Interferon-γ Is Associated with Cerebral Atrophy in Systemic Lupus Erythematosus.

OBJECTIVE: We evaluated the cerebrospinal fluid (CSF) cytokine profile and magnetic resonance imaging (MRI) findings in systemic lupus erythematosus (SLE) patients with central nervous system (CNS) involvement. METHODS: Consecutive SLE patients followed at the rheumatology unit were enrolled into this study. Neurologically asymptomatic controls were matched for age and sex and recruited during myelography. SLE patients were assessed for disease activity (Systemic Lupus Erythematosus Disease Activity Index; SLEDAI) and cumulative damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; SDI). All subjects underwent MRI scans and blood and CSF withdrawal. Immunoglobulin G (IgG) and albumin were measured by nephelometry and link indexes were calculated according to the literature. Interleukin (IL)-12 p40/p70, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and IL-10 were measured by enzyme-linked immunosorbent assay. RESULTS: We included 20 SLE patients (18 women, mean age 30.2 ± 9.2 years, range 19-45) with CNS manifestations. Increased IL-12 p40/p70, IFN-γ, TNF-α, and IL-10 CSF levels were observed in SLE patients. Mild pleocytosis was observed in 8 (66%) SLE patients and intrathecal production of IgG was observed in 2 (10%) SLE patients. Three (15%) SLE patients had demyelinating lesions, 5 (25%) patients had cerebral atrophy, and 12 (60%) patients had ischemic lesions on MRI. We observed that the cerebral lesion count was associated with CNS manifestations and SDI scores. We observed a significant cerebral volume reduction in SLE patients compared to controls (p < 0.001). Moreover, a direct correlation between cerebral volume reduction and CSF IFN-γ levels was observed (r = 0.5, p = 0.01). CONCLUSIONS: IL-12 p40/p70, IFN-γ, TNF-α, and IL-10 CSF levels were increased in SLE patients with CNS manifestations, but only IFN-γ was associated with a cerebral volume reduction in SLE, suggesting an immunological basis for global atrophy in SLE.

Depressive symptoms are associated with tumor necrosis factor alpha in systemic lupus erythematosus.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) is deeply related to pathogenesis of neurodevelopmental disorders, especially depression. The aim of this study was to explore potential relationships between sera TNF-α levels and mood and anxiety disorders in systemic lupus erythematosus (SLE) patients. METHODS: We included 153 consecutive SLE patients (women 148; median age 30; range 10-62) and 40 (women 37; mean age 28.5; range 12-59) age- and sex-matched healthy controls. Mood and anxiety disorders were determined through Beck Depression and Beck Anxiety Inventory. SLE patients were further assessed for clinical and laboratory SLE manifestations. TNF-α levels were measured by enzyme-linked immunosorbent assay using commercial kits. RESULTS: Depressive symptoms were identified in 70 (45.7 %) SLE patients and in 10 (25 %) healthy controls (p < 0.001). Anxiety symptoms were identified in 93 (60.7 %) SLE patients and in 16 controls (40 %) (p < 0.001). Sera TNF-α levels were increased in SLE patients with depressive symptoms (p < 0.001) and with anxiety symptoms (p = 0.014). A direct correlation between the severity of depressive symptoms and sera TNF-α levels (r = 0.22; p = 0.003) was observed. TNF-α levels were significantly increased in patients with active disease (p = 0.012). In addition, we observed a correlation between sera TNF-α levels and disease activity (r = 0.28; p = 0.008). In the multivariate analysis, sera TNF-α levels were independently associated with depressive symptoms (t = 3.28; 95 % CI 1.08-2.2; p = 0.002). CONCLUSIONS: Sera TNF-α levels are increased in SLE patients with mood and anxiety disorders. In SLE, sera TNF-α levels are independently associated with mood disorders. The etiology of mood disorders is still debated in SLE, but our findings suggest the presence of immunological basis for depression in SLE.

