External Validation of an Online Wound Infection and Wound Reoperation Risk Calculator After Metastatic Spinal Tumor Surgery.

STUDY DESIGN: This was a single-institutional retrospective cohort study. OBJECTIVE: Wound infections are common following spine metastasis surgery and can result in unplanned reoperations. A recent study published an online wound complication risk calculator but has not yet undergone external validation. Our aim was to evaluate the accuracy of this risk calculator in predicting 30-day wound infections and 30-day wound reoperations using our operative spine metastasis population. METHODS: An internal operative database was used to identify patients between 2012 and 2022. The primary outcomes were 1) any surgical site infection and 2) wound-related revision surgery within 30 days following surgery. Patient details were manually collected from electronic medical records and entered into the calculator to determine predicted complication risk percentages. Predicted risks were compared to observed outcomes using receiver operator characteristic (ROC) curves with areas under the curve (AUC). RESULTS: A total of 153 patients were included. The observed 30-day postoperative wound infection incidence was 5% while the predicted wound infection incidence was 6%. In ROC analysis, good discrimination was found for the wound infection model (AUC = 0.737; P = 0.024). The observed wound reoperation rate was 5% and the predicted wound reoperation rate was 6%. ROC analysis demonstrated poor discrimination for wound reoperations (AUC = 0.559; P = 0.597). CONCLUSIONS: The online wound-related risk calculator was found to accurately predict wound infections but not wound reoperations within our metastatic spine surgery cohort. We suggest that the model may be clinically useful despite underlying population differences, but further work must be done to generate and validate accurate prediction tools.

Metal allergy and neurovascular stenting: A systematic review.

BACKGROUND: Intracranial stents and flow diverters contain significant amounts of metals, notably nickel, which can cause allergic reactions in a considerable portion of the population. These allergic responses may lead to complications like in-stent stenosis (ISS) and TIA/Stroke in patients receiving stents or flow diverters for intracranial aneurysms. METHODS: We conducted a systematic review of studies from inception until July 2023, which reported outcomes of patients with metal allergy undergoing neurovascular stenting. The skin patch test was used to group patients into those with positive, negative, or absent patch test results but with a known history of metal allergy. RESULTS: Our review included seven studies with a total of 39 patients. Among them, 87% had a history of metal allergy before treatment. Most aneurysms (89%) were in the anterior circulation and the rest (11%) were in the posterior circulation. Skin patch tests were performed in 59% of patients, with 24% showing positive results and 33% negative. Incidental ISS was observed in 18% of patients, and the rate of TIA/Stroke was reported in 21%. The pooled rates of ISS and TIA/Stroke were higher in the first group (43% and 38%) compared to the second (18% and 9%) and third groups (15% and 15%), but these differences were not statistically significant. CONCLUSIONS: The current neurosurgical literature does not provide a conclusive association between metal allergy and increased complications among patients undergoing neurovascular stenting. Further studies are necessary to gain a more comprehensive understanding of this topic.

The role of venous anatomy in guiding treatment approach for dural arteriovenous fistulas of the craniocervical junction; case series & systematic review.

BACKGROUND: Dural arteriovenous fistulas (DAVF) of the craniocervical junction (CCF) are an uncommon entity with the following venous drainage pattern: inferior, superior and mixed. Patients may present with subarachnoid hemorrhage, myelopathy or brainstem dysfunction. CCJ DAVF can be treated with microsurgery or with transarterial and transvenous embolization, depending on the venous drainage pattern. We present our institutional experience of treating CCJ DAVFs along with a systematic review of the literature. METHODS: Six patients with CCJ DAVF were treated at our institution over five years. Data was collected using electronic medical record review. Systematic review was performed on CCJ DAVF using the PubMed database from 1990 to 2021. We characterized venous drainage patterns, treatment choices, and outcomes to create a classification system. RESULTS: 50 case reports, consisting of 115 patients, were included in our review. 61 (53.0 %) patients had inferior drainage while 32 (27.8 %) patients had superior drainage and 22 (19.2 %) patients had mixed venous drainage. Patients with inferior drainage had the fistulous connection at the foramen magnum while patients with superior drainage had a fistulous connection at C1-C2 (p value = 0.026). Patients with inferior drainage were more likely to present with myelopathy while patients with superior drainage presented with hemorrhage (p value = 0.000). CONCLUSIONS: Classifying the venous drainage pattern is essential in making treatment decision. Transvenous embolization works best with large superior venous drainage. If endovascular treatment is not an option, then surgical clipping can achieve successful cure. Transarterial embolization is a reasonable option in cases with a large arterial feeder.

