Complement genes contribute sex-biased vulnerability in diverse disorders.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Galectin-9 as a biomarker for disease activity in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by elevated interferon (IFN) signature genes. Galectin-9 (Gal-9) is a ß-galactoside-binding lectin that is reportedly useful as a biomarker for IFN gene signatures. In a cross-sectional study of Japanese patients with recent-onset SLE, we aimed to determine whether raised serum Gal-9 levels were associated with the disease activity or organ damage seen in SLE patients. METHODS: The current study included 58 Japanese patients with SLE and 31 age-matched healthy individuals. Disease activity and organ damage were assessed using SLE Disease Activity 2000 (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics (SLICC) damage index. Serum and cerebrospinal fluid (CSF) Gal-9 concentrations were quantified using ELISA. Correlation analyses between Gal-9 and clinical parameters including disease activity were performed. RESULTS: Serum levels of Gal-9 were significantly increased in patients with SLE compared with the control group (16.6 ng/ml, [interquartile range (IQR); 3.6-59.7] versus 4.74 ng/ml, [IQR; 3.0-9.5], p<0.0001). Gal-9 was significantly correlated with disease activity measures in the SLEDAI-2K. Serum Gal-9 levels were significantly greater in patients with SLE-related organ involvement (23.1 ng/ml, [IQR; 5.1-59.7] versus 12.5ng/ml, [IQR; 3.6-39.0], p = 0.013). Whereas there was no difference in serum levels of CXCL10 or M2BPGi between patients with and without SLE-related organ involvement. Serum levels of Gal-9 were significantly higher in SLE patients with active renal involvement determined by BILAG renal score (A-B) compared to those without active renal involvement (C-E). Whereas there was no significant difference in serum levels of Gal-9 between SLE patients with or without active other organ involvements (neurological or hematological) determined by BILAG score. SLE patients with detectable circulating IFN-α had raised serum Gal-9 levels. Levels of Gal-9 were significantly higher in the CSF from patients with recent-onset neuropsychiatric SLE (NPSLE) than in those from non-SLE controls (3.5 ng/ml, [IQR; 1.0-27.2] versus 1.2 ng/ml, [IQR; 0.9-2.1], p = 0.009). CONCLUSIONS: Gal-9 could be a serologic marker of disease activity and organ involvement in SLE patients. Future studies evaluating the role of Gal-9 in the SLE phenotype may provide insights into SLE pathogenesis.

Evaluation of a Novel Immunoassay for Quantification of C1q for Clinical Diagnostic Use.

Objectives: C1q is a valuable biomarker of disease activity in systemic lupus erythematosus (SLE). The "gold standard" assay, rocket immunoelectrophoresis (RIE), is time-consuming, and thus a shift to soluble immune precipitation techniques such as nephelometry has occurred. However, quantification of C1q with these techniques has been questioned as a result of the antibody binding properties of C1q. In the present work, we have compared results using various techniques (RIE, nephelometry, and ELISA) and have developed and validated a new magnetic bead-based sandwich immunoassay (MBSI). Methods: C1q was quantified by nephelometry and the new sandwich immunoassay in 45 serum samples analyzed using RIE. C1q was also assessed in plasma using RIE and sandwich immunoassay in samples from SLE patients with nephritis (n = 69), SLE patients without nephritis (n = 310) as classified by BILAG score, and matched controls (n = 322). In addition, cerebrospinal fluid (CSF) samples from 31 patients, previously analyzed with ELISA, were also analyzed with the MBSI to test the behavior of this new assay in the lower detection range. Results: We found a strong correlation between the new MBSI, RIE, and ELISA, but not with nephelometry. The MBSI demonstrated lower levels of C1q in SLE patients than in matched controls (p < 0.0001), and patients with nephritis had lower levels than patients without nephritis (p < 0.01). Similarily, RIE showed significant differences between the patient groups (p < 0.0001). An association was also found between the levels of C1q and the SLE disease activity index (SLEDAI). Furthermore, there was good correlation between the values obtained by MBSI and ELISA, in both serum (r = 0.960) and CSF (r = 0.786), underscoring the ability of both techniques to measure low concentrations of C1q with high accuracy. Conclusion: The sandwich immunoassay correlated well with RIE, but soluble immune precipitation techniques, such as nephelometry, did not appear suitable alternatives, since C1q itself, and possibly anti-C1q antibodies, interfered with the measurements. The new sandwich immunoassay is therefore a good replacement for RIE in monitoring SLE disease activity.

