Ectopic CD4+ T cells in choroid plexus mediate neuropsychiatric lupus symptoms in mice via interferon-γ induced microglia activation.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a disabling and potentially life-threatening complication of SLE. This study aims to investigate whether ectopic CD4+ T cells in the choroid plexus mediate NPSLE in mice. Intracerebroventricular (ICV) injection of anti-CD4 antibody effectively depleted CP-resident CD4+ T cells and alleviated NPSLE-like symptoms in MRL/lpr mice. Following ICV injection, the majority of isolated lupus CD4+ T cells from donor MRL/lpr mice predominantly stayed in the CP for at least 28 days in recipient C57BL/6 mice, while nearly all isolated CD4+ T cells from MRL/MpJ mice disappeared within 7 days. ICV injection of lupus CD4+ T cells resulted in NPSLE-like symptoms, including impaired behavioral performances, increased microglial activation, and abnormal microstructure changes. Flow cytometry analysis revealed that the majority of isolated lupus CD4+ T cells were positive for IFN-γ. Neutralizing intracerebral IFN-γ alleviated NPSLE-like symptoms in MRL/lpr mice. Moreover, ICV injection of anti-IFN-γ antibody or microglial depletion by PLX3397 benefited most NPSLE-like symptoms in lupus CD4+ T-treated mice, while ICV injection of IFN-γ mimicked most NPSLE-like symptoms. In conclusion, CP-resident lupus CD4+ T cells contribute to NPSLE-like symptoms in mice via Interferon-γ induced microglia activation. Depleting CP-resident lupus CD4+ T cells, interferon-γ, or activated microglia may be potential therapeutic targets for NPSLE.

Association of elevated serum soluble CD226 levels with the disease activity and flares of systemic lupus erythematosus.

CD226 is an activating receptor expressed on the cell surface of natural killer cells and T cells. Although CD226 polymorphism is known to be involved in systemic lupus erythematosus (SLE), the involvement of soluble CD226 (sCD226) in SLE is still unknown. In the present study, we measured serum sCD226 levels using an enzyme-linked immunosorbent assay in 58 SLE patients and 33 healthy controls (HCs) and evaluated their associations with SLE Disease Activity Index 2000 (SLEDAI-2K), clinical manifestations, laboratory data, and the cumulative probability of flare. Serum sCD226 levels showed no significant differences between SLE patients and HCs. However, sCD226 levels were significantly elevated in active SLE patients with a SLEDAI-2K score of ≥ 20 compared with HCs. In SLE patients, sCD226 levels were significantly correlated with SLEDAI-2K scores and anti-dsDNA antibody titers. Moreover, the cumulative probability of flare was markedly higher in patients with high sCD226 than in those with low sCD226. In patients with neuropsychiatric involvement, sCD226 levels were elevated and reflected neuropsychiatric disease activity. These findings indicate that serum sCD226 levels are associated with disease activity and flares of SLE. Thus, it may be a useful biomarker for SLE, and its monitoring allows for more precise SLE management.

Neuropathological spectrum in systemic lupus erythematosus: A single institute autopsy experience.

