Mariana Postal

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.

Neuropsychiatric Manifestations in Systemic Lupus Erythematosus Epidemiology, Pathophysiology and Management

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.

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.

Biological Therapy in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a prototypic inflammatory autoimmune disorder characterized by multisystem involvement and fluctuating disease activity. Symptoms range from rather mild manifestations such as rash or arthritis to life-threatening end-organ manifestations. Despite new and improved therapy having positively impacted the prognosis of SLE, a subgroup of patients do not respond to conventional therapy. Moreover, the risk of fatal outcomes and the damaging side effects of immunosuppressive therapies in SLE call for an improvement in the current therapeutic management. New therapeutic approaches are focused on B-cell targets, T-cell downregulation and costimulatory blockade, cytokine inhibition, and the modulation of complement. Several biological agents have been developed, but this encouraging news is associated with several disappointments in trials and provide a timely moment to reflect on biologic therapy in SLE.

Th1/Th2 cytokine profile in childhood-onset systemic lupus erythematosus

OBJECTIVE To determine the serum levels of Th1 (IL-12, IFN-γ,TNF-α) and Th2 (IL-5, IL-6 and IL-10) cytokines in childhood-onset SLE, first-degree relatives and healthy controls. To elucidate their association with disease activity, laboratory and treatment features. METHODS We included 60 consecutive childhood-onset SLE patients [median age 18 years (range 10-37)], 64 first-degree relatives [median 40 (range 28-52)] and 57 healthy [median age 19 years (range 6-30 years)] controls. Controls were age and sex-matched to SLE patients. SLE patients were assessed for clinical and laboratory SLE manifestations, disease activity (SLEDAI), damage (SDI) and current drug exposures. Mood and anxiety disorders were determined through Becks Depression (BDI) and Anxiety Inventory (BAI). Th1 (IL-12, IFN-γ,TNF-α) and Th2 (IL-5, IL-6 and IL-10) cytokines levels were measured by ELISA and compared by non-parametric tests. RESULTS Serum TNF-α (p=0.004), IL-6 (p=0.007) and IL-10 (p=0.03) levels were increased in childhood-onset SLE patients when compared to first-degree relatives and healthy controls. TNF-α levels were significantly increased in patients with active disease (p=0.014) and correlated directly with SLEDAI scores (r=0.39; p=0.002). IL-12 (p=0.042) and TNF-α (p=0.009) levels were significantly increased in patients with nephritis and TNF-α in patients with depression (p=0.001). No association between cytokine levels and SDI scores or medication was observed. CONCLUSION Th1 cytokines may play a role in the pathogenesis of neuropsychiatric and renal manifestations in childhood-onset SLE. The correlation with SLEDAI suggests that TNF-α may be a useful biomarker for disease activity in childhood-onset SLE, however longitudinal studies are necessary to determine if increase of this cytokine may predict flares in childhood-onset SLE.

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/m2. 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.

Prevalence and clinical significance of anti-ribosomal P antibody in childhood-onset systemic lupus erythematosus.

Objective: To investigate the prevalence of the anti-ribosomal P (anti-P) antibodies in childhood-onset systemic lupus erythematosus patients (cSLE), healthy controls and first degree relatives. To elucidate the association between anti-P and disease activity, laboratory and treatment features in cSLE patients. Methods: We included consecutive SLE patients with disease onset before 16 years. Controls were age- and sex-matched. SLE patients were assessed for clinical and laboratory SLE manifestations, disease activity (SLE Disease Activity Index (SLEDAI)), damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)) and current drug exposures. Mood disorders were determined through Becks Depression and Becks Anxiety Inventory. Anti-P measured by enzyme-linked immunosorbent assay. Results: We included 50 consecutive cSLE patients (mean age of 16.82 ± 3.46 years), 35 first degree relatives (mean age of 38.73 ± 3.89 years) and 20 health control (mean age of 18.3 ± 4.97 years). Anti-P was observed in 13 (26%) cSLE patients and in no first-degree relative (p < 0.01) or control (p < 0.01). Anti-P was more frequently observed in patients with anxiety (p < 0.002). No other clinical, laboratory or treatment features, including SLEDAI and SDI scores were associated with the presence of anti-P in cSLE patients. Conclusion: Anti-P is frequently observed in cSLE patients and was associated with the presence of anxiety in this cohort of 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 first-degree 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 first-degree 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.

Dysregulation of antiviral helicase pathways in systemic lupus erythematosus

In the autoimmune disease systemic lupus erythematosus (SLE), our normal antiviral defenses are inappropriately activated, resulting in over-activity of the type I interferon (IFN) pathway. This increased activity of the type I IFN pathway is an important primary pathogenic factor in the disease. Emerging evidence has implicated the antiviral helicases in this process. The antiviral helicases normally function as nucleic acid receptors in viral immunity. Genetic variations in antiviral helicase genes have been associated with SLE, supporting the idea that helicase pathways are involved in the primary pathogenesis of SLE. Studies have documented functional consequences of these genetic variations within the type I IFN pathway in human cell lines and SLE patients. In this review, we summarize the function of helicases in the anti-viral immune response, and how this response is dysregulated in SLE patients. In particular, we will focus on known functional genetic polymorphisms in the IFIH1 (MDA5) and mitochondrial antiviral signaling protein genes which have been implicated in human SLE. These data provide fascinating evidence for dysregulation of helicase-mediated innate immunity in SLE, and may support novel therapeutic strategies in the disease.

Reduction of Cerebral and Corpus Callosum Volumes in Childhood-Onset Systemic Lupus Erythematosus: A Volumetric Magnetic Resonance Imaging Analysis.

There have been few studies in which the prevalence of cerebral atrophy in childhood‐onset systemic lupus erythematosus (SLE) was evaluated using magnetic resonance imaging (MRI) volumetric measurements. This study was undertaken to determine the prevalence of cerebral and corpus callosum atrophy in childhood‐onset SLE and to determine the possible relationships between atrophy and clinical, laboratory, and treatment features of the disease.