Cerebrospinal fluid orexin-A levels in systemic lupus erythematosus patients presenting with excessive daytime sleepiness.

Objective Involvement of the hypothalamus is rare in patients with systemic lupus erythematosus (SLE). In this study, we measured cerebrospinal fluid (CSF) orexin-A levels in SLE patients with hypothalamic lesions to investigate whether the orexin system plays a role in SLE patients with hypothalamic lesions who present with excessive daytime sleepiness (EDS). Methods Orexin-A levels were measured in CSF from four patients with SLE who presented with hypothalamic lesions detected by MRI. Three patients underwent repeated CSF testing. All patients met the updated American College of Rheumatology revised criteria for SLE. Results Tests for serum anti-aquaporin-4 antibodies, CSF myelin basic protein and CSF oligoclonal bands were negative in all patients. All patients presented with EDS. Low to intermediate CSF orexin-A levels (92-180 pg/ml) were observed in three patients in the acute stage, two of whom (patients 1 and 2) underwent repeated testing and showed increased CSF orexin-A levels, reduced abnormal hypothalamic lesion intensities detected by MRI and EDS dissipation at follow-up. In contrast, CSF orexin-A levels were normal in one patient (patient 4) while in the acute stage and at follow-up, despite improvements in EDS and MRI findings. Patient 4 showed markedly increased CSF interleukin-6 levels (1130 pg/ml) and a slightly involved hypothalamus than the other patients. Conclusions Our findings suggest that the orexinergic system has a role in EDS in SLE patients with hypothalamic lesions. Furthermore, cytokine-mediated tissue damage might cause EDS without orexinergic involvement.

Effects of sustained i.c.v. infusion of lupus CSF and autoantibodies on behavioral phenotype and neuronal calcium signaling.

Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease that is often accompanied by brain atrophy and diverse neuropsychiatric manifestations of unknown origin. More recently, it was observed that cerebrospinal fluid (CSF) from patients and lupus-prone mice can be neurotoxic and that acute administration of specific brain-reactive autoantibodies (BRAs) can induce deficits in isolated behavioral tasks. Given the chronic and complex nature of CNS SLE, the current study examines broad behavioral performance and neuronal Ca2+ signaling in mice receiving a sustained infusion of cerebrospinal fluid (CSF) from CNS SLE patients and putative BRAs (anti-NR2A, anti-ribosomal P, and anti-α-tubulin). A 2-week intracerebroventricular (i.c.v.) infusion of CSF altered home-cage behavior and induced olfactory dysfunction, excessive immobility in the forced swim test, and perseveration in a learning task. Conversely, sustained administration of purified BRAs produced relatively mild, both inhibitory and stimulatory effects on olfaction, spatial learning/memory, and home-cage behavior. In vitro studies revealed that administration of some CSF samples induces a rapid influx of extracellular Ca2+ into murine neurons, an effect that could be partially mimicked with the commercial anti-NR2A antibody and blocked with selective N-methyl-D-aspartate (NMDA) receptor antagonists. The current findings confirm that the CSF from CNS SLE patients can be neuroactive and support the hypothesis that intrathecal BRAs induce synergistically diverse effects on all domains of behavior. In addition, anti-NMDA receptor antibodies may alter Ca2+ homeostasis of central neurons, thus accounting for excitotoxicity and contributing to the heterogeneity of psychiatric manifestations in CNS SLE and other autoantibody-related brain disorders.

A critical analysis of the tools to evaluate neuropsychiatric lupus.

