Current concepts in neuropsychiatric lupus: Potential mechanisms and therapeutic avenues

Abstract

The central nervous system manifestations of systemic lupus erythematosus, known as neuropsychiatric lupus (NPSLE), are categorized by two overarching phenotypes. These include focal disease that is similar to other forms of cerebrovascular disease, and diffuse disease, which includes symptoms such as depression. anxiety. memory deficits and general cognitive decline. The mechanistic underpinnings of focal NPSLE are well characterized, including lupus related hypercoagulability, such as the anti-phospholipid syndrome. The pathogenesis of diffuse NPSLE, however, has proven more challenging to define.;An important issue when studying any immune pathology involving the central nervous system (CNS) relates to the immunopriveledge of the CNS. Owing in large part to the blood brain barrier (BBB), the CNS is not typically exposed to appreciable amounts of circulating leukocytes or antibodies. In NPSLE, there is a long held belief that BBB disruption is a component of disease pathogenesis, allowing penetration of systemically derived autoantibodies to neural antigens, as well as other soluble and cellular immune effectors. While this is indeed likely to be the case in focal disease, attempts to correlate serum autoantibodies with diffuse manifestations of NPSLE have yielded mixed results. Additionally. NPSLE may appear both before SLE diagnosis, and as an initial presentation. before there is sufficient time for systemic disease to impact CNS function.;We first hypothesized that NPSLE may represent a process that develops independently of systemic disease manifestations. Utilizing the MRL/ faslpr/lpr (MRL/lpr) mouse, our lab has previously found that depression occurs as early as five weeks of age, well before there are elevated autoantibody titers or manifestations of lupus nephritis. Here, we generated chimeric mice between MRL/+ (donor control) and MRL/Ipr (recipient) mice to evaluate the effects reversal of systemic immunity would have on NPSLE. We found that, despite near complete reversal of systemic autoimmunity, neuropsychiatric behavior persisted. Additionally, we found that cellular infiltration through the choroid plexus (CP) persisted. highlighting this region as an important focus of neuroinflammation in MRL/lpr mice.;The persistent expectation of BBB disruption in SLE is rooted in findings of an elevated albumin quotient in the CSF of patients, as well as the presence of serum autoantibodies with neural antigenic determinants that presumably must penetrate the CNS to exert their effects. In practice, there is little direct evidence of BBB disruption in SLE patients or model organisms. Here, we extensively evaluated barrier function by transmission electron microscopy, immunofluorescent and computational means. We were surprised to find the BBB intact in MRL/lpr mice. despite evidence of mitophagy in astrocytic end feet and endothelium of the neurovascular unit (NVU). Additionally, we found decreased vascular topological complexity in the cortex of these mice, with only minor leukocyte infiltrations across cortical brain vasculature. Finally, we observed, as others have previously, that the clear majority of leukocytes entering the CNS do so through the CP.;We finally went on to characterize the CP infiltrate that is characteristic in MRL/lpr mice, and identified the presence of a tertiary lymphoid structure (TLS). These structures, which occur in contexts of chronic inflammation, allow for rapid, localized responses to enriched pools of antigens. We found evidence of germinal center activity in the CP TLS of MRL/lpr mice, as well as complex transcriptional signature, including various chemokines and cytokines driving its formation. Importantly, the cytokines found locally within the CNS may generate pathology remotely, after penetration into the CSF.;Collectively, we found that CNS disease may develop absent major contribution from systemic immune effectors, suggesting that serum autoantibodies, while potentially contributory are not essential to NPSLE pathogenesis. We further present evidence that BBB disruption is not a component of disease development in MRL/lpr mice, though there are vascular anomalies that may result in a state of chronic ischemia. Finally, we characterized the infiltrate in the CP of MRL/lpr mice to be a TLS, with the potential to generate specific adaptive responses to neurological antigens.