Aptamer-Based Screen of Neuropsychiatric Lupus Cerebrospinal Fluid Reveals Potential Biomarkers That Overlap With the Choroid Plexus Transcriptome.

OBJECTIVE: As no gold-standard diagnostic test exists for neuropsychiatric systemic lupus erythematosus (NPSLE), we undertook this study to execute a broad screen of NPSLE cerebrospinal fluid (CSF) using an aptamer-based platform. METHODS: CSF was obtained from NPSLE patients and subjected to proteomic assay using the aptamer-based screen. Potential biomarkers were identified and validated in independent NPSLE cohorts in comparison to other neurologic diseases. RESULTS: Forty proteins out of the 1,129 screened were found to be elevated in NPSLE CSF. Based on enzyme-linked immunosorbent assay validation, CSF levels of angiostatin, α2-macroglobulin, DAN, fibronectin, hepatocellular carcinoma clone 1, IgM, lipocalin 2, macrophage colony-stimulating factor (M-CSF), and serine protease inhibitor G1 were significantly elevated in a predominantly White NPSLE cohort (n = 24), compared to patients with other neurologic diseases (n = 54), with CSF IgM (area under the curve [AUC] 0.95) and M-CSF (AUC 0.91) being the most discriminatory proteins. In a second Hong Kong-based NPSLE cohort, CSF IgM (AUC 0.78) and lipocalin 2 (AUC 0.85) were the most discriminatory proteins. Several CSF proteins exhibited high diagnostic specificity for NPSLE in both cohorts. Elevated CSF complement C3 was associated with an acute confusional state. Eleven molecules elevated in NPSLE CSF exhibited concordant elevation in the choroid plexus, suggesting shared origins. CONCLUSION: Lipocalin 2, M-CSF, IgM, and complement C3 emerge as promising CSF biomarkers of NPSLE with diagnostic potential.

CXCL13 Neutralization Attenuates Neuropsychiatric Manifestations in Lupus-Prone Mice.

Neuropsychiatric lupus (NPSLE), the nervous system presentation of systemic lupus erythematosus (SLE), remains challenging to treat due to its unclear pathogenesis and lack of available targeted therapies. A potential contributor to disease progression is brain tertiary lymphoid structures (TLS); these ectopic lymphoid follicles that can develop tissue-targeted antibodies have recently been described in the MRL/lpr lupus mouse strain, a classic model for studying NPSLE. The brains of MRL/lpr mice show a significant increase of CXCL13, an important chemokine in lymphoid follicle formation and retention that may also play a role in the disease progression of NPSLE. The aim of the present study was to inhibit CXCL13 and examine the effect of this intervention on lymphoid formation and the development of neurobehavioral manifestations in lupus mice. Female MRL/lpr mice were injected with an anti-CXCL13 antibody, an IgG1 isotype-matched antibody, or PBS either three times a week for 12 weeks intraperitoneally (IP) starting at 6-8 weeks of age, or continuously intracerebroventricularly (ICV) with an osmotic pump over a two-week period starting at 15 weeks of age. Cognitive dysfunction and depression-like behavior were assessed at the end of treatment. When treatment was delivered IP, anti-CXCL13 treated mice showed significant improvement in cognitive function when compared to control treated mice. Depression-like behavior was attenuated as well. Furthermore, mice that received anti-CXCL13 by the ICV route showed similar beneficial effects. However, the extent of lymphocyte infiltration into the brain and the general composition of the aggregates were not substantively changed by anti-CXCL13 irrespective of the mode of administration. Nevertheless, analysis of brain gene expression in anti-CXCL13 treated mice showed significant differences in key immunological and neuro-inflammatory pathways that most likely explained the improvement in the behavioral phenotype. Our results indicate that CXCL13 affects the behavioral manifestations in the MRL/lpr strain and is important to the pathogenesis of murine NPSLE, suggesting it as a potential therapeutic target.

Separation surgery for metastatic epidural spinal cord compression: comparison of a minimally invasive versus open approach.