Neuropsychiatric symptoms occur commonly in patients with systemic lupus erythematosus, but they are not always due to active disease. It is crucial to identify cases that are due to active systemic lupus erythematosus so that appropriate treatment can be instituted. There is no single serological or imaging test that distinguishes active neuropsychiatric systemic lupus erythematosus from neuropsychiatric manifestations caused by other factors such as infection. Most patients with neuropsychiatric systemic lupus erythematosus have generalised features of disease activity. Raised anti-dsDNA and low C3 complement levels are often seen, but are not an invariable guide. The presence of antiphospholipid antibodies is more suggestive of thrombotic than inflammatory causation. A number of other autoantibody tests have been proposed as biomarkers for neuropsychiatric systemic lupus erythematosus, but results in clinical studies have been inconsistent and none has so far entered routine clinical practice. Cerebrospinal fluid features and magnetic resonance imaging appearances are non-specific in neuropsychiatric systemic lupus erythematosus, but are useful in excluding other causes of neuropsychiatric symptoms. Newer magnetic resonance imaging sequences show promise for distinguishing new neuropsychiatric systemic lupus erythematosus activity from previous damage and recent research suggests these may correlate with changes in cognitive function in patients with systemic lupus erythematosus. However, formal cognitive testing is seldom carried out in the acute setting.

Balance between inflammatory and regulatory cytokines in systemic lupus erythematosus.

To investigate the cytokine profile in serum and cerebrospinal fluid (CSF) from patients with systemic lupus erythematosus (SLE) and central nervous system infection, we measured interferon-g (IFN-g), interleukin-1b (IL-1b), IL-4, IL-6, IL-8, IL-10, and IL-17 levels in serum and CSF from 50 SLE patients and 38 matched controls. In patients with active compared to quiescent disease, serum levels were higher for IL-1b (P = 0.042) and IL-17 (P = 0.041) but we found no significant correlation between IL-1b and IL-17 and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (r = 0.055, r = 0.219, respectively). IL-10 level in active patients was lower compared to that in quiescent controls (P = 0.032). When comparing specific disease manifestations, IL-1b levels in patients with fever (P = 0.035) and IL-6 (P = 0.048) and IL-8 (P = 0.048) levels in those showing nervous system involvement were higher than in controls. Based on MRI results, we found that only increased cerebral ischemia was associated with increased IFN-g levels (P = 0.009). In neuropsychiatric lupus erythematous patients, CSF levels of IL-6 (P = 0.002), IL-8 (P = 0.009), and IL-17 (P = 0.034) were significantly higher when compared with control patients. IL-10:IL-1b ratio in patients with moderate and quiescent disease was higher than in patients with disease activity (P = 0.000). Pro-inflammatory adaptive cytokines were elevated during disease flare, while regulatory mediators were elevated during periods of stable disease. Alterations in the balance between inflammatory and regulatory mediators may be targets for novel immunotherapeutic agents for managing autoimmune diseases.

Migraine in patients with systemic lupus erythematosus is associated with reduced cerebral grey matter volume but not with measures of glial activation or anti-NR2 or anti-P antibodies.

BACKGROUND AND PURPOSE: Migraine is frequent in patients with systemic lupus erythematosus (SLE), but the pathogenesis and pathophysiology are poorly understood. Migraine is assumed to be a consequence of abnormal neuronal excitability. Based on the hypothesis that the threshold for migraine is lower in SLE patients due to cerebral disturbances, whether structural abnormalities of the brain or relevant biomarkers are associated with headaches in SLE was investigated. METHODS: Sixty-seven SLE patients and age- and gender-matched healthy subjects participated. Volumes of grey matter (GM) and white matter (WM) were estimated from cerebral magnetic resonance images with SPM8 software. Anti-NR2 and anti-P antibodies and protein S100B were measured in cerebrospinal fluid. RESULTS: In regression analyses, larger GM volumes in SLE patients reduced the odds for headache in general [odds ratio (OR) 0.98, P = 0.048] and for migraine in particular (OR 0.95, P = 0.004). No localized loss of GM was observed. Larger WM volumes in patients increased the odds for migraine (OR 1.04, P = 0.007). These findings could not be confirmed in healthy subjects. Neither anti-NR2 and anti-P antibodies nor S100B were associated with headaches in SLE patients. CONCLUSIONS: Systemic lupus erythematosus patients with migraine have a diffuse reduction in GM compared to patients without migraine. This finding was not observed in healthy subjects with migraine, and selected biomarkers did not indicate specific pathophysiological processes in the brain. These findings indicate that unknown pathogenic processes are responsible for the increased frequency of migraine in SLE patients.