AIM: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by circulating autoantibodies and immune complexes involving virtually every organ of the body. However, with respect to central nervous system (CNS), the mechanism of injury is still debated as complement mediated or thrombo-ischemic in nature. We studied the spectrum of neuropathological changes in twelve autopsy cases of SLE and evaluated the role of immune-complexes and complement activation in contributing to the thrombo-ischemic injury and correlated these features with clinical profile. METHODS: Autopsy records of all cases of SLE over a period of 20 years (2000-2019) were reviewed. Clinical history including neuropsychiatric symptoms and detailed histopathological analysis was performed. Direct immunofluorescence for IgM, IgG, IgA, C1q, C3, C4d, Kappa, Lambda and immunohistochemistry for C5b-9 was performed on lesional areas in paraffin embedded brain sections. Control tissue from brain was taken from two patients who died of sudden cardiac event. RESULTS: Our cohort comprised of 12 cases with age range from 12 to 40 years and all were female patients. Microinfarction and vasculopathy seen in eight cases were the commonest findings. Four cases with microinfarcts had non-bacterial thrombotic endocarditis in heart. Microthrombi adjacent to microinfarcts were seen in 4 cases. Variable deposition of immunoglobulins (predominantly IgG) and complements (C1q, C3, C4d) was evident in cortical arterioles (2 cases) and small capillaries (1 case). Neurological symptoms were seen in four cases, of which, three had associated invasive fungal infection with secondary vasculitis. Active lupus vasculitis was identified in a single case. C5b-9 immunoexpression was not detected in any of the cases. CONCLUSIONS: Our study adds observational data to the existing literature that the predominant neuropathological features of SLE are related to thrombo-ischemic injury and small vasculopathic changes. Only in a minor subset (25%), it is mediated by immune-complexes and complements. Immune-complex deposition on immunofluorescence in cortical vessels (cerebral lupus vasculopathy) is a novel finding which has not been reported earlier.

Identification and stratification of systemic lupus erythematosus patients into two transcriptionally distinct clusters based on IFN-I signature.

OBJECTIVE: Despite the significant advancement in the understanding of the pathophysiology of systemic lupus erythematosus (SLE) variable clinical response to newer therapies remain a major concern, especially for patients with lupus nephritis and neuropsychiatric systemic lupus erythematosus (NPSLE). We performed this study with an objective to comprehensively characterize Indian SLE patients with renal and neuropsychiatric manifestation with respect to their gene signature, cytokine profile and immune cell phenotypes. METHODS: We characterized 68 Indian SLE subjects with diverse clinical profiles and disease activity and tried to identify differentially expressed genes and enriched pathways. To understand the temporal profile, same patients were followed at 6 and 12-months intervals. Additionally, auto-antibody profile, levels of various chemokines, cytokines and the proportion of different immune cells and their activation status were captured in these subjects. RESULTS: Multiple IFN-related pathways were enriched with significant increase in IFN-I gene signature in SLE patients as compared to normal healthy volunteers (NHV). We identified two transcriptionally distinct clusters within the same cohort of SLE patients with differential immune cell activation status, auto-antibody as well as plasma chemokines and cytokines profile. CONCLUSIONS: Identification of two distinct clusters of patients based on IFN-I signature provided new insights into the heterogeneity of underlying disease pathogenesis of Indian SLE cohort. Importantly, patient within those clusters retain their distinct expression dynamics of IFN-I signature over the time course of one year despite change in disease activity. This study will guide clinicians and researchers while designing future clinical trials on Indian SLE cohort.

Developmental process in diffuse psychological/neuropsychiatric manifestations of neuropsychiatric systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) involves excessive autoimmune reactions, with pathogenesis characterized by autoantibody production. Although the specific mechanism underlying the development of neuropsychiatric syndromes in SLE (NPSLE) is still unclear, recent studies indicate the involvement of autoimmune pathophysiology. We previously identified the presence of anti-N-methyl-d-aspartate receptor subunit GluN2 antibody (anti-GluN2) as a functional autoantibody which is able to impair neurons and is essential for the diagnosis of diffuse psychiatric/neuropsychological syndromes in NPSLE (dNPSLE). Other autoantibodies like anti-Sm antibodies and anti-glucose-regulated protein 78 antibodies are known to compromise blood brain barrier (BBB) integrity. We demonstrated that high mobility group box-1 protein (HMGB1) decorates synapses on neurons damaged by anti-neuron antibodies, including anti-GluN2, where it behaves as a linker to enhance C1q binding to synapses in a dNPSLE model mouse. This C1q binding via HMGB1 is a critical step for remodeling by activated microglia, which leads to reductions in neuronal complexity and long-term behavioral abnormalities. Suppression of activated microglia can significantly reduce central nervous system (CNS) dysfunction. In this review, we describe the critical steps in the development of dNPSLE in particular, including the phases of BBB breakdown, acute neuronal damage by autoantibodies and neuronal remodeling due to activated microglia.