OBJECTIVE: The aim of this study was to compare outcomes of separation surgery for metastatic epidural spinal cord compression (MESCC) in patients undergoing minimally invasive surgery (MIS) versus open surgery. METHODS: A retrospective study of patients undergoing MIS or standard open separation surgery for MESCC between 2009 and 2019 was performed. Both groups received circumferential decompression via laminectomy and a transpedicular approach for partial corpectomy to debulk ventral epidural disease, as well as instrumented stabilization. Outcomes were compared between the two groups. RESULTS: There were 17 patients in the MIS group and 24 in the open surgery group. The average age of the MIS group was significantly older than the open surgery group (65.5 vs 56.6 years, p < 0.05). The preoperative Karnofsky Performance Scale score of the open group was significantly lower than that of the MIS group, with averages of 63.0% versus 75.9%, respectively (p = 0.02). This was also evidenced by the higher proportion of emergency procedures performed in the open group (9 of 24 patients vs 0 of 17 patients, p = 0.004). The average Spine Instability Neoplastic Score, number of levels fused, and operative parameters, including length of stay, were similar. The average estimated blood loss difference for the open surgery versus the MIS group (783 mL vs 430 mL, p < 0.05) was significant, although the average amount of packed red blood cells transfused was not significantly different (325 mL vs 216 mL, p = 0.39). Time until start of radiation therapy was slightly less in the MIS than the open surgery group (32.8 ± 15.6 days vs 43.1 ± 20.3 days, p = 0.069). Among patients who underwent open surgery with long-term follow-up, 20% were found to have local recurrence compared with 12.5% of patients treated with the MIS technique. No patients in either group developed hardware failure requiring revision surgery. CONCLUSIONS: MIS for MESCC is a safe and effective approach for decompression and stabilization compared with standard open separation surgery, and it significantly reduced blood loss during surgery. Although there was a trend toward a faster time to starting radiation treatment in the MIS group, both groups received similar postoperative radiotherapy doses, with similar rates of local recurrence and hardware failure. An increased ability to perform MIS in emergency settings as well as larger, prospective studies are needed to determine the potential benefits of MIS over standard open separation surgery.

COVID-19 Infection Among Healthcare Workers: Serological Findings Supporting Routine Testing.

A growing body of evidence demonstrates that asymptomatic and pre-symptomatic transmission of SARS-CoV-2 is a major contributor to the COVID-19 pandemic. Frontline healthcare workers in COVID-19 hotspots have faced numerous challenges, including shortages of personal protective equipment (PPE) and difficulties acquiring clinical testing. The magnitude of the exposure of healthcare workers and the potential for asymptomatic transmission makes it critical to understand the incidence of infection in this population. To determine the prevalence of asymptomatic SARS-CoV-2 infection amongst healthcare workers, we studied frontline staff working in the Montefiore Health System in New York City. All participants were asymptomatic at the time of testing and were tested by RT-qPCR and for anti-SARS-CoV-2 antibodies. The medical, occupational, and COVID-19 exposure histories of participants were recorded via questionnaires. Of the 98 asymptomatic healthcare workers tested, 19 (19.4%) tested positive by RT-qPCR and/or ELISA. Within this group, four (4.1%) were RT-qPCR positive, and four (4.1%) were PCR and IgG positive. Notably, an additional 11 (11.2%) individuals were IgG positive without a positive PCR. Two PCR positive individuals subsequently developed COVID-19 symptoms, while all others remained asymptomatic at 2-week follow-up. These results indicate that there is considerable asymptomatic infection with SARS-CoV-2 within the healthcare workforce, despite current mitigation policies. Furthermore, presuming that asymptomatic staff are not carrying SARS-CoV-2 is inconsistent with our results, and this could result in amplified transmission within healthcare settings. Consequently, aggressive testing regiments, such as testing frontline healthcare workers on a regular, multi-modal basis, may be required to prevent further spread within the workforce and to patients.

Managing a Specialty Service During the COVID-19 Crisis: Lessons From a New York City Health System.

The COVID-19 pandemic has stretched health care resources to a point of crisis throughout the world. To answer the call for care, health care workers in a diverse range of specialties are being retasked to care for patients with COVID-19. Consequently, specialty services have had to adapt to decreased staff available for coverage coupled with a need to remain available for specialty-specific emergencies, which now require a dynamic definition. In this Invited Commentary, the authors describe their experiences and share lessons learned regarding triage of patients, staff safety, workforce management, and the psychological impact as they have adapted to a new reality in the Department of Neurosurgery at Montefiore Medical Center, a COVID-19 hot spot in New York City.

