Pathogenesis of neuropsychiatric lupus

Many avenues of research have been pursued in an effort to clarify the pathogenic mechanisms underlying the development of diffuse neuropsychiatric systematic lupus erythematosus (NPSLE). Given their overall importance in the development of SLE, the identification of specific autoreactive antibodies with neural antigenic determinants has been aggressively sought. The leading candidate autoantibodies appear to be anti-NMDAR and anti-P antibodies, which have repeatedly (albeit somewhat inconsistently) been associated with various presentations of NPSLE both in human patients and mouse models. However, this inconsistency may represent an underappreciated facet of NPSLE pathogenesis, namely that the source of immune penetrance into the central nervous system (CNS) is unclear. Furthermore, the potential for a CNS-derived aberrant immunity (i.e., local production of neurotoxic antibodies and other pathogenic mediators) tends to be discounted. When factoring in cytokine and chemokine contributors to its overall pathogenesis, it is clear that NPSLE is a particularly complex manifestation of SLE. It is more than likely that several contributors may operate convergently in the development of NPSLE, the various combinations of which potentially contribute to the diverse presentations found in lupus patients.