Centrally Acting Angiotensin-Converting Enzyme Inhibitor Suppresses Type I Interferon Responses and Decreases Inflammation in the Periphery and the CNS in Lupus-Prone Mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage. Neuropsychiatric lupus (NPSLE) is one of the most common manifestations of human SLE, often causing depression. Interferon-α (IFNα) is a central mediator in disease pathogenesis. Administration of IFNα to patients with chronic viral infections or cancers causes depressive symptoms. Angiotensin-converting enzyme (ACE) is part of the kallikrein-kinin/renin-angiotensin (KKS/RAS) system that regulates many physiological processes, including inflammation, and brain functions. It is known that ACE degrades bradykinin (BK) into inactive peptides. We have previously shown in an in vitro model of mouse bone-marrow-derived dendritic cells (BMDC) and human peripheral blood mononuclear cells that captopril (a centrally acting ACE inhibitor-ACEi) suppressed Type I IFN responsive gene (IRG) expression. In this report, we used the MRL/lpr lupus-prone mouse model, an established model to study NPSLE, to determine the in vivo effects of captopril on Type I IFN and associated immune responses in the periphery and brain and effects on behavior. Administering captopril to MRL/lpr mice decreased expression of IRGs in brain, spleen and kidney, decreased circulating and tissue IFNα levels, decreased microglial activation (IBA-1 expression) and reduced depressive-like behavior. Serotonin levels that are decreased in depression were increased by captopril treatment. Captopril also reduced autoantibody levels in plasma and immune complex deposition in kidney and brain. Thus, ACEi's may have potential for therapeutic use for systemic and NPSLE.

Association of anti-NR2 and U1RNP antibodies with neurotoxic inflammatory mediators in cerebrospinal fluid from patients with neuropsychiatric systemic lupus erythematosus.

BACKGROUND: Autoantibodies (auto Abs) and inflammatory mediators (IMs) in cerebrospinal fluid (CSF) may be involved in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). It is suggested that anti-N-methyl D-aspartate receptor NR2 subunit (NR2) Ab can develop NP manifestation after blood-brain barrier (BBB) abruption. We also reported the association between NPSLE and CSF anti-U1RNP Ab. In the present study, combined effects of CSF anti-NR2 and anti-U1RNP Abs on IMs in patients with NPSLE were examined. METHODS: CSF samples were collected from 69 patients with NPSLE and 13 non-NPSLE controls. CSF anti-NR2 and anti-U1RNP Abs were determined using ELISA. Levels of IL-6, IL-8, and monokine induced by IFN-γ (MIG) in CSF were measured by quantitative multiplex cytokine analysis. RESULTS: CSF IL-6 levels were higher in CSF anti-NR2-positive than in CSF anti-NR2-negative patients (p = 0.003) and non-NPSLE controls (p = 0.015) and were positively correlated with anti-NR2 titer (r = 0.42). CSF IL-8 levels were higher in CSF anti-U1RNP-positive than in CSF anti-U1RNP-negative patients (p = 0.041). CSF MIG levels were more elevated in CSF anti-NR2-positive (p = 0.043) and anti-U1RNP-positive patients (p = 0.029) than in non-NPSLE controls. Additionally, in double positive (DP; both anti-NR2 and U1RNP Ab positive) group, CSF IL-6 and MIG levels were significantly higher than in the double negative (DN; both anti-NR2 and U1RNP Ab negative) group. However, combined effect of both Abs on IM elevation and clinical manifestation was not clear. CONCLUSIONS: CSF anti-NR2 and anti-U1RNP Abs have different effects on the elevation of CSF IM levels in patients with NPSLE. Additional effect of anti-U1RNP Abs on anti-NR2 Ab-mediated NP manifestation, however, was not recognized in our study.

Absence of Neuronal Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus.