A Novel Microglia-Specific Transcriptional Signature Correlates With Behavioral Deficits in Neuropsychiatric Lupus.

Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) affect over one-half of SLE patients, yet underlying mechanisms remain largely unknown. We demonstrate that SLE-prone mice (CReCOM) develop NP-SLE, including behavioral deficits prior to systemic autoimmunity, reduced brain volumes, decreased vascular integrity, and brain-infiltrating leukocytes. NP-SLE microglia exhibit numerical expansion, increased synaptic uptake, and a more metabolically active phenotype. Microglia from multiple SLE-prone models express a "NP-SLE signature" unrelated to type I interferon. Rather, the signature is associated with lipid metabolism, scavenger receptor activity and downregulation of inflammatory and chemotaxis processes, suggesting a more regulatory, anti-inflammatory profile. NP-SLE microglia also express genes associated with disease-associated microglia (DAM), a subset of microglia thought to be instrumental in neurodegenerative diseases. Further, expression of "NP-SLE" and "DAM" signatures correlate with the severity of behavioral deficits in young SLE-prone mice prior to overt systemic disease. Our data are the first to demonstrate the predictive value of our newly identified microglia-specific "NP-SLE" and "DAM" signatures as a surrogate for NP-SLE clinical outcomes and suggests that microglia-intrinsic defects precede contributions from systemic SLE for neuropsychiatric manifestations.

Tertiary lymphoid structures in the choroid plexus in neuropsychiatric lupus.

The central nervous system manifestations of systemic lupus erythematosus (SLE) remain poorly understood. Given the well-defined role of autoantibodies in other lupus manifestations, extensive work has gone into the identification of neuropathic autoantibodies. However, attempts to translate these findings to patients with SLE have yielded mixed results. We used the MRL/MpJ-Faslpr/lpr mouse, a well-established, spontaneous model of SLE, to establish the immune effectors responsible for brain disease. Transcriptomic analysis of the MRL/MpJ-Faslpr/lpr choroid plexus revealed an expression signature driving tertiary lymphoid structure formation, including chemokines related to stromal reorganization and lymphocyte compartmentalization. Additionally, transcriptional profiles indicated various stages of lymphocyte activation and germinal center formation. The extensive choroid plexus infiltrate present in MRL/MpJ-Faslpr/lpr mice with overt neurobehavioral deficits included locally proliferating B and T cells, intercellular interactions between lymphocytes and antigen-presenting cells, as well as evidence for in situ somatic hypermutation and class switch recombination. Furthermore, the choroid plexus was a site for trafficking lymphocytes into the brain. Finally, histological evaluation in human lupus patients with neuropsychiatric manifestations revealed increased leukocyte migration through the choroid plexus. These studies identify a potential new pathway underlying neuropsychiatric lupus and support tertiary lymphoid structure formation in the choroid plexus as a novel mechanism of brain-immune interfacing.

Neuropsychiatric lupus: new mechanistic insights and future treatment directions.

Patients with systemic lupus erythematosus (SLE) frequently show symptoms of central nervous system (CNS) involvement, termed neuropsychiatric SLE (NPSLE). The CNS manifestations of SLE are diverse and have a broad spectrum of severity and prognostic implications. Patients with NPSLE typically present with nonspecific symptoms, such as headache and cognitive impairment, but might also experience devastating features, such as memory loss, seizures and stroke. Some features of NPSLE, in particular those related to coagulopathy, have been characterized and an evidence-based treatment algorithm is available. The cognitive and affective manifestations of NPSLE, however, remain poorly understood. Various immune effectors have been evaluated as contributors to its pathogenesis, including brain-reactive autoantibodies, cytokines and cell-mediated inflammation. Additional brain-intrinsic elements (such as resident microglia, the blood-brain barrier and other neurovascular interfaces) are important facilitators of NPSLE. As yet, however, no unifying model has been found to underlie the pathogenesis of NPSLE, suggesting that this disease has multiple contributors and perhaps several distinct aetiologies. This heterogeneity presents a challenge for clinicians who have traditionally relied on empirical judgement in choosing treatment modalities for patients with NPSLE. Improved understanding of this manifestation of SLE might yield further options for managing this disease.

