Pathogenesis Of Neuropsychiatric Systemic Lupus Erythematosus Research Articles

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

Given the early onset of neuropsychiatric disease and the potential response to immunosuppressive therapy, neuropsychiatric disease is considered a primary disease manifestation in systemic lupus erythematosus (SLE). However, the pathogenesis is not fully understood and optimal treatment has yet to be determined. TWEAK is a TNF family ligand that mediates pleotropic effects through its receptor Fn14, including the stimulation of inflammatory cytokine production by astrocytes, endothelial cells, and other non-hematopeotic cell types, and induction of neuronal death. Furthermore, TWEAK-inducible mediators are implicated in neuropsychiatric lupus. Thus, we hypothesized that the TWEAK/Fn14 pathway may be involved in the pathogenesis of neuropsychiatric SLE. We generated MRL-lpr/lpr (MRL/lpr) mice deficient for Fn14, the sole known signaling receptor for TWEAK. Neuropsychiatric disease was compared in age- and gender-matched MRL/lpr Fn14 wild type (WT) and knockout (KO) mice, using a comprehensive battery of neurobehavioral tests. We found that MRL/lpr Fn14WT mice displayed profound depression-like behavior as seen by increased immobility in a forced swim test and loss of preference for sweetened fluids, which were significantly ameliorated in Fn14KO mice. Similarly, MRL/lpr Fn14WT mice had impaired cognition, and this was significantly improved in Fn14KO mice. To determine the mechanism by which Fn14 deficiency ameliorates neuropsychiatric disease, we assessed the serum levels of autoantibodies and local expression of cytokines in the cortex and hippocampus of lupus mice. No significant differences were found in the serum levels of antibodies to nuclear antigens, or autoantibodies specifically associated with neuropsychiatric disease, between MRL/lpr Fn14WT and KO mice. However, MRL/lpr Fn14KO mice had significantly decreased brain expression of RANTES, C3, and other proinflammatory mediators. Furthermore, MRL/lpr Fn14KO mice displayed improved blood brain barrier integrity. In conclusion, several central manifestations of neuropsychiatric lupus, including depression-like behavior and altered cognition, are normalized in MRL/lpr mice lacking Fn14. Our results are the first to indicate a role for the TWEAK/Fn14 pathway in the pathogenesis of neuropsychiatric lupus, and suggest this ligand–receptor pair as a potential therapeutic target for a common and dangerous disease manifestation.

Neuropsychiatric Lupus = المتلازمة العصبية و النفسية لمرض الذئبة الحمراء

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Involvement of the nervous system, either primary or secondary, is common in SLE, and 19 different neuropsychiatric clinical syndromes have been recognised in association with the disease. Several pathophysiological mechanisms have been implicated in the pathogenesis of neuropsychiatric SLE (NPSLE), including vasculopathy, autoantibodies, and cytokine-mediated tissue injury. Careful evaluation of the patient is required to rule out secondary causes before attributing the neurological symptoms to SLE. Treatment depends on the nature and severity of NPSLE syndrome.

Neuropsychiatric Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystemic involvement and diverse manifestations. Neuropsychiatric systemic lupus erythematosus (NPSLE) is a complex neurological disorder characterized by neuropsychological dysfunction. NPSLE is associated with increased morbidity and mortality. In 1999, the American College of Rheumatology developed 19 discrete neuropsychiatric syndromes that comprised NPSLE. Nervous system disease in systemic lupus erythematosus is manifested by a wide variety of clinical manifestations. The pathogenesis of NPSLE is due to autoantibodies, neuronal and non neuronal antigens and the generation of proinflammatory cytokines and mediators. Anatomopathological lesions are attributed to in situ thrombosis, edema, hemorrhage, vasculitis, atherosclerosis or atheroembolism. The diagnosis of NPSLE remains largely one of exclusion and is approached by clinical evaluation, and supported when necessary by autoantibody profiles, diagnostic imaging, electrophysiologic studies and objective assessment of cognitive performance. Brain MRI abnormalities in NPSLE might show small punctate focal lesions in white matter being the most common MRI finding, followed by cortical atrophy, ventricular dilation, cerebral edema, diffuse white matter abnormalities, focal atrophy, cerebral infarction, acute leukoencephalopathy and intracranial hemorrhage. The treatment is based on the use of symptomatic therapies, immunosuppressives and non-pharmacologic interventions. This review paper was designed to understand the pathophysiology for better management of NPSLE.