This study aimed to characterise both neuronal autoantibodies and levels of interferon α, two proposed causative agents in neuropsychiatric systemic lupus erythematosus (NPSLE). Cerebrospinal fluid (CSF) and plasma from 35 patients with systemic lupus erythematosus (SLE; 15 with NPSLE) showed no antibodies against natively expressed N-methyl-D-aspartate receptors (NMDARs), or the surface of live hippocampal neurons. By comparison to controls (n = 104), patients with SLE had antibodies that bound to a peptide representing the extracellular domain of NMDARs (p < 0.0001), however, binding was retained against both rearranged peptides and no peptide (r = 0.85 and r = 0.79, respectively, p < 0.0001). In summary, neuronal-surface reactive antibodies were not detected in NPSLE. Further, while interferon α levels were higher in SLE (p < 0.0001), they lacked specificity for NPSLE. Our findings mandate a search for novel biomarkers in this condition. ANN NEUROL 2020;88:1244-1250.

The T Cell Receptor Repertoire in Neuropsychiatric Systemic Lupus Erythematosus.

Objective: In systemic lupus erythematosus (SLE), widespread T cell infiltration into target organs contributes to inflammation and organ damage. Autoreactive T cells become aberrantly activated in this disease due to dysfunctional T cell receptor signaling that lowers the activation threshold. Characterizing the T cell repertoire can provide further insight into the specific homing and proliferation of these T cells into lupus target organs. In the spontaneous lupus model, MRL/lpr, the TCR repertoire has not been fully elucidated, especially for T cells infiltrating the brain. Our aim was to investigate and compare the TCR repertoire between MRL/lpr mice and its congenic controls, MRL/MpJ, and within MRL/lpr tissues. Methods: Spleen, salivary gland, and brain choroid plexus were isolated from female MRL/lpr mice and MRL/MpJ mice. The TCRß CDR3 region was analyzed by multiplex PCRs and sequencing. Results: Significant differences were seen not only between the MRL/lpr and MRL/MpJ spleens, but also between MRL/lpr tissues. The TCR repertoire in MRL/lpr choroid plexus tissues had significantly increased clonality and sequence homology compared to MRL/lpr spleen and salivary gland. The consensus sequence, CASSQDWGGYEQYFF, was identified in the MRL/lpr choroid plexus repertoire. Conclusions: The TCR repertoire in lupus prone mice is not uniform between target organs, and suggests that T cells are specifically recruited into the choroid plexus of MRL/lpr mice. Further studies are needed to determine the antigen specificities for these infiltrating T cells in target organs of lupus mice, and their possible contribution to the pathogenesis of neuropsychiatric disease and other lupus manifestations.

HMGB1 in Systemic Lupus Erythematosus.

The high-mobility group box 1 (HMGB1) has been shown to exert proinflammatory effects on many cells of the innate immune system. Originally identified as a nuclear protein, HMGB1 has been found to play an important role in mediating inflammation when released from apoptotic or necrotic cells as a damage-associated molecular pattern (DAMP). Systemic lupus erythematosus (SLE) is a disease of non-resolving inflammation, characterized by the presence of autoantibodies and systemic inflammation involving multiple organ systems. SLE patients have impaired clearance of apoptotic debris, which releases HMGB1 and other DAMPs extracellularly. HMGB1 activity is implicated in multiple disease phenotypes in SLE, including lupus nephritis and neuropsychiatric lupus. Elucidating the various properties of HMGB1 in SLE provides a better understanding of the disease and opens up new opportunities for designing potential therapeutics.

Advanced neuroimaging in neuropsychiatric systemic lupus erythematosus.