Serum interleukin-17 levels are associated with nephritis in childhood-onset systemic lupus erythematosus

OBJECTIVES: To determine the serum interleukin-17 (IL-17) levels in childhood-onset systemic lupus erythematosus patients and to evaluate the association between IL-17 and clinical manifestations, disease activity, laboratory findings and treatment. METHODS: We included 67 consecutive childhood-onset systemic lupus erythematosus patients [61 women; median age 18 years (range 11-31)], 55 first-degree relatives [50 women; median age 40 years (range 29-52)] and 47 age- and sex-matched healthy controls [42 women; median age 19 years (range 6-30)]. The childhood-onset systemic lupus erythematosus patients were assessed for clinical and laboratory systemic lupus erythematosus manifestations, disease activity [Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)], cumulative damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index] and current drug use. Serum IL-17 levels were measured by an enzyme-linked immunosorbent assay using commercial kits. RESULTS: The median serum IL-17 level was 36.3 (range 17.36-105.92) pg/mL in childhood-onset systemic lupus erythematosus patients and 29.47 (15.16-62.17) pg/mL in healthy controls (p=0.009). We observed an association between serum IL-17 levels and active nephritis (p=0.01) and migraines (p=0.03). Serum IL-17 levels were not associated with disease activity (p=0.32), cumulative damage (p=0.34), or medication use (p=0.63). CONCLUSION: IL-17 is increased in childhood-onset systemic lupus erythematosus and may play a role in the pathogenesis of neuropsychiatric and renal manifestations. Longitudinal studies are necessary to determine the role of IL-17 in childhood-onset systemic lupus erythematosus. .

The importance of cytokines and autoantibodies in depression.

The relationship between depression and immunity has been widely discussed. Cytokines, such as TNF-α, play an important role in immune system; these cytokines interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and synaptic plasticity. Antibodies have also been implicated in the pathophysiology of depression. The association between decreased serotonin levels and excessive glutamatergic activity forms the first biochemical basis for cytokine-induced depression. Cytokines and antibodies (anti-ribosomal-P and anti-N-methyl-D-aspartate receptor antibodies) are deeply related to pathogenesis of neurodevelopmental disorders, especially depression. Tumor necrosis factor alpha (TNF-α) may underlie the mechanism of depression by an activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, an activation of neuronal serotonin transporters and the stimulation of the indoleamine 2,3-dioxygenase which leads to tryptophan depletion. In the last 20 years since the initial reports of neural-immune interactions in depression, studies have shown a clear association between activation of the immune system mediated by proinflammatory cytokines. Genes encoding cytokines are highly polymorphic and single nucleotide polymorphisms, associated with increased or reduced cytokine production, have been described. To date, there are only few studies that investigated the relationship between depression and proinflammatory cytokines in patients with autoimmune diseases. Although an associative link between neuroinflammation and mood disorders is widely accepted, further studies are necessary to establish the cause-effect relationship. In this paper, we review the role of cytokines, focusing on TNF-α and antibodies in the depression and hypothesize how TNF-α may underlie and mediate the inflammatory process depression in patients with autoimmune disease.

Obesity and cytokines in childhood-onset systemic lupus erythematosus.

BACKGROUND: In systemic lupus erythematosus (SLE), atherosclerosis is attributed to traditional and lupus related risk factors, including metabolic syndrome (MetS), obesity, and inflammation. Objective. To evaluate the association between obesity, measures of body fat content, serum tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6 and -10 levels in childhood-onset SLE (cSLE). METHODS: We screened consecutive cSLE patients followed up in the Pediatric Rheumatology Outpatient Clinic of the State University of Campinas. cSLE patients were assessed for disease and damage. Obesity was definite as body mass index (BMI) ≥30 kg/m(2). Serum TNF-α, IL-6, and IL-10 levels were measured by ELISA. Dual-energy X-ray absorptiometry was used to determine total fat mass, lean mass, and percent of body fat. RESULTS: We included 52 cSLE patients and 52 controls. cSLE patients had higher serum TNF-α (P = 0.004), IL-6 (P = 0.002), and IL-10 (P < 0.001) levels compared to controls. We observed higher serum TNF-α (P = 0.036) levels in cSLE patients with obesity. An association between serum TNF-α levels and body fat percent (P = 0.046) and total fat mass on trunk region (P = 0.035) was observed. CONCLUSION: Serum TNF-α levels were associated with obesity and body fat content in cSLE. Our finding suggests that obesity may contribute to the increase of serum TNF-α levels in cSLE.