Systemic Lupus Erythematosus Patients with and without Neuropsychiatric Manifestations: A Neck and Transcranial Duplex Sonography Study

Neuropsychiatric manifestations are not rarely associated with systemic lupus erythematosus (SLE). Magnetic resonance angiography and positron emission tomography can provide excellent images of cerebral perfusion and metabolism whereas information is still lacking on a possible diagnostic role of ultrasound. In this study we aim to assess whether duplex sonography of neck and intracranial vessels may be useful in distinguishing patients with and without neuropsychiatric SLE (NPSLE). Neck and transcranial duplex sonography was performed by a single operator on 33 women affected by SLE (mean age +/- SD: 47.69+/-8.17 years) and on 15 healthy control subjects. Nineteen patients presented NPSLE. Pulsatility and resistivity indices (PI and RI) were automatically calculated by the ultrasound instrument in internal carotid (ICA) and middle cerebral artery (MCA), on both sides, according to standard methods. No significant haemodynamic differences were found in mean and median PI and RI values of ICA and MCA comparing SLE with NPSLE patients and with healthy control subjects. No correlation was found between MCA and ICA parameters in the same group of patients. Duplex sonography of cerebral vessels is unable to distinguish SLE and NPSLE patients. Heterogeneity of causes in the pathogenesis of NPSLE and the different vascular adaptation of cerebral macrocirculation as opposed to cerebral microcirculation may represent possible reasons that explain the inability of ultrasound to differentiate SLE patients from NPSLE patients.

Neuropsychiatric Systemic Lupus Erythematosus

Neuropsychiatric systemic lupus erythematosus (NPSLE) is the least understood, yet perhaps the most prevalent manifestation of lupus. The pathogenesis of NPSLE is multifactorial and involves various inflammatory cytokines, autoantibodies, and immune complexes resulting in vasculopathic, cytotoxic and autoantibody-mediated neuronal injury. The management of NPSLE is multimodal and has not been subjected to rigorous study. Different treatment regimens include nonsteroidal anti-inflammatory drugs, anticoagulation, and immunosuppressives such as cyclophosphamide, azathioprine, mycophenolate mofetil, and methotrexate. For refractory NPSLE, intravenous immunoglobulin (IVIG), plasmapheresis, and rituximab have been used. Adjunctive symptomatic treatment complements these therapies by targeting mood disorders, psychosis, cognitive impairment, seizures or headaches. Several new biological agents are being tested including Belimumab, a human monoclonal antibody that targets B lymphocyte stimulator. This review focuses on the pathophysiology, treatment, and new potential therapies for neuropsychiatric manifestations of systemic lupus erythematosus.

Neuropsychiatric Manifestations in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a relapsing-remitting autoimmune disease with CNS involvement occurring in up to 75% of patients. However, the frequency of neuropsychiatric manifestations in SLE studies varies widely, depending on the type of manifestations included and the method used for evaluation. CNS involvement may be considered primary if directly related to SLE activity in the CNS or secondary when related to treatment, infections, metabolic abnormalities or other systemic manifestations such as uraemia and hypertension. The pathogenesis of neuropsychiatric SLE is as yet unknown, though numerous autoantibodies and cytokines have been suggested as possible mediators. However, independent of the aetiology of the insult, the final common pathway in neuropsychiatric SLE is the involvement of the cerebral microvasculature. The diagnosis of primary CNS involvement by SLE is often difficult, as both focal and diffuse manifestations may occur and there is no gold standard for diagnosis. A high index of clinical suspicion, in addition to laboratory and neuroimaging findings may support the diagnosis. Treatment is mostly empirical, although one randomized controlled trial has shown that cyclophosphamide in addition to methylprednisolone is superior to methylprednisolone alone in severe neuropsychiatric SLE.

