Micro-RNA analysis of renal biopsies in human lupus nephritis demonstrates up-regulated miR-422a driving reduction of kallikrein-related peptidase 4.

BACKGROUND: Aberrancies in gene expression in immune effector cells and in end-organs are implicated in lupus pathogenesis. To gain insights into the mechanisms of tissue injury, we profiled the expression of micro-RNAs in inflammatory kidney lesions of human lupus nephritis (LN). METHODS: Kidney specimens were from patients with active proliferative, membranous or mixed LN and unaffected control tissue. Micro-RNAs were quantified by TaqMan Low Density Arrays. Bioinformatics was employed to predict gene targets, gene networks and perturbed signaling pathways. Results were validated by transfection studies (luciferase assay, real-time PCR) and in murine LN. Protein expression was determined by immunoblotting and immunohistochemistry. RESULTS: Twenty-four micro-RNAs were dysregulated (9 up-regulated, 15 down-regulated) in human LN compared with control renal tissue. Their predicted gene targets participated in pathways associated with TGF-ß, kinases, NF-κB, HNF4A, Wnt/ß-catenin, STAT3 and IL-4. miR-422a showed the highest upregulation (17-fold) in active