Clinical and serological manifestations associated with interferon-α levels in childhood-onset systemic lupus erythematosus

OBJECTIVE: To determine the serum levels of interferon alpha in childhood-onset systemic lupus erythematosus patients, their first-degree relatives and healthy controls and to evaluate the associations between serum interferon alpha and disease activity, laboratory findings and treatment features. METHODS: We screened consecutive childhood-onset systemic lupus erythematosus patients in a longitudinal cohort at the pediatric rheumatology unit of the State University of Campinas between 2009 and 2010. All patients demonstrated disease onset before the age of 16. Disease status was assessed according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Interferon alpha levels were measured using an enzyme-linked immunoabsorbent assay. RESULTS: We included 57 childhood-onset systemic lupus erythematosus patients (mean age 17.33±4.50), 64 firstdegree relatives (mean age 39.95±5.66), and 57 healthy (mean age 19.30±4.97) controls. Serum interferon alpha levels were significantly increased in childhood-onset systemic lupus erythematosus patients compared to their firstdegree relatives and healthy controls. Interferon alpha levels were significantly increased in patients with positive dsDNA antibodies, patients with cutaneous vasculitis, patients with new malar rash and patients who were not receiving medication. Interferon alpha levels correlated with C3 levels and systemic lupus erythematosus Disease Activity Index scores. In addition, we observed an inverse correlation between patient age and interferon alpha levels. CONCLUSION: Interferon alpha may play a role in the pathogenesis of childhood-onset systemic lupus erythematosus, especially in cutaneous manifestations and dsDNA antibody formation. The observation that interferon alpha levels are increased in patients who are not taking medication should be investigated in longitudinal studies to determine whether elevated interferon alpha levels may predict systemic lupus erythematosus flares.

The role of Tumor Necrosis Factor-alpha (TNF-α) in the pathogenesis of systemic lupus erythematosus.

The Tumor Necrosis Factor-alpha (TNF-α) is a pleiotropic cytokine that produces different stimuli in various physiological and pathological conditions. TNF-α contributes importantly to the development of T cells, B cells, and dendritic cells. However, TNF-α is also a potent inflammatory mediator and apoptosis inducer. The significance of the TNF-α involvement in the pathogenesis of systemic lupus erythematosus (SLE) remains controversial. From the genetic standpoint, a number of studies suggest that the TNF-α gene polymorphism is involved in the susceptibility of SLE. Moreover, there is a close association between the TNF-α gene expression and clinical manifestations. In addition, the increased serum level of TNF-α is observed in SLE patients and associated with disease activity and certain systemic manifestations. Treatment with anti-TNF agents is, however, controversial in SLE since induction of antinuclear antibodies, anti-dsDNA, anticardiolipin antibodies, and cases of drug-induced lupus have been observed in rheumatoid arthritis patients. In this context, this study reviewed the importance of TNF-α in the pathogenesis of SLE.

Influência dos polimorfismos da glutationa s-transferase na ototoxicidade dos aminoglicosídeos / Influence of glutathione s-transferase on the ototoxicity caused by aminoglycosides

The process of hair cell damage and death as a result of exposure to noise and ototoxins seems to be mediated by reactive oxygen species. AIM: To investigate the relationship between genetic polymorphisms in the Glutathione S-transferase and the susceptibility to hearing loss induced by aminoglycosides. MATERIALS AND METHODS: Null genotypes were analyzed by multiplex-PCR in the DNA samples from 50 patients and 72 controls. The patients were divided into 3 groups, 10 with hearing loss using aminoglycosides (group A), 20 with hearing loss without exposure to the drug (group B) and 20 hearing individuals who used the antibiotic (group C). STUDY DESIGN: Experimental. RESULTS: Polymorphisms in the GSTM1 and GSTT1 genes were found in 16 percent and 42 percent of patients and in 18 percent and 53 percent of the control group, respectively. After statistical analysis no significant difference was observed between the control groups and A (p=0.86) and (p=0.41), controls and B (p=0.27) and (p=0.24), controls and C (p=0.07) and (p=0.47), controls and A + C (p=0.09) and (p=0.47), C and A (p=0.32) and (p=0.75), GSTT1 and GSTM1, respectively. CONCLUSION: Our data show that polymorphisms in GSTM1 and GSTT1 genes have no influence on the ototoxicity of aminoglycosides.

O processo de morte e danos em células ciliadas devido à exposição ao ruído e ototoxinas parece ser mediado por espécies reativas de oxigênio. OBJETIVO: Investigar a relação entre polimorfismos gênicos na Glutationa S-transferase e a susceptibilidade à deficiência auditiva induzida pelos aminoglicosídeos. CASUÍSTICA E MÉTODO: Genótipos nulos foram analisados por PCR-multiplex em amostras de DNA de 50 pacientes e 72 controles. Os pacientes foram divididos em três grupos, sendo 10 com deficiência auditiva e uso de aminoglicosídeos (grupo A), 20 com deficiência auditiva sem exposição à droga (grupo B), e 20 ouvintes que utilizaram o antibiótico (grupo C). FORMA DE ESTUDO: Experimental. RESULTADOS: Polimorfismos nos genes GSTT1 e GSTM1 foram encontrados em 16 por cento e 42 por cento dos pacientes e em 18 por cento e 53 por cento do grupo controle, respectivamente. Após a análise estatística nenhuma diferença significativa foi observada entre os grupos controle e A (p=0,86) e (p=0,41), controle e B (p=0,27) e (p=0,24), controle e C (p=0,07) e (p=0,47), controle e A+C (p=0,09) e (p=0,47), C e A (p=0,32) e (p=0,75), GSTT1 e GSTM1, respectivamente. CONCLUSÃO: Nossos dados demonstram que polimorfismos na GSTT1 e GSTM1 não exercem influência sobre a ototoxicidade dos aminoglicosídeos.

Mutação mitocondrial C1494T, deficiência auditiva e uso de antibióticos aminoglicosídeos / C1494T mitochondrial dna mutation, hearing loss, and aminoglycosides antibiotics

Tendo em vista a complexidade do mecanismo da audição, não é difícil compreender que a deficiência auditiva possa resultar de ampla variedade de anomalias geneticamente determinadas, bem como de diversos fatores ambientais. Mutações específicas no gene 12S rRNA em DNA mitocondrial são responsáveis por perda da audição não-sindrômica de herança materna, e pelo aumento da susceptibilidade ototóxica dos antibióticos aminoglicosídeos. Objetivo: Neste trabalho, nós avaliamos a presença da mutação C1494T entre os indivíduos ouvintes e com deficiência auditiva que utilizaram aminoglicosídeos e os que não tiveram contato com o antibiótico. Material e método: Foram estudados 20 pacientes com deficiência auditiva neurossensorial não-sindrômica sem histórico de sensibilização aos aminoglicosídeos e 40 recém-nascidos, prematuros e de alto-risco que utilizaram a droga ototóxica, dos quais 20 eram ouvintes e 20 com perda auditiva. As amostras foram analisadas por PCR-RFLP com a enzima de restrição Hph I. Forma de estudo: Experimental. Resultados: A mutação mitocondrial C1494T no gene 12S rRNA não foi detectada em nenhuma das amostras analisadas. Conclusão: Nossos dados sugerem que a deficiência auditiva dos indivíduos analisados não está relacionada com a ototoxicidade da mutação C1494T, demonstrando que esta mutação não é frequente em nossa população.

In view of the complex mechanism of hearing, it is not difficult to understand that hearing impairment may result from a wide variety of genetically determined anomalies and various environmental factors. Specific mutations in the mitochondrial DNA 12S rRNA gene are responsible for maternally inherited non-syndromic hearing loss, and for increased susceptibility to the ototoxicity of aminoglycoside antibiotics. AIM: To asses the presence of C1494T mutation among individuals with normal hearing and hearing impairment who used aminoglycosides and those who had not had contact with the antibiotic. Material and method: The study was composed of 20 patients with nonsyndromic sensorineural hearing loss without prior use of aminoglycosides and 40 premature and high-risk newborns who used ototoxic drugs, of whom 20 had good hearing and 20 had hearing loss. The samples were analyzed by PCR-RFLP with the restriction enzyme Hph I. Study design: Experimental. Results: The mitochondrial 12S rRNA C1494T mutation was not detected in any of the samples analyzed. Conclusion: Our data suggest that the hearing loss of the individuals we analyzed was not related to the ototoxicity of mutation C1494T, showing that this mutation is not frequent in our population.