Cerebrospinal fluid levels of a proliferation-inducing ligand (APRIL) are increased in patients with neuropsychiatric systemic lupus erythematosus

Objectives: A proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are B-cell stimulation and survival molecules. We have investigated whether APRIL and/or BAFF activity is enhanced in the systemic and/or intrathechal compartment of patients with neuropsychiatric systemic lupus erythematosus (NPSLE). In particular, the association between fatigue and APRIL/BAFF activity was investigated.Methods: Twenty-eight NPSLE patients were evaluated clinically, with sampling of cerebrospinal fluid (CSF) and blood, and magnetic resonance imaging (MRI). CSF and blood samples from 13 multiple sclerosis (MS) patients and 17 patients with other neurological diseases (OND) were used as controls. Protein levels of BAFF and APRIL were quantified in CSF and plasma, mRNA expression levels of BAFF and APRIL were determined in peripheral blood (PBMC) and CSF mononuclear cells (CSF-MC). The Fatigue Severity Scale (FSS) was used to quantify the degree of fatigue.Results: NPSLE patients had higher levels of APRIL in CSF as compared to OND (p < 0.01). No corresponding increase in APRIL mRNA levels was detected in CSF-MC. BAFF levels in plasma were higher in NPSLE than in OND (p < 0.001). BAFF mRNA expression in PBMC was also higher in NPSLE patients than in controls (p < 0.05). FSS scores in patients with NPSLE correlated significantly with APRIL levels in CSF.Conclusions: Protein levels of APRIL in CSF were increased in NPSLE as compared to OND. Moreover, there was a positive correlation between CSF APRIL levels and fatigue. Our results suggest that APRIL and possibly also BAFF may be involved in the pathogenesis of NPSLE and in SLE-related fatigue.

Localization of cerebral functional deficits in patients with non‐neuropsychiatric systemic lupus erythematosus

Neuropsychiatric systemic lupus erythematosus (NP-SLE) is a common complication of systemic lupus erythematosus (SLE), and clinical interventions are of only limited efficacy despite relatively high prevalence. Such complications have been studied extensively, but the pathoetiology of NP-SLE has not yet been elucidated. Diagnosis of NP-SLE focuses primarily on psychological manifestations, and the underlying mechanisms leading to neuropsychiatric complications remain unknown. To address potential changes in brain function before NP-SLE development, we used resting-state functional magnetic resonance imaging (MRI) to compare regional brain activity in SLE patients versus matched controls. We report that regional activity in cerebellum and in areas of the default mode network are attenuated in patients with SLE, and moreover individual alterations in cerebellar activity correlated positively with the disease activity index. These findings provide direct evidence that significant alteration of brain function, resembling that observed in patients with NP-SLE, is already present in SLE patients without neuropsychiatric complications, highlighting the need for early evaluation and intervention in SLE patients. Furthermore, the disease activity rating correlated with regional functional alterations in the cerebellum, suggesting that the cerebellum could play a role in the pathogenesis of NP-SLE.