Utility of TWEAK to assess neuropsychiatric disease activity in systemic lupus erhytematosus.

OBJECTIVE: The purpose of this study was to assess the utility of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) in serum and cerebrospinal fluid (CSF) as a biomarker in neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Thirty three NPSLE patients were evaluated at hospitalization and six months later. As controls, five SLE patients with septic meningitis, 51 hospitalized SLE patients without a history of neuropsychiatric (NP) manifestations and without infections, 16 SLE patients without NP manifestations (surgical-SLE), four patients with primary neuropsychiatric disorders, and 25 patients with non-autoimmune diseases were also studied. Serum and CSF samples were drawn at hospitalization, except non-NPSLE patients, in whom only serum was studied, and six months later in 19 NPSLE and 27 non-NPSLE patients. Serum and CSF TWEAK levels were measured by ELISA; values are expressed in pg/mL. RESULTS: The mean ± SD age of NPSLE patients was 31 ± 13.1 years, which was similar across study groups (p = 0.54). TWEAK levels in serum were not different across the study groups. In CSF, TWEAK levels were higher in NPSLE, surgical-SLE and primary neuropsychiatric groups than in non-autoimmune patients: median (IQR) 159.2 (94.1-374.9), 172.3 (125.3-421.9), 371.3 (143-543) vs. 122.1 (76.1-212.4), respectively; all p < 0.05. Six months later, when the neuropsychiatric manifestations were clinically in remission, serum or CSF TWEAK did not vary from baseline in NPSLE patients. CONCLUSIONS: TWEAK levels are slightly elevated in CSF in SLE patients compared with non-autoimmune controls, irrespective of the presence of NP manifestations. TWEAK levels in serum and CSF do not seem to be a useful biomarker of CNS involvement in SLE.

Association of hippocampal atrophy with cerebrospinal fluid antibodies against the NR2 subtype of the N-methyl-D-aspartate receptor in patients with systemic lupus erythematosus and patients with primary Sjögren's syndrome.

OBJECTIVE: Cognitive dysfunction is common in both systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (SS). Antibodies against the NR2 subtype of the N-methyl-D-aspartate receptor (anti-NR2 antibodies) cause hippocampal atrophy and cognitive impairment in mice and have been associated with memory impairment in both patients with SLE and patients with primary SS. In addition, a reduced volume of hippocampal gray matter has been demonstrated in both SLE and primary SS. This study was undertaken to investigate whether there is a connection between the presence of anti-NR2 antibodies and hippocampal atrophy in human diseases. METHODS: Fifty patients with SLE and 50 patients with primary SS underwent clinical examination and cerebral magnetic resonance imaging. Anti-NR2 antibodies in cerebrospinal fluid (CSF) were measured, and hippocampal gray matter volumes were compared between patients who were positive for and those who were negative for anti-NR2 antibodies. RESULTS: Patients with anti-NR2 antibodies in CSF had less hippocampal gray matter than patients without these antibodies. No other differences regarding gray matter volumes in other parts of the brain were identified. CONCLUSION: The present findings indicate that anti-NR2 antibodies in patients with SLE and primary SS cause neuronal death manifested as reduced hippocampal gray matter, as has been previously demonstrated in mice with autoimmune disease.

Hypertrophic pachymeningitis associated with cerebral spinal fluid hypovolemia as initial presentation of systemic lupus erythematous.