Neuropsychiatric Systemic Lupus Erythematosus Is Dependent on Sphingosine-1-Phosphate Signaling.

About 40% of patients with systemic lupus erythematosus experience diffuse neuropsychiatric manifestations, including impaired cognition and depression. Although the pathogenesis of diffuse neuropsychiatric SLE (NPSLE) is not fully understood, loss of brain barrier integrity, autoreactive antibodies, and pro-inflammatory cytokines are major contributors to disease development. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, prevents lymphocyte egress from lymphoid organs through functional antagonism of S1P receptors. In addition to reducing the circulation of autoreactive lymphocytes, fingolimod has direct neuroprotective effects such as preserving brain barrier integrity and decreasing pro-inflammatory cytokine secretion by astrocytes and microglia. Given these effects, we hypothesized that fingolimod would attenuate neurobehavioral deficits in MRL-lpr/lpr (MRL/lpr) mice, a validated neuropsychiatric lupus model. Fingolimod treatment was initiated after the onset of disease, and mice were assessed for alterations in cognitive function and emotionality. We found that fingolimod significantly attenuated spatial memory deficits and depression-like behavior in MRL/lpr mice. Immunofluorescent staining demonstrated a dramatic lessening of brain T cell and macrophage infiltration, and a significant reduction in cortical leakage of serum albumin, in fingolimod treated mice. Astrocytes and endothelial cells from treated mice exhibited reduced expression of inflammatory genes, while microglia showed differential regulation of key immune pathways. Notably, cytokine levels within the cortex and hippocampus were not appreciably decreased with fingolimod despite the improved neurobehavioral profile. Furthermore, despite a reduction in splenomegaly, lymphadenopathy, and circulating autoantibody titers, IgG deposition within the brain was unaffected by treatment. These findings suggest that fingolimod mediates attenuation of NPSLE through a mechanism that is not dependent on reduction of autoantibodies or cytokines, and highlight modulation of the S1P signaling pathway as a novel therapeutic target in lupus involving the central nervous system.

Mechanisms of neuropsychiatric lupus: The relative roles of the blood-cerebrospinal fluid barrier versus blood-brain barrier.

The pathogenesis of neuropsychiatric lupus (NPSLE) is believed to include the entry of circulating neuropathic antibodies to the brain via a pathologically permeable blood-brain barrier (BBB). Nevertheless, direct evidence of BBB pathology or mechanisms underlying BBB dysfunction is missing. Here, we examined BBB integrity in an established NPSLE mouse model (MRL/faslpr/lpr). Surprisingly, challenging the barrier with various exogenous tracers demonstrated insignificant changes in BBB permeability. Furthermore, electron microscopy showed no ultrastructure changes supporting hyper-permeability. However, we found that abnormal function of the blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus underlies brain exposure to neuropathic antibodies. Considerable intrathecal lymphocyte infiltration likely occurs through the BCSFB, accompanied by epithelial hyper-permeability to antibodies. Our results challenge the commonly held view of BBB disruption in NPSLE, supporting a shift in focus to BCSFB dysfunction as a causative factor in the disease.

A Distinct T Follicular Helper Cell Subset Infiltrates the Brain in Murine Neuropsychiatric Lupus.

Neuropsychiatric symptoms in systemic lupus erythematosus (SLE) are not uncommon, yet the mechanisms underlying disease initiation and progression in the brain are incompletely understood. Although the role of T cells in other lupus target organs such as the kidney is well defined, which T cells contribute to the pathogenesis of neuropsychiatric SLE is not known. The present study was aimed at characterizing the CD4 T cell populations that are present in the choroid plexus (CP) of MRL/MpJ-faslpr mice, the primary site of brain infiltration in this classic lupus mouse model which exhibits a prominent neurobehavioral phenotype. T cells infiltrating the CP of MRL/MpJ-faslpr mice were characterized and subset identification was done by multiparameter flow cytometry. We found that the infiltrating CD4 T cells are activated and have an effector phenotype. Importantly, CD4 T cells have a T follicular helper cell (TFH) like phenotype, as evidenced by their surface markers and signature cytokine, IL-21. In addition, CD4 TFH cells also secrete significant levels of IFN-γ and express Bcl-6, thereby conforming to a potentially pathogenic T helper population that can drive the disease progression. Interestingly, the regulatory axis comprising CD4 T regulatory cells is diminished. These results suggest that accumulation of CD4 TFH in the brain of MRL/MpJ-faslpr mice may contribute to the neuropsychiatric manifestations of SLE, and point to this T cell subset as a possible novel therapeutic candidate.