PURPOSE OF REVIEW: Neuropsychiatric lupus (NPSLE) comprises a disparate collection of syndromes affecting the central and peripheral nervous systems. Progress in the attribution of neuropsychiatric syndromes to SLE-related mechanisms and development of targeted treatment strategies has been impeded by a lack of objective imaging biomarkers that reflect specific neuropsychiatric syndromes and/or pathologic mechanisms. The present review addresses recent publications of neuroimaging techniques in NPSLE. RECENT FINDINGS: Imaging studies grouping all NPSLE syndromes together are unable to differentiate between NPSLE and non-NPSLE. In contrast, diffusion tensor imaging, FDG-PET, resting, and functional MRI techniques in patients with stable non-NPSLE demonstrate abnormal network structural and functional connectivity and regional brain activity in multiple cortical areas involving the limbic system, hippocampus, frontal, parietal, and temporal lobes. Some of these changes associate with impaired cognitive performance or mood disturbance, autoantibodies or inflammatory proteins. Longitudinal data suggest progression over time. DCE-MRI demonstrates increased Blood-brain barrier permeability. SUMMARY: Study design issues related to patient selection (non-NPSLE vs. NPSLE syndromes, SLE disease activity, medications) are critical for biomarker development. Regional and network structural and functional changes identified with advanced brain imaging techniques in patients with non-NPSLE may be further developed as biomarkers for cognitive and mood disorders attributable to SLE-related mechanisms.

What are the latest clinical findings regarding the association of neurotoxic brain antibodies found in the cerebrospinal fluid in patients with autoimmune disorders?

PURPOSE OF REVIEW: Recently, experiments show that the autoantibodies with direct access to neurons following blood brain barrier (BBB) disruption destroy neurons and lead to remodeling in damaged neurons. These are critical steps in autoantibody-mediated central nervous system disorder called neuropsychiatric syndromes in systemic lupus erythematosus (NPSLE). The purpose of this review is to examine therapeutic opportunities to repress neuronal remodeling by microglia after acute neuronal injury by autoantibodies. RECENT FINDINGS: Recent studies have demonstrated that BBB disruption is a critical step for developing NPSLE, and serum anti-Sm antibodies have been significantly associated with BBB breakdown. In addition, it has been reported that antiglucose regulated protein-78 in patients with SLE also disrupt the BBB. Experiments with anti-N-methyl-D-aspartate antibodies show that HMGB1 and C1q were essential to activate microglia which, in turn, remodel damaged neurons in vivo. Interestingly treatment with angiotensin-converting enzyme inhibitor inactivated microglia and blunted neuronal remodeling as well as positively affected behavioral abnormalities. SUMMARY: BBB disruption, acute neuronal damage and neuronal remodeling by activated microglia are all critical steps for NPSLE development, and each step will afford novel therapeutic targets.

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.

Autoantibodies associated with neuropsychiatric systemic lupus erythematosus: the quest for symptom-specific biomarkers.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs, including the central nervous system. Neuropsychiatric SLE (NPSLE) is a severe and potentially fatal condition. Several factors including autoantibodies have been implicated in the pathogenesis of NPSLE. However, definitive biomarkers of NPSLE are yet to be identified owing to the complexity of this disease. This is a major barrier to accurate and timely diagnosis of NPSLE. Studies have identified several autoantibodies associated with NPSLE;some of these autoantibodies are well investigated and regarded as symptom-specific. In this review, we discuss recent advances in our understanding of the manifestations and pathogenesis of NPSLE. In addition, we describe representative symptom-specific autoantibodies that are considered to be closely associated with the pathogenesis of NPSLE.

Accelerated immune aging was correlated with lupus-associated brain fog in reproductive-age systemic lupus erythematosus patients.

