Autoantibody-Mediated Synaptopathy: Redefining Neuropsychiatric SLE as a Disorder of Neuroimmune Synapse

Abstract

Neuropsychiatric systemic lupus erythematosus (NPSLE) constitutes a severe and often refractory dimension of SLE, manifesting as clinically heterogeneous syndromes—including cognitive impairment, psychosis, and mood disorders—that follow a relapsing–remitting course. Vascular and inflammatory mediator models were developed to explain focal NPSLE and global encephalopathy, respectively. They were never designed to account for the circuit specific, often reversible symptoms of diffuse NPSLE—and they should not be faulted for failing to do so. The fault lies in our continued reliance on them as exclusive frameworks. Converging evidence now positions pathogenic autoantibodies targeting neuronal surface antigens as direct effectors of synaptic dysfunction. This Review synthesizes recent advances to propose a unifying ‘synaptopathy’ model for diffuse NPSLE pathogenesis. We propose the following four-step pathogenic cascade: (i) autoantibody access to the CNS following blood–brain barrier (BBB) compromise; (ii) acute synaptic dysfunction via receptor binding; (iii) complement-dependent synaptic tagging, amplified by DAMPs such as HMGB1; and (iv) irreversible synaptic loss driven by microglial pruning. These four steps define distinct therapeutic windows: steps (i) and (ii) are potentially fully reversible, step (iii) marks the transition to structural tagging, and step (iv) represents fixed-circuit damage. We aligned these windows with stage-specific biomarker profiles and targeted interventions. We then mapped these cellular events onto specific neural circuit disruptions (hippocampal, prefrontal-limbic, and cortico-thalamo-cortical), directly linking molecular pathology to clinical phenotypes. We operationalize this framework into a precision medicine strategy: three CSF biomarker profiles distinguish reversible synaptic dysfunction from irreversible structural loss, and a stage-matched therapeutic algorithm—B-cell depletion for antibody-driven disease, complement inhibition for synaptic tagging, and neuromodulation for fixed circuit deficits—is aligned with the four-step cascade. This framework reframes diffuse NPSLE as a mechanistically tractable disorder of the neuroimmune synapse—a conceptual advance that opens new avenues for biomarker discovery and targeted intervention.