B-Cell Maturation Antigen, A Proliferation-Inducing Ligand, and B-Cell Activating Factor Are Candidate Mediators of Spinal Cord Injury-Induced Autoimmunity

Abstract

Autoimmunity is thought to contribute to poor neurological outcomes after spinal cord injury (SCI). There are few mechanism-based therapies, however, designed to reduce tissue damage and neurotoxicity after SCI because the molecular and cellular bases for SCI-induced autoimmunity are not completely understood. Recent groundbreaking studies in rodents indicate that B cells are responsible for SCI-induced autoimmunity. This novel paradigm, if confirmed in humans, could aid in the design of neuroprotective immunotherapies. The aim of this study was to investigate the molecular signaling pathways and mechanisms by which autoimmunity is induced after SCI, with the goal of identifying potential targets in therapies designed to reduce tissue damage and inflammation in the chronic phase of SCI. To that end, we performed an exploratory microarray analysis of peripheral blood mononuclear cells to identify differentially expressed genes in chronic SCI. We identified a gene network associated with lymphoid tissue structure and development that was composed of 29 distinct molecules and five protein complexes, including two cytokines, a proliferation-inducing ligand (APRIL) and B-cell-activating factor (BAFF), and one receptor, B-cell maturation antigen (BMCA) involved in B cell development, proliferation, activation, and survival. Real-time polymerase chain reaction analysis from ribonucleic acid samples confirmed upregulation of these three genes in SCI. To our knowledge, this is the first report that peripheral blood mononuclear cells produce increased levels of BAFF and APRIL in chronic SCI. This finding provides evidence of systemic regulation of SCI-autoimmunity via APRIL and BAFF mediated activation of B cells through BMCA and points toward these molecules as potential targets of therapies designed to reduce neuroinflammation after SCI.

Fenbendazole improves pathological and functional recovery following traumatic spinal cord injury

“…This was originally described in mice, with supportive evidence of increased B cell activation and autoantibody production also evident in human SCI subjects (Hayes et al, 2002, Saltzman et al, 2013). Although normal IgG isolated from pooled human serum has been shown to attenuate neuroinflammation following SCI (Fehlings and Nguyen, 2010), IgG obtained following SCI activates intraspinal complement and cells bearing Fc receptors (Ankeny et al, 2009).…”

The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury

“…Together, these data provide a basis for a deeper understanding why recovery from SCI is improved and neuropathology is reduced in mice lacking B cells (Ankeny, et al, 2009). SCI also triggers autoimmune T and B cell responses in humans but the pathogenic significance of these responses remains uncertain (Kil et al, 1999; Saltzman et al, 2013). Autoimmunity after SCI is considered a dynamic process, which is likely to be a function of the extent of SCI-IDS (Meisel et al, 2005; Kopp et al, 2013) and consecutive infections (Enouz et al 2012) supported by clinical observations demonstrating elevated auto-antibody titers in patients with concomitant infections (Davis et al, 2007) (Fig.…”

Characterization of the Antibody Response after Cervical Spinal Cord Injury

“…7,8 Moreover, SCI patients exhibit increased expression of the B-cell activating factor of the tumor necrosis factor family, a proliferation-inducing ligand and B-cell maturation antigen in peripheral blood mononuclear cells, which are associated with autoantibody-mediated pathologies. 9 Despite the evidence for the existence of autoantibodies in spinal cord-injured patients, their role in recovery after SCI in humans is unknown. Of note, mice lacking B-cells were shown to have improved outcomes following mid-thoracic SCI, suggesting that autoantibodies are pathogenic.…”