AIMS: Cognitive impairment is common in systemic lupus erythematosus (SLE) patients with substantial adverse effects on function and quality of life. One hypothesis to understand the mechanisms of cognitive impairment in SLE is accelerated immunosenescence. The aim of this study is to observe the correlation between immunosenescence with cognitive impairment in patients with SLE. METHODS: Sixty-one female SLE patient were measured for CD4 and CD8 T cell-associated senescence markers, including percentage of end-stage differentiated T cells (CD4 and CD8 T cells expressing CD57+ or loss of CD28 expression), of naïve T cells (CD4+ CD45RA+ and CD8+ CD45RA+ ), memory T cells (CD4+ CD45RO+ and CD8+ CD45RO+ ), and antigen-experienced T cells (CD4+ KLRG1+ and CD8+ KLRG1+ ) which were measured using flow cytometry. One hallmark of immunosenescence called immune risk profile (IRP) was defined by an inverted ratio of CD4 and CD8. Cognitive functions were measured by Mini-Mental State Examination (MMSE) and Montréal Cognitive Assessment (MOCA) questionnaire. RESULTS: Thirty-six (59.1%) SLE patients who had IRP develop significantly lower attention and recall from both MMSE (P = .005 and P = .000) and MOCA (P = .017 and P = .000) examinations. Decreased visuospatial ability was also found in patients with IRP measured by MOCA (P = .046). There was a negative correlation between memory CD4+ CD45RO+ T cells with recall and visuospatial domain (R = -0.204, P = .039 and R = -0.250, P = .033; respectively), and negative correlation between CD8+ CD28- T cells with recall and attention domain (R = -0.249, P = .027 and R = -0.145, P = .048, respectively). CONCLUSION: Systemic lupus erythematosus patients develop an accelerated immunosenescence which contributes to cognitive dysfunction, especially in attention, recall, and visuospatial domains.

Immunological biomarkers in neuropsychiatric systemic lupus erythematosus: a comparative cross-sectional study from a tertiary care center in South India.

INTRODUCTION: The prevalence of various immunological biomarkers in neuropsychiatric systemic lupus erythematosus (NPSLE) differs among various patients with varied neuropsychiatric manifestations and different populations. We studied the prevalence of these biomarkers; especially the neuron specific autoantibodies in patients with systemic lupus erythematosus (SLE) and compared them among patients with and without neuropsychiatric involvement. METHODOLOGY: This is a comparative cross-sectional study conducted in a tertiary care hospital in South India. The prevalence of immunological biomarkers including complement levels, systemic and brain specific autoantibodies (anti-myelin antibody, anti-myelin oligodendrocyte glycoprotein and anti-myelin-associated glycoprotein antibody) were assessed and compared among those with and without NPSLE and with different NPSLE manifestations. RESULTS: A total of 522 SLE patients were enrolled in the study. The mean age of the study participants was 28.5 ± 8.8 years and 93.5% were women. Neuropsychiatric manifestations were seen in 167 (32%) patients. Seizure was the most common neuropsychiatric manifestation seen in 41.3%, followed by psychosis (18.6%), mood disorder (16.8%), stroke (10.8%), mononeuropathy (10.2%), headache (9.6%), acute confusional state (6.6%) and aseptic meningitis (5.4%). Patients with NPSLE had a higher SLE disease activity index score. Most of the autoantibodies, that is anticardiolipin antibody (aCL), anti-ß2 glycoprotein 1 antibody (ß2GP1), lupus anticoagulant (LA), anti-nucleosome, anti-ribosomal P, anti-Ro52, anti-Ro60 and anti-La, were seen in higher proportion in the NPSLE group, although the difference failed to reach statistical significance. On subgroup analysis, psychosis was significantly higher in patients with anti-ribosomal P positivity than without (11.8% versus 4.1%, p.0.007; odds ratio (OR) 3.1, confidence interval (CI) 1.4-6.8), while stroke had a higher proportion among those with positive b2GP1 IgG (6.3% versus 1.8%, p.0.03; OR 3.6, CI 1.2-11.0). A higher proportion of demyelination was seen among the LA positive than the negative (10.3% versus 0.2%, p.0.03; OR 5.39, CI 1.15-24.17) and anti-myelin oligodendrocyte glycoprotein in mood disorder (14.3% versus 3.4%, p = 0.03; OR 4.66, CI 1.13-19.13). CONCLUSION: No single biomarker correlated with NPSLE. Among different NPSLE manifestations, the prevalence of IgG ß2GP1 in stroke, LA in demyelination, anti-ribosomal P in psychosis and anti-myelin oligodendrocyte glycoprotein in mood disorder were higher. Further studies on the pathogenic mechanisms underlying NPSLE and its different manifestations may help us to identify better biomarkers.