Antibodies in patients with neuropsychiatric systemic lupus erythematosus

To investigate a target for antibodies in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Pathogenesis of NPSLE may be related to autoantibody-mediated neural dysfunction, vasculopathy, and coagulopathy. However, very few autoantibodies are sensitive and specific to NPSLE because the neuropsychiatric syndromes associated with SLE are diverse in cause and presentation. We identified antibodies against brain antigens in the sera of 7 patients with NPSLE and 12 healthy controls by 2-dimensional electrophoresis, followed by Western blotting and liquid chromatography-tandem mass spectrometry (LC-MS/MS), using rat brain proteins as the antigen source. Six antibodies were detected in patients with NPSLE. One of these 6 antibodies was found in antibodies against Rab guanosine diphosphate dissociation inhibitor alpha (alphaGDI) (which is specifically abundant in neurons and regulates synaptic vesicle exocytosis) in patients with NPSLE with psychosis. We tested more samples by 1-dimensional immunoblotting of human recombinant alphaGDI. Positivity of the anti-alphaGDI antibody was significantly higher in patients with NPSLE with psychosis (80%, 4 of 5) than in patients with NPSLE without psychosis (0%, 0 of 13), patients with systemic lupus erythematosus without neuropsychiatric symptoms (5.3%, 1 of 19), patients with multiple sclerosis (0%, 0 of 12), patients with infectious meningoencephalitis (0%, 0 of 13), patients with polyneuropathy (0%, 0 of 10), patients with psychotic syndromes (0%, 0 of 10), and healthy controls (0%, 0 of 12). We propose that the anti-Rab guanosine diphosphate dissociation inhibitor alpha antibody is a candidate for further exploration as diagnostic marker of psychosis associated with neuropsychiatric systemic lupus erythematosus.

The therapeutic potential of targeting anti-Ribosomal-P antibody in treating SLE patients with depression

Neuropsychiatric systemic lupus erythematosus (NPSLE) involves the central and peripheral nervous system. The pathogenesis of NPSLE is poorly understood. The condition is recognised as one of the major causes of mortality in SLE patients. The main autoantibody population associated with NPSLE is directed to ribosomal-phosphoproteins (anti-Ribos.P), which can bind the limbic area of mouse brain and penetrate into neuronal cells in vitro. Intracerebroventricular injection of these antibodies, induce experimental depression-like models in naive mice. Based on these observations, targeting anti-Ribos.P antibodies may be a new therapeutic approach to treat NPSLE patients with depression.

Potential role of interleukin-6 and chemokines in the pathogenesis of neuropsychiatric SLE

Potential role of interleukin-6 and chemokines in the pathogenesis of neuropsychiatric SLE

Diffusion tensor imaging in patients with acute onset of neuropsychiatric systemic lupus erythematosus: a prospective study of apparent diffusion coefficient, fractional anisotropy values, and eigenvalues in different regions of the brain

To investigate whether apparent diffusion coefficient (ADC), fractional anisotropy (FA), and eigenvalues in neuropsychiatric systemic lupus erythematosus (NPSLE) patients differ from those of healthy controls. Eight NPSLE patients (aged 23-55 years, mean 42.9 years) and 20 healthy age-matched controls (aged 22-59 years, mean 44.4 years) underwent conventional brain magnetic resonance (MR) and diffusion tensor imaging (DTI). The ADC, FA, principal eigenvalue (lambda parallel), and the corresponding average perpendicular eigenvalue (lambda perpendicular) (=(lambda2+lambda3)/2) were measured in selected regions of normal appearing gray and white matter brain parenchyma. For statistical evaluation of differences between the two groups, a Student's t-test was used. The P value for statistical significance was set to P=0.0025 after Bonferroni correction for multiple measurements. Significantly increased ADC values were demonstrated in normal-appearing areas in the insular cortex (P<0.001), thalamus (P<0.001), and the parietal and frontal white matter (P<0.001 and P<0.001, respectively) in NPSLE patients. Significantly decreased FA values were demonstrated in normal-appearing thalamus (P<0.001), corpus callosum (P=0.002), and in the parietal and frontal white matter (P<0.001 and P<0.001, respectively) in NPSLE patients compared to healthy controls. The lambda perpendicular was significantly higher in several of these regions in NPSLE patients compared to healthy controls. Our study demonstrates alterations in normal-appearing gray and white matter brain parenchyma of patients with NPSLE by means of abnormal ADC, FA, and eigenvalues. These alterations may be based on loss of tissue integrity in part due to demyelination. It is possible that DTI in the future could assist in the diagnosis of NPSLE and possibly help to further elucidate the pathogenesis of NPSLE.

