The central hypothesis guiding our work is that tissue trauma causes neural activation of the innate and adaptive systems of immunity, with localized neoantigen expression in the injured tissue and corresponding spinal cord triggering lymph organ germinal center reactions characterized by the formation germinal B cells, with subsequent pronociceptive immune complex deposition and complement activation supporting localized chronic nociceptive sensitization. The primary objective of this proposal is to identify specific pharmacologic targets for the successful treatment of LBP and OA. The specific aims are; 1) to identify the autoimmune responses mediating nociceptive sensitization in the lumbar disc puncture (DP) mouse model of chronic LBP and in the monosodium iodoacetate arthritis (MIA) mouse model of chronic OA knee pain, to determine the prevalence of pronociceptive antibodies in LBP and OA patients, and to identify adaptive immune responses in LBP patient spinal discs and OA patient joints, 2) to temporally map the formation of lymph node germinal centers, characterized by the induction of T follicular helper cells (Tfh), germinal center B cells, and the production of pronociceptive antibodies in the DP and MIA mouse models, and 3) to determine whether sensory neuropeptide and sympathetic adrenergic signaling constitute a unifying mechanism for the activation and maintenance of the immune response to tissue injury. These experiments potentially will establish a rigorous foundation for exploring mechanisms ...