Highly selective inhibition of Bruton's tyrosine kinase attenuates skin and brain disease in murine lupus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects different end organs, including skin and brain. We and others have previously shown the importance of macrophages in the pathogenesis of cutaneous and neuropsychiatric lupus. Additionally, autoantibodies produced by autoreactive B cells are thought to play a role in both the skin and central nervous system pathologies associated with SLE. METHODS: We used a novel inhibitor of Bruton's tyrosine kinase (BTK), BI-BTK-1, to target both macrophage and B cell function in the MRL-lpr/lpr murine model of SLE, and examined the effect of treatment on skin and brain disease. RESULTS: We found that treatment with BI-BTK-1 significantly attenuated the lupus associated cutaneous and neuropsychiatric disease phenotypes in MRL/lpr mice. Specifically, BI-BTK-1 treated mice had fewer macroscopic and microscopic skin lesions, reduced cutaneous cellular infiltration, and diminished inflammatory cytokine expression compared to control mice. BTK inhibition also significantly improved cognitive function, and decreased accumulation of T cells, B cells, and macrophages within the central nervous system, specifically the choroid plexus. CONCLUSIONS: Directed therapies may improve the response rate in lupus-driven target organ involvement, and decrease the dangerous side effects associated with global immunosuppression. Overall, our results suggest that inhibition of BTK may be a promising therapeutic option for cutaneous and neuropsychiatric disease associated with SLE.

The blood brain barrier and neuropsychiatric lupus: new perspectives in light of advances in understanding the neuroimmune interface.

Experts have previously postulated a linkage between lupus associated vascular pathology and abnormal brain barriers in the immunopathogenesis of neuropsychiatric lupus. Nevertheless, there are some discrepancies between the experimental evidence, or its interpretation, and the working hypotheses prevalent in this field; specifically, that a primary contributor to neuropsychiatric disease in lupus is permeabilization of the blood brain barrier. In this commonly held view, any contribution of the other known brain barriers, including the blood-cerebrospinal fluid and meningeal barriers, is mostly excluded from the discussion. In this review we will shed light on some of the blood brain barrier hypotheses and try to trace their roots. In addition, we will suggest new research directions to allow for confirmation of alternative interpretations of the experimental evidence linking the pathology of intra-cerebral vasculature to the pathogenesis of neuropsychiatric lupus.

The role of B cells and autoantibodies in neuropsychiatric lupus.

The central nervous system manifestations of SLE (neuropsychiatric lupus, NPSLE) occur frequently, though are often difficult to diagnose and treat. Symptoms of NPSLE can be quite diverse, including chronic cognitive and emotional manifestations, as well as acute presentations, such as stroke and seizures. Although the pathogenesis of NPSLE has yet to be well characterized, B-cell mediated damage is believed to be an important contributor. B-cells and autoantibodies may traverse the blood brain barrier promoting an inflammatory environment consisting of glia activation, neurodegeneration, and consequent averse behavioral outcomes. This review will evaluate the various suggested roles of B-cells and autoantibodies in NPSLE, as well as therapeutic modalities targeting these pathogenic mediators.

B cell and/or autoantibody deficiency do not prevent neuropsychiatric disease in murine systemic lupus erythematosus.

BACKGROUND: Neuropsychiatric lupus (NPSLE) can be one of the earliest clinical manifestations in human lupus. However, its mechanisms are not fully understood. In lupus, a compromised blood-brain barrier may allow for the passage of circulating autoantibodies into the brain, where they can induce neuropsychiatric abnormalities including depression-like behavior and cognitive abnormalities. The purpose of this study was to determine the role of B cells and/or autoantibodies in the pathogenesis of murine NPSLE. METHODS: We evaluated neuropsychiatric manifestations, brain pathology, and cytokine expression in constitutively (JhD/MRL/lpr) and conditionally (hCD20-DTA/MRL/lpr, inducible by tamoxifen) B cell-depleted mice as compared to MRL/lpr lupus mice. RESULTS: We found that autoantibody levels were negligible (JhD/MRL/lpr) or significantly reduced (hCD20-DTA/MRL/lpr) in the serum and cerebrospinal fluid, respectively. Nevertheless, both JhD/MRL/lpr and hCD20-DTA/MRL/lpr mice showed profound depression-like behavior, which was no different from MRL/lpr mice. Cognitive deficits were also observed in both JhD/MRL/lpr and hCD20-DTA/MRL/lpr mice, similar to those exhibited by MRL/lpr mice. Furthermore, although some differences were dependent on the timing of depletion, central features of NPSLE in the MRL/lpr strain including increased blood-brain barrier permeability, brain cell apoptosis, and upregulated cytokine expression persisted in B cell-deficient and B cell-depleted mice. CONCLUSIONS: Our study surprisingly found that B cells and/or autoantibodies are not required for key features of neuropsychiatric disease in murine NPSLE.