Neuroprotective effect of microglia against impairments of auditory steady-state response induced by anti-P IgG from SLE patients in naïve mice.

OBJECTIVE: Autoantibodies against ribosomal P proteins (anti-P antibodies) are strongly associated with the neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE). The present study was designed to assess whether anti-P antibodies can induce abnormal brain electrical activities in mice and investigate the potential cytopathological mechanism. METHODS: Affinity-purified human anti-ribosomal P antibodies were injected intravenously into mice after blood-brain barrier (BBB) disruption. The auditory steady-state response (ASSR) was evaluated based on electroencephalography (EEG) signals in response to 40-Hz click-train stimuli, which were recorded from electrodes implanted in the skull of mice. Immunofluorescence staining was used to examine the morphology and density of neurons and glia in the hippocampus and cortex. The presence of apoptosis in the brain tissues was studied using the TUNEL assay. A PLX3397 diet was used to selectively eliminate microglia from the brains of mice. RESULTS: Circulating anti-P antibodies caused an enhancement of the ASSR and the activation of microglia through the disrupted BBB, while no obvious neural apoptosis was observed. In contrast, when microglia were depleted, anti-P antibodies induced a serious reduction in the ASSR and neural apoptosis. CONCLUSION: Our study indicates that anti-P antibodies can directly induce the dysfunction of auditory-evoked potentials in the brain and that microglia are involved in the protection of neural activity after the invasion of anti-P antibodies, which could have important implications for NPSLE.

Advances in the diagnosis, pathogenesis and treatment of neuropsychiatric systemic lupus erythematosus.

PURPOSE OF REVIEW: Diagnosing and treating neuropsychiatric systemic lupus erythematosus (NPSLE) remains challenging as the pathogenesis is still being debated. In this review, we discuss studies evaluating recent advances in diagnostic methods, pathogenic mediators and potential treatments. RECENT FINDINGS: Screening tools used for neurodegenerative diseases were found to be both sensitive and moderately specific for cognitive dysfunction in NPSLE. Neuroimaging can be used to distinguish systemic lupus erythematosus (SLE) patients from healthy controls, but further refinement is needed to differentiate between lupus patients with and without neuropsychiatric manifestations. Elevated levels of specific molecules in the cerebrospinal fluid and/or serum, as well as the presence of certain autoantibodies, have been identified as potential biomarkers in attempts to facilitate a more accurate and objective diagnosis. Among such autoantibodies, anti-NR2 and anti-ribosomal P autoantibodies also have a pathogenic role, although newer studies demonstrate that blood-brain barrier damage may not always be required as previously believed. These and other observations, together with new evidence for disease attenuation after microglial modulation, suggest direct involvement of the central nervous system in NPSLE pathogenesis. SUMMARY: Neuropsychiatric involvement of SLE includes a variety of symptoms that impact quality of life and patient prognosis. There have been recent advances in improving the diagnosis of NPSLE as well as in dissecting the underlying pathogenesis. The attenuation of neuropsychiatric disease in mouse models demonstrates the potential for targeted therapies, which are based on a clearer understanding of the pathogenesis of NPSLE. Further assessment of these treatments is required in NPSLE patients, as well as the potential use of neuroimaging to distinguish between SLE patients with or without neuropsychiatric manifestations.

Refractory epilepsy associated with anti-ribosomal P antibodies successfully treated with topiramate.

We report the case of a 25-year-old woman who developed temporal lobe epilepsy associated with systemic lupus erythematosus (SLE). Serum and cerebrospinal fluid samples showed high titers of anti-ribosomal P (anti-P) antibodies with negative anti-NMDAR antibodies. She was receiving prednisone and azathioprine, with normalization of SLE serum markers, but without changes in titers of anti-P antibodies. No seizure control was achieved using valproic acid, levetiracetam and lamotrigine. However, she had a selective response to topiramate, an AMPAR blocker, maintained during 6 years of follow-up. We discuss the pathophysiology of this autoimmune epilepsy associated with high titer anti-P antibodies.