Background Systemic lupus erythematosus (SLE) patients exhibit T-cell dysfunction which can be regulated through the mitochondrial transmembrane potential (Δψm) and mammalian target of rapamycin (mTOR) by glutathione. Therefore, the safety, tolerance, and efficacy of glutathione-precursor N-acetylcysteine (NAC) were examined in this randomized double-blind placebo-controlled study. Methods 36 SLE patients received daily placebo or 1.2 g, 2.4 g or 4.8 g of NAC. Disease activity was monthly evaluated by BILAG, SLEDAI and fatigue assessment scale (FAS) before, during, and after 3-month treatment. Δψm and mTOR were assessed by flow cytometry. 42 healthy subjects matched for patients’ age, gender, and ethnicity were studied as controls. Results NAC was tolerated by all patients up to 2.4 g/day while 33% of those receiving 4.8 g/day had reversible nausea. Placebo or 1.2 g/day NAC did not influence disease activity. Considered together, 2.4 g and 4.8 g NAC reduced: 1) SLEDAI after 1 month (p=0.0007), 2 months (p=0.0009), 3 months (p=0.0030) and 4 months (p=0.0046); 2) BILAG after 1 month (p=0.029) and 3 months (p=0.0009); and 3) FAS after 2 months (p=0.002) and 3 months (p=0.004). NAC increased Δψm (p=0.0001) in all T cells, it profoundly reduced mTOR activity (p=0.0001), enhanced apoptosis (p=0.0004) and reversed expansion of CD4−/CD8− T cells (1.35 ± 0.12-fold; p=0.008), stimulated Foxp3 expression in CD4+/CD25+ T cells (p=0.045), and reduced anti-DNA production (p=0.049). Conclusions This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.

Pfizer, the National Institutes of Health, and the Central New York Community Foundation.

The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T-cell lineage development, however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear. Here, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBL relative to SLE disease activity index (SLEDAI) during 274 visits of 59 patients and 54 matched healthy subjects. Partial least square-discriminant analysis identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (p<0.0005); increased mitochondrial mass of CD3+/CD4−/CD8− double-negative (DN) T cells (p=1.1×10−22) and FoxP3 depletion in CD4+/CD25+ T cells were top contributors (p=6.7×10−7). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥4) relative to 61 visits of remission (SLEDAI decrease ≥4). mTOR activation in DN T cells was also noted at pre-flare visits of SLE patients relative to those of stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25+/CD19+B cells. Rapamycin treatment in vivo blocked the IL-4 production and necrosis of DN T cells, increased the expression of FoxP3 in CD25+/CD4+T cells, and expanded CD25+/CD19+ B cells. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells in patients with SLE.

The higher prevalence of cardiovascular disease in obese individuals is indirectly mediated, to a large extent, by the increased frequency of various well known risk factors like hypertension, diabetes, and dyslipidemia, either individually or as part of the metabolic syndrome. However, there are several ways in which obesity directly affects the cardiovascular system; these will be discussed in detail. We also focus on various challenges posed by obesity in the performance and interpretation of cardiac investigations and how they can be addressed. (J Am Board Fam Med 2008;21:562-8.)

We report a fatal case of toxic myopathy in a patient with a transplanted heart for severe ischemic coronary artery disease. He was on long-term cyclosporine, prednisone, and mycofenolate. Four months before the development of proximal muscle weakness, his simvastatin dose was doubled, and he was also started on colchicine for acute exacerbation of gout. He developed progressive muscle weakness leading to shortness of breath and hospitalization for respiratory failure. Colchicine and simvastatin were stopped on admission. He received high-dose methylprednisolone for continued muscle weakness while he was sedated with propofol. These changes led to a marked elevation of creatine kinase, peaking at 33,580 U/ml. The muscle biopsy revealed toxic vacuolization, mitochondrial damage, and no evidence of inflammation. Based on the timing of events, the combination of propofol, high-dose methylprednisolone, and cyclosporine have triggered rhabdomyolysis, which may have been facilitated by prior administration of colchicine and simvastatin.

Objective To investigate whether attention deficit hyperactivity disorder (ADHD) may serve as a marker of neuropsychiatric disease and as a target for N-acetylcysteine (NAC) treatment in patients with systemic lupus erythematosus (SLE). Methods The ADHD Self-Report Scale (ASRS) was used to assess 49 patients with SLE and 46 matched healthy control subjects. Twenty-four of the patients with SLE were randomized to receive either placebo, NAC at a dosage of 2.4 gm/day, or NAC at a dosage of 4.8 gm/day. Disease activity was evaluated monthly using the British Isles Lupus Assessment Group (BILAG) index, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the Fatigue Assessment Scale (FAS), and the ASRS, before and during the 3-month treatment period and after a 1-month washout period. Results The cognitive/inattentive (ASRS part A), hyperactivity/impulsive (ASRS part B), and combined (total) ASRS scores were increased in patients with SLE compared with control subjects (mean ± SEM 17.37 ± 1.03 [P = 3 × 10−7], 14.51 ± 0.89 [P = 2 × 10−4], and 31.92 ± 1.74 [P = 8 × 10−7], respectively, versus 10.41 ± 1.02, 9.61 ± 1.21, and 20.02 ± 1.98, respectively. ASRS part A scores correlated with SLEDAI (r = 0.53, P < 0.0001) and BILAG scores (r = 0.36, P = 0.011). ASRS total scores also correlated with SLEDAI (r = 0.45, P = 0.0009) and BILAG scores (r = 0.31, P = 0.025). ASRS part A (r = 0.73, P < 0.0001), ASRS part B (r = 0.47, P = 0.0006), and ASRS total scores (r = 0.67, P < 0.0001) correlated with the FAS score. Relative to the scores in placebo-treated patients, ASRS total scores were reduced in SLE patients treated with NAC dosages of 2.4 gm/day and 4.8 gm/day combined (P = 0.037). ASRS part A scores were reduced by NAC dosages of 2.4 gm/day (P = 0.001) and 4.8 gm/day (P < 0.0001) as well as by NAC at dosages of 2.4 gm/day and 4.8 gm/day combined (P = 0.001). Conclusion In patients with SLE, elevated ASRS scores reveal previously unrecognized and clinically significant symptoms of ADHD that respond to NAC treatment.

Infectious agents have long been implicated in the pathogenesis of systemic lupus erythematosus. Common viruses, such as the Epstein-Barr virus, transfusion transmitted virus, parvovirus and cytomegalovirus, have an increased prevalence in patients with systemic lupus erythematosus. They may contribute to disease pathogenesis through triggering autoimmunity via structural or functional molecular mimicry, encoding proteins that induce cross-reactive immune responses to self antigens or modulate antigen processing, activation, or apoptosis of B and T cells, macrophages or dendritic cells. Alternatively, some infectious agents, such as malaria, Toxoplasma gondii and Helicobacter pylori, may have a protective effect. Vaccinations may play dual roles by protecting against friend and foe alike. Keywords autoimmunity; infections; protective; systemic lupus erythematosus; vaccination Systemic lupus erythematosus (SLE) is a systemic autoimmune disease and the mechanisms of the aberrant immune responses remain unclear. Several environmental factors have been implicated in the etiology of SLE. There is a concordance rate of 25% in monozygotic twins for SLE, which indicates a discordance rate of 70% contributed to by environmental factors [1].The possibility of a viral etiology was raised by the finding of virion-like tubuloreticular structures in endothelial cells and lymphocytes, and demonstration of increased concentration of type 1 interferon (IFN) in lupus patients [1]. Many viruses have been implicated in the etiology of SLE, which includes the Epstein-Barr virus (EBV), transfusion-transmitted virus (tissue transplant virus or Torque tenovirus), retroviruses, paramyxovirus, cytomegalovirus (CMV), parvovirus B19 and corona virus (Table 1). EBV, retroviruses and parvovirus B19 may play a role in the pathogenesis of SLE, when compared with other viruses such as CMV, transfusion transmitted virus, type C oncorna virus and measles virus which play a minor role. Immunodeficiency, such as C4 or C1q deficiency, may predispose to both lupus and infection without the two being directly linked. Infectious agents may induce autoimmune disease by several mechanisms. Structural & functional molecular mimicryMolecular mimicry may be structural or functional. Structural molecular mimicry occurs when a viral peptide has an amino acid sequence similar or identical to an amino acid sequence of a self peptide, resulting in cross-reactive T-cell and B-cell responses. A potentially autoreactive NIH Public Access Author ManuscriptInt J Clin Rheumtol. Author manuscript; available in PMC 2010 December 1. Published in final edited form as:Int J Clin Rheumtol. Stimulation of pathogen recognition receptorsExogenous stimuli are products of bacteria and viruses and have been termed pathogenassociated molecular patterns (PAMPs) [6]. Dendritic cells recognize PAMPs using pathogen recognition receptors, such as Toll-like receptors (TLRs). Necrotic debris from the cell death pathways, bacterial lipopolysaccharide, viral RNA and viral DNA act...

Purpose of review Systemic lupus erythematosus is characterized by the production of antinuclear autoantibodies and dysfunction of T-cells, B-cells, and dendritic cells. Here, we review newly recognized genetic factors and mechanisms that underlie abnormal intracellular signal processing and intercellular communication within the immune system in systemic lupus erythematosus. Recent findings Activation of the mammalian target of rapamycin plays a pivotal role in abnormal activation of T and B-cells in systemic lupus erythematosus. In T-cells, increased production of nitric oxide and mitochondrial hyperpolarization were identified as metabolic checkpoints upstream of mammalian target of rapamycin activation. Mammalian target of rapamycin controls the expression T-cell receptor-associated signaling proteins CD4 and CD3ζ through increased expression of the endosome recycling regulator HRES-1/Rab4 gene, mediates enhanced Ca2+ fluxing and skews the expression of tyrosine kinases both in T and B-cells, and blocks the expression of Foxp3 and the expansion of regulatory T-cells. Mitochondrial hyperpolarization and the resultant ATP depletion predispose T-cells to necrosis, thus promoting the dendritic cell activation, antinuclear autoantibody production, and inflammation. Summary Mitochondrial hyperpolarization, increased activity of mammalian target of rapamycin and Syk kinases, enhanced receptor recycling and Ca2+ flux have emerged as common T and B-cell biomarkers and targets for treatment in systemic lupus erythematosus.