Intracerebroventricular administration of TNF-like weak inducer of apoptosis induces depression-like behavior and cognitive dysfunction in non-autoimmune mice.

Fn14, the sole known signaling receptor for the TNF family member TWEAK, is inducibly expressed in the central nervous system (CNS) in endothelial cells, astrocytes, microglia, and neurons. There is increasing recognition of the importance of the TWEAK/Fn14 pathway in autoimmune neurologic conditions, including experimental autoimmune encephalomyelitis and neuropsychiatric lupus. Previously, we had found that Fn14 knockout lupus-prone MRL/lpr mice display significantly attenuated neuropsychiatric manifestations. To investigate whether this improvement in disease is secondary to inhibition of TWEAK/Fn14 signaling within the CNS or the periphery, and determine whether TWEAK-mediated neuropsychiatric effects are strain dependent, we performed intracerebroventricular (ICV) injection of Fc-TWEAK or an isotype matched control protein to C57Bl6/J non-autoimmune mice. We found that Fc-TWEAK injected C57Bl6/J mice developed significant depression-like behavior and cognitive dysfunction. Inflammatory mediators associated with lupus brain disease, including CCL2, C3, and iNOS, were significantly elevated in the brains of Fc-TWEAK treated mice. Furthermore, Fc-TWEAK directly increased blood brain barrier (BBB) permeability, as demonstrated by increased IgG deposition in the brain and reduced aquaporin-4 expression. Finally, Fc-TWEAK increased apoptotic cell death in the cortex and hippocampus. In conclusion, TWEAK can contribute to lupus-associated neurobehavioral deficits including depression and cognitive dysfunction by acting within the CNS to enhance production of inflammatory mediators, promote disruption of the BBB, and induce apoptosis in resident brain cells. Our study provides further support that the TWEAK/Fn14 signaling pathway may be a potential therapeutic target for inflammatory diseases involving the CNS.

Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice.

BACKGROUND: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease marked by both B and T cell hyperactivity which commonly affects the joints, skin, kidneys, and brain. Neuropsychiatric disease affects about 40 % of SLE patients, most frequently manifesting as depression, memory deficits, and general cognitive decline. One important and yet unresolved question is whether neuropsychiatric SLE (NPSLE) is a complication of systemic autoimmunity or whether it is primarily driven by brain-intrinsic factors. METHODS: To dissect the relative contributions of the central nervous system from those of the hematopoietic compartment, we generated bone marrow chimeras between healthy control (MRL/+) and lupus-prone MRL/Tnfrsf6 (lpr/lpr) mice (MRL/+ → MRL/lpr), as well as control chimeras. After bone marrow reconstitution, mice underwent extensive behavioral testing, analysis of brain tissue, and histological assessment. RESULTS: Despite transfer of healthy MRL/+ bone marrow and marked attenuation of systemic disease, we found that MRL/+ → MRL/lpr mice had a behavioral phenotype consisting of depressive-like behavior and visuospatial memory deficits, comparable to MRL/lpr → MRL/lpr control transplanted mice and the behavioral profile previously established in MRL/lpr mice. Moreover, MRL/+ → MRL/lpr chimeric mice displayed increased brain RANTES expression, neurodegeneration, and cellular infiltration in the choroid plexus, as well as blood brain barrier disruption, all in the absence of significant systemic autoimmunity. CONCLUSIONS: Chimeric MRL/+ → MRL/lpr mice displayed no attenuation of the behavioral phenotype found in MRL/lpr mice, despite normalized serum autoantibodies and conserved renal function. Therefore, neuropsychiatric disease in the MRL/lpr lupus-prone strain of mice can occur absent any major contributions from systemic autoimmunity.