Autoantibodies and Interferon Signaling in Neuropsychiatric Lupus

Abstract

Neuropsychiatric lupus (NPSLE) encompasses a disease subset that impacts up to 80% of patients with lupus, presenting with anxiety, fatigue, and other sickness behaviors. Type 1 interferons (IFN) are cytokines linked to constitutional symptoms related to viral infections and have also been implicated in autoimmune diseases such as SLE. In an accelerated mouse model of lupus (Sle1,yaa), NPSLE-like behaviors develop along with elevated IFN signatures and increased circulating autoantibody titers. In the subcortical brain, Sle1,yaa mice express interferon-stimulated genes (ISGs) in a patch-like pattern, with greater density in the hippocampal-thalamic region. We integrated data from unbiased single-nucleus sequencing (sNucSeq) with spatial information achieved via Multiplex Error-Robust Fluorescence In-Situ Hybridization (MERFISH) and found reactive astrocytes with neurotoxic signatures enriched in ISG-high patches at the neurovascular interface. Cells within patches downregulate pathways supporting neurogenesis, and neurons responding to ISG demonstrate dysregulated neurotransmitter pathways. In the neuro-vasculature of Sle1,yaa mice post-perfusion, we observed a strong presence of immunoglobulin (Ig) deposits, which colocalized with complement proteins C1q and C3, indicating immune complex activating the complement cascade. Antibody presence begins prior to ISG signatures in the brain, and we postulated that IFN production in the CNS is driven by immune complex depositions in the neurovasculature. We transferred Sle1,yaa serum serially into wild-type mice starting at P1 and recapitulated CNS IgG deposits, ISG patches proximal to cerebral ventricles, and anxiety behavior. We found that the calvaria bone marrow and dura of Sle1,yaa mice had an expanded population of antibody-secreting cells (ASCs) which could provide a direct source of autoantibodies to the CNS. Adoptive transfer of total CD138+ ASCs from Sle1,yaa mice into P1 wild-type recipients saw a prominent induction of ISG patches in the CNS. This body of work explores behavioral NPSLE by bridging humoral immunity and cytokine release in the brain, providing insight into targetable pathways for neuropsychiatric diseases in autoimmunity and other diseases of type 1 interferon dysregulation.