The potential pathogenetic link between peripheral immune activation and the central innate immune response in neuropsychiatric systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. Neuropsychiatric disturbances unexplained by drugs or by other untoward manifestations of disease are present in up to one-half of SLE patients and have profound economic and social impact. In patients with neuropsychiatric SLE, structural lesions have been identified in the hippocampus and proinflammatory cytokines have been detected in the cerebrospinal fluid. Similarly, murine models of lupus, such as MRL- lpr/lpr mice display behavioral disturbances which map to the hippocampus and exhibit overexpression of proinflammatory cytokine genes in hippocampal homogenates. Neuropsychiatric SLE typically occurs in the presence of serologically and clinically active lupus. In animal models of SLE, such as MRL- lpr/lpr, NZB, BXSB, and [NZB x NZW]F 1, uncontrolled autoreactivity in the periphery is accompanied by behavioral disturbances that are chronic and progressive. These observations suggest the hypothesis that central nervous system disease in SLE is driven by cross-talk between the peripheral immune system and the brain’s innate immune system, which results in the inexorable activation of astrocytes, microglia, and/or neurons within the hippocampus. This leads to overproduction of brain cytokines, which induce the synthesis of pro-oxidant molecules, such as eicosanoids and reactive oxygen species, with resultant tissue injury. The cascade becomes self-perpetuating and eventuates in neuronal death, which is followed by impaired cognition. A better understanding of the molecular events that operate in the pathogenesis of neuropsychiatric SLE may provide the basis for a more rational therapeutic approach to this incompletely understood disease.

Lymphocyte and neuronal antigens in neuropsychiatric lupus: presence of an elutable, immunoprecipitable lymphocyte/neuronal 52 kd reactivity.

To examine specific lymphocyte or neuronal antigens immuno-precipitated by systemic lupus erythematosus (SLE) sera. SLE sera were screened for the presence of antibodies binding to surface antigens of CD4(+) HUT-78 or SK-N-SH and IMR-6 neuroblastoma cells using Western blotting or radioimmunoprecipitation. IgG eluates from both lymphocytes and neuroblastoma cells recognised a 52 kd band in HUT 78 cell lysates. Eight sera studied further using radioimmunoprecipitation also demonstrated binding to a 52 kd antigen (4/8 on HUT-78, 8/8 on SK-N-SH cells), partially depleted by absorption with viable HUT-78. A 52 kd antigen recognised by SLE sera on lymphocytes and neuronal cells may play a role in the pathogenesis of neuropsychiatric-SLE.

Lymphocyte Antigens in Neuropsychiatric Systemic Lupus Erythematosus

To examine the relationships among specific lymphocyte antigenic reactivities of lupus sera and central nervous system complications of systemic lupus erythematosus (SLE), lymphocytotoxic antibody (LCA) positivity, and specific cognitive impairment. Sera from 115 patients with SLE were examined for the presence of IgM- and IgG-class autoantibodies binding to surface target antigens on lymphocytes, by immunoblotting and microdroplet lymphocytotoxicity studies. Seventy-three of these patients also underwent detailed neuropsychological testing within the same time period. Significant associations were found between reactivities to several lymphocyte antigenic moieties and neuropsychiatric SLE (NPSLE) or cognitive impairment. Specifically, immunoblot reactivities to 31-32-kd, 50-52-kd, 54-56-kd, and 97-98-kd targets were associated with clinical NPSLE; there was a significant association between reactivity to the 50-52-kd moiety in particular and cognitive impairment. There were also associations between LCA and immunoblot reactivity. Furthermore, the previously reported association between LCA positivity and specific visuospatial cognitive impairment was confirmed with data obtained from 2 different batteries of neuropsychological tests. In some cases, specific antigenic targets of LCA-containing sera may be implicated in the pathogenesis of NPSLE: