Kritikos Hd

Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression

Objective MicroRNAs (miRNAs) regulate the expression of genes involved in immune activation. A study was undertaken to characterise the miRNA signature and identify novel genes involved in the regulation of immune responses in systemic lupus erythematosus (SLE). Methods The expression of 365 miRNAs in peripheral blood mononuclear cells of patients with SLE and healthy controls was analysed using TaqMan Low Density Arrays. The results were validated by quantitative real-time PCR and potential target genes were identified using prediction analysis software. The effect of miR-21 on T cell function was assessed by transfection with antago-miR-21 or pre-miR-21. Results A 27-miRNA signature was identified in patients with SLE; 19 miRNAs correlated with disease activity. Eight miRNAs were deregulated specifically in T cells and four miRNAs in B cells. miR-21 was upregulated and strongly correlated with SLE disease activity (r2=0.92). Compared with controls, CD4 T lymphocytes from patients with SLE had higher basal and activation-induced miR-21 expression. Silencing of miR-21 reversed the activated phenotype of T cells from patients with SLE—namely, enhanced proliferation, interleukin 10 production, CD40L expression and their capacity to drive B cell maturation into Ig-secreting CD19+CD38hiIgD−(plasma cells. Overexpression of mMiR-21 in normal T cells led to acquisition of an activated phenotype. Investigation of putative gene- targets showed that PDCD4 (a selective protein translation inhibitor) was suppressed by miR-21 and its expression was decreased in active SLE. Conclusions miRNAs represent potential biomarkers in SLE as their expression reflects underlying pathogenic processes and correlates with disease activity. Upregulated miR-21 affects PDCD4 expression and regulates aberrant T cell responses in human SLE.

Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis

Objective: Bone marrow (BM) mesenchymal stem cells (MSCs) are being considered as potential therapeutic agents in various inflammatory autoimmune diseases for their tissue-repair and anti-inflammatory tissue-protective properties. This study investigates the reserves and function, the molecular and proteomic profile and the differentiation potential of BM MSCs in patients with active rheumatoid arthritis (RA). Methods: We evaluated the frequency of MSCs in the BM mononuclear cell fraction using a limiting dilution assay, the proliferative/clonogenic potential and the capacity of cells to differentiate towards the osteogenic/chondrogenic/adipogenic lineages using appropriate culture conditions. We also assessed the molecular and proteomic characteristics in terms of inflammatory cytokine gene and protein expression, the relative telomere length and the survival characteristics of BM MSCs. Results: MSCs from patients with RA (n = 26) and age- and sex-matched healthy individuals (n = 21) were similar in frequency, differentiation potential, survival, immunophenotypic characteristics, and protein profile. Patient MSCs, however, had impaired clonogenic and proliferative potential in association with premature telomere length loss. Transcriptome analysis revealed differential expression of genes related to cell adhesion processes and cell cycle progression beyond the G1 phase. Previous treatment with methotrexate, corticosteroids, anti-cytokine and biological agents or other disease-modifying anti-inflammatory drugs did not correlate with the clonogenic and proliferative impairment of BM MSCs. Conclusion: In spite of some restrictions related to the impaired clonogenic and proliferative potential, our findings support the use of autologous BM MSCs in RA and may have important implications for the ongoing efforts to repair tissue injury commonly seen in the course of the disease.

Lupus nephritis flares.

The clinical course of lupus nephritis varies remarkably among SLE patients, even between those with the same histological type. Current immunosuppressive agents induce remission in the majority of the patients with proliferative lupus nephritis, but a substantial proportion of them - ranging in different studies from 27% to 66% - will flare. Flares represent a significant problem because of the potential for cumulative damage that may lead to deterioration of renal function as well as toxicity due to the additional immunosuppression. Maintenance therapy with azathioprine, mycophenolate mofetil or quarterly pulses of cyclophosphamide is usually recommended. Renal flares can be characterized as nephritic or nephrotic and can be mild or severe. The majority of the patients that flare restore renal function, if diagnosed early and treated promptly. However, current immunosuppressive agents have limitations concerning efficacy and toxicity profiles. Unresolved management issues include the value of repeat renal biopsy and issues related to optimal strategy/regimen to prevent flares. Renal flares are an important feature of the natural history of lupus nephritis and provide an opportunity for additional preventive strategies, as well as measures of efficacy in future therapeutic trials.

Association of the nitric oxide synthase (eNOS) gene polymorphism with increased risk for both lupus glomerulonephritis and rheumatoid arthritis in a single genetically homogeneous population.

Nitric oxide (NO), a short-lived gaseous free radical, synthesized from L-arginine by NO synthases (NOS), is a potent mediator of biologic responses involved in the pathogenesis of autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Most biological necessary NO is produced by the family of three NOS. To date, several functionally relevant genetic polymorphisms in the eNOS gene have been associated with various vascular, infectious and autoimmune diseases. To our knowledge, no study has explored these polymorphisms for both SLE and RA in the same population. The objective of this study was to investigate the influence of the eNOS gene intron 4 a/b VNTR polymorphism (a 27-base-pair tandem repeat-based polymorphism) on susceptibility to SLE and RA in patients living in the island of Crete, a genetically homogeneous population. A group of 145 healthy subjects and 190 SLE patients were included in this study. Similarly, a second group of 235 healthy controls and 202 RA patients were analysed. In both cases, patients and controls were sex- and age-matched. Herein we report that the presence of a/b genotype of the eNOS gene may act as a risk factor not for the presence of SLE but for the development of glomerulonephritis (OR 2.71, 95% CI: 1.4—5.2), while it may be a susceptibility gene for RA (OR: 2.005, 95% CI: 1.31—3.07). Thus, in our population, the a/b genotype of the eNOS gene represents a severity rather than a susceptibility genotype for SLE. Lupus (2007) 16, 867—874.

Pulse cyclophosphamide treatment for severe refractory cutaneous lupus erythematosus

Cutaneous lupus erythematosus includes a variety of lupus erythematosus specific skin lesions that, in some cases, can be disfiguring and refractory to conventional therapy. This short report describes our experience in treating six patients with severe, refractory subacute cutaneous lupus erythematosus with monthly cyclophosphamide pulses, followed by azathioprine as maintenance therapy. Significant clinical improvement of the subacute cutaneous lupus erythematosus lesions was achieved in all patients, with four patients in complete remission and two in partial remission. Mean time to clinical response was 4.33 ± 1.36 months. Minor adverse events and no relapses were noted in a follow-up period of more than 3 years. Lupus (2010) 19, 744—747.

Non-Hodgkin's Lymphoma in Patients with Systemic Lupus Erythematosus

Two cases of non-Hodgkins lymphoma (NHL) associated with systemic lupus erythematosus (SLE) are described. Patient-1 was a 65-year-old woman in whom SLE and diffuse large B-cell lymphoma were concurrently diagnosed. The patient presented with low-grade fever, butterfly rash, arthritis and generalized lymphadenopathy without splenomegaly or bone marrow involvement. Complete remission of NHL and SLE was achieved with cyclophosphamide, adriamycin, vincristine and prednisone. Patient-2 was a 56-year-old woman in whom SLE had been diagnosed 14 years earlier. The patient presented with low-grade fever, bulky splenomegaly without lymphadenopathy, IgM   paraproteinemia, and expansion of a monoclonal CD19 + /CD22 +   -type B-cell population in both bone marrow and peripheral blood. Diagnosis of a lympho-plasmacytoid lymphoma was established histologically after splenectomy. A partial remission of the neoplasm was achieved with cyclophosphamide, vincristine and prednisone. We suggest that the development of NHLs in patients with SLE may not be coincidental and we recommend the search for NHL in cases of SLE with prominent lymphadenopathy, massive splenomegaly or expansion of a monoclonal CD19 + /CD22 + B-cell population.

A rare case of angioimmunoblastic T-cell lymphoma presenting with fever and late polyarthritis

Whilst the primary analyses were of the ILD parameters, all patients had evidence of active myositis with elevated CK levels prior to starting tacrolimus. A significant reduction in serum CK levels was observed in addition to an improvement in muscle strength and reductions in corticosteroid dosing, highlighting the role of tacrolimus as a steroid-sparing agent. Oddis et al. [9] have also reported similar findings in eight anti-synthetase antibodypositive patients treated with tacrolimus 0.075mg/kg/day. Reductions in corticosteroid doses were possible and significant improvements were noted in terms of muscle strength, serum CK levels and functional status. Our case series highlights tacrolimus as an additional therapeutic option in patients with refractory IIM in the presence or absence of ILD. Clearly further work is necessary in this patient group and on the basis of our experience we believe that a prospective, randomized controlled trial is indicated.

Micro RNA analysis reveals novel genes in human systemic lupus erythematosus: miR-21 affects PDCD4 expression and regulates aberrant T cell responses

MicroRNAs (miRNAs) are potent negative regulators of gene expression involved in innate and adaptive immune responses. The authors examined whether miRNAs are implicated in immune deregulation and lymphocyte hyperactivity in human systemic lupus erythematosus (SLE). TaqMan miRNA arrays were used to study the expression of 365 miRNAs. …