We report a case of a 61-year-old man with thickening of the dura mater associated with the presence of subdural collections as a consequence of cerebral spinal fluid hypovolemia (CSFH) and hypertrophic pachymeningitis (HP) as presentation of systemic lupus erythematous (SLE). The patient complained about fatigue, musculoskeletal pain, headache and skin lesions. In the laboratory tests minimal normocytic anemia, mild leukopenia, polyclonal hypergammaglobulinemia and antinuclear antibodies (ANA), anti-double-stranded DNA antibodies (dsDNA), antibodies against extractable nuclear antigens (ENA) type SSA-Ro, anti-Smith antigen antibodies (anti-Sm) and anti-ribonucleoprotein antibodies (anti-RNP) were detected. Cranial magnetic resonance imaging (MRI), with and without gadolinium enhancement, revealed generalized thickening of the dura mater more severe at the right parieto-occipital lobes with the presence of subdural collections. The patient was diagnosed with SLE associated both with CSFH and HP. A conservative treatment with prednisone 60 mg daily, mycophenolate mofetil (MMF) 1 g daily and hydroxychloroquine 200 mg twice a day was started with significant clinical and radiological improvement (almost complete resolution of the subdural collections and clear decrease of meningeal thickness). The authors emphasize that HP associated with CSFH in the context of SLE is a rare entity, which makes this case unique.

Utility of interferon-α as a biomarker in central neuropsychiatric involvement in systemic lupus erythematosus.

OBJECTIVE: To assess the utility of interferon-α (IFN-α) in serum and cerebrospinal fluid (CSF) as a biomarker of disease activity in central neuropsychiatric systemic lupus erythematosus (cNPSLE). METHODS: Serum and CSF samples were drawn at hospitalization in 34 patients with cNPSLE, 16 surgical SLE, 4 primary neuropsychiatric conditions, and 25 with nonautoimmune conditions, except in 44 non-NPSLE patients in whom only serum was studied. Six months later, serum/CSF and serum samples were taken in 20 cNPSLE and 35 non-NPSLE patients, respectively. SLE activity was assessed at hospitalization, and 6 months later in cNPSLE and non-NPSLE patients. IFN-α was detected by Luminex technology. RESULTS: The mean ± SD age of patients with cNPSLE was 31.4 ± 12.2 years, which was similar across the study groups (p = 0.46). Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores among cNPSLE, non-NPSLE, and SLE-surgical patients were 15.3 ± 8.2, 12.4 ± 8.2, and 3.8 ± 1.5, respectively. IFN-α levels in serum were higher in cNPSLE than in nonautoimmune patients (p = 0.02), but were similar to non-NPSLE and SLE-surgical groups. In CSF samples, IFN-α levels were higher in cNPSLE than in nonautoimmune patients (p = 0.03), and were nonsignificantly higher than in SLE-surgical and primary neuropsychiatric patients. Six months later, serum levels of IFN-α did not vary from baseline values despite a significant decrease in SLEDAI-2K score in cNPSLE and non-NPSLE patients. IFN-α levels in the CSF of patients with cNPSLE also remained stable. Among specific cNPSLE syndromes, CSF IFN-α levels were significantly higher among patients with acute confusional syndrome. CONCLUSION: IFN-α does not seem to represent a useful biomarker of cNPSLE syndromes; its utility in specific cNPSLE manifestations merits further investigation.

Neutralization by human serum samples of a transmissible agent isolated from the cerebrospinal fluid of neurological patients.

A transmissible cytotoxic agent thought to be associated with one or more misfolded protein(s) was found in several cerebrospinal fluid (CSF) samples from neurological patients. Since some experiments carried out to identify this unusual infectious factor showed the block of its propagation by rabbit gammaglobulins (IgGs), the search for such an activity by human IgGs was programmed. Neutralizing assays carried out using human sera as IgGs source showed a blocking property displayed by: twenty serum samples from as many patients with a diagnosis of acute infection, two of ten sera from healthy subjects and four serum samples from patients with lupus erythematous (SLE). When neutralizing sera were tested on cell cultures in immunofluorescence assays for the serum ability to label specific protein( s), similar fluorescent pictures resulted in treated and control cells. On the other hand, the SLE serum samples disclosed a granulosity of the nuclear material of cytotoxic cells in accordance with the DNA apoptotic laddering reported in previous papers. Oxidative disorders, as suggested by the immunoblotting analysis of the antioxidant enzymes Mn-superoxide dismutase (SOD2) and heme-oxygenase 1 (HO-1), point to an alteration of the oxidative pathway among the causes of the DNA damage induced by the cytotoxic transmissible agent under study.

Utility of serum S100B protein for identification of central nervous system involvement in systemic lupus erythematosus.

OBJECTIVE: To evaluate utility of S100B protein in serum as a marker of central nervous system involvement in systemic lupus erythematosus (SLE). METHODS: Forty patients with SLE, hospitalized because of central neuropsychiatric (cNP) manifestations (n = 36) and peripheral NP manifestations (pNP, n = 4) were studied. Patients were evaluated at hospitalization and 6 months later, including a serum and cerebrospinal fluid (CSF) sample. As controls, 4 SLE patients with septic meningitis (SLEsm), 13 surgical SLE patients (SLE surgical), 14 patients with nonautoimmune diseases, and 4 patients with primary NP syndromes were included. Serum and CSF S100B protein levels were determined by ELISA. RESULTS: At baseline, serum levels of S100B protein did not differ across SLE groups. Using an arbitrary cutoff value, positive S100B levels in serum were observed in 7 (19%), 6 (46%), and 1 patient from the cNPSLE, SLE surgical, and SLEsm groups, respectively. S100B protein levels in cNPSLE and SLE surgical patients were similar. In CSF, S100B protein levels did not differ among SLE groups, except in patients with SLEsm. Paired serum/CSF samples were obtained in 23 patients with cNPSLE at 6 months after the acute event. Overall, levels of S100B protein in serum did not change despite the decrease observed in CSF (p = 0.004). The correlation coefficient of serum and CSF S100B protein levels among all the SLE patients at baseline was poor (r = 0.23). CONCLUSION: Serum levels of S100B protein do not differentiate SLE patients with and those without central neurological manifestations.

Potential role of IFNα in adult lupus.

Patients with lupus have a continuous production of IFNα and display an increased expression of IFNα-regulated genes. The reason for the ongoing IFNα synthesis in these patients seems to be an activation of plasmacytoid dendritic cells (pDCs) by immune complexes (ICs), consisting of autoantibodies in combination with DNA-containing or RNA-containing autoantigens. The mechanisms behind the activation of pDCs by such ICs have to some extent been elucidated during the last years. Thus, interferogenic ICs are internalized via the FcγRIIa expressed on pDCs, reach the endosomes and stimulate Toll-like receptor (TLR) 7 or 9, which subsequently leads to IFNα gene transcription. Variants of genes involved in both the IFNα synthesis and response have been linked to an increased risk to develop lupus. Among these genes are interferon regulatory factor 5 (IRF5), which is involved in TLR signaling, and the signal transducer and activator of transcription 4 (STAT4) that interacts with the type I interferon receptor. Produced IFNα may at least partially be responsible for several of the observed alterations in the immune system of lupus patients and contribute to the autoimmune disease process, which will be discussed in the present review. How produced IFNα can contribute to some clinical manifestations will briefly be described, as well as the possible consequences of this knowledge in clinical practice for disease monitoring and therapy.

Intrathecal cytokine and chemokine profiling in neuropsychiatric lupus or lupus complicated with central nervous system infection.

The aims of this study are to investigate the cytokine, chemokine and adhesion molecule profiles in cerebrospinal fluid from patients with neuropsychiatric systemic lupus erythematosus and systemic lupus erythematosus with central nervous system infection. Experimental sets were established which included 108 patients and 132 cerebrospinal fluid samples. The patients were grouped as neuropsychiatric systemic lupus erythematosus (n = 54), systemic lupus erythematosus with central nervous system infection (n = 16), systemic lupus erythematosus controls (n=20), and non-inflammatory neurological disease (n=18). The dynamic changes of 21 patients in the neuropsychiatric systemic lupus erythematosus group before and after induction therapy were further analyzed. IL-1 beta, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, TNFalpha, IFN gamma, IP-10, MCP-1, RANTES, VCAM-1, and P-selectin were measured in cerebrospinal fluid samples by using a fluorescent bead-based assay. Cerebrospinal fluid levels of IL-8, MCP-1, P-selectin and VCAM-1 were significantly increased in neuropsychiatric systemic lupus erythematosus compared with systemic lupus erythematosus controls. IL-6, IL-17, IL-8 and VCAM-1 were higher in systemic lupus erythematosus with central nervous system infection than in systemic lupus erythematosus controls. Among systemic lupus erythematosus with central nervous system infection, the IL-6, IL-17, IL-8 and IP-10 levels were higher than those in neuropsychiatric systemic lupus erythematosus. After sufficient induction therapy, IL-8, MCP-1, P-selectin, VCAM-1 and IL-6 in patients with neuropsychiatric systemic lupus erythematosus decreased significantly. Levels of all molecules tested in non-inflammatory central nervous system disease were not different from those of systemic lupus erythematosus controls. From our data, the intrathecal cytokine/chemokine profile is different among patients with neuropsychiatric systemic lupus erythematosus, systemic lupus erythematosus complicated with central nervous system infection and systemic lupus erythematosus controls. IL-8, MCP-1, VCAM-1, P-selectin and IL-6 in cerebrospinal fluid are effective parameters to monitor neuropsychiatric systemic lupus erythematosus disease activity and response to treatment. Significantly elevated IL-17, IL-6, and to a lesser extent, IL-8, favors central nervous system infection in systemic lupus erythematosus.

Isolated tricuspid valve Libman-Sacks endocarditis and valvular stenosis: unusual manifestations of systemic lupus erythematosus.

The most common valves involved in systemic lupus erythematosus are the mitral and aortic valves. Although isolated tricuspid valve involvement is quite rare, the authors report such a case. A 42-year-old woman presented with exertional dyspnea and was found to have a cardiac murmur. Echocardiography showed a stenotic tricuspid valve with vegetations on all 3 cusps. No other valvular vegetation could be detected. Concomitant tricuspid regurgitation was noted too. Blood culture results were negative. Clinical findings and serologic tests confirmed the diagnosis of systemic lupus erythematosus. The patient was successfully treated with prednisolone and hydroxychloroquine, and follow-up echocardiography showed the disappearance of the vegetations.

Serum and cerebrospinal fluid autoantibodies in patients with neuropsychiatric lupus erythematosus. Implications for diagnosis and pathogenesis.

BACKGROUND: Despite the uncertainty in the diagnosis of neuropsychiatric involvement in systemic lupus erythematosus (SLE), attempts have been made to record the association of certain antibodies in serum with neuropsychiatric (NP) manifestations. We aimed to assess the behaviour and the association of serum and cerebrospinal fluid (CSF) autoantibodies with NP manifestations in SLE patients (NPSLE). METHODOLOGY/PRINCIPAL FINDINGS: Forty-seven SLE patients, hospitalized because of NP manifestations were included. They were evaluated at hospitalization and six months later, and serum and CSF samples were obtained at each evaluation. As controls, serum samples were taken from 49 non-NPSLE patients at hospitalization and six months later; serum and CSF samples were also obtained from 6 SLE patients with septic meningitis, 16 surgical SLE patients and 25 patients without autoimmune diseases. Antinuclear, anti-dsDNA, anti-ribosomal P, Anti-N-Methyl-D-Aspartate receptor (NMDAR), anti-cardiolipin, and anti-beta2 glycoprotein-I antibodies were measured. In serum, anti-ribosomal P, anti-NMDAR, and other antibodies did not differentiate among SLE groups, and the levels of all antibodies were similar among the SLE groups. Six-months later, this scenario remained unchanged and the decrease in the levels of some autoantibodies reflected a decline in disease activity, rather than a change in NPSLE. In CSF, only the presence and the levels of anti-NMDAR antibodies showed a characteristic distribution in central NPSLE and septic meningitis patients. Six months later the prevalence of most antibodies in CSF did not change, however the levels of anti-dsDNA, anti-ribosomal P, and anti-NMDAR decreased. CONCLUSION: In NPSLE, autoantibodies in serum do not reflect their behaviour in CSF. All autoantibodies were elevated in septic meningitis reflecting the global penetration of serum antibodies into the CSF in this condition. Anti-NMDAR antibodies in CSF identified patients with central NPSLE; their continued presence in CSF 6 months after neurologic symptoms raise questions regarding the conditions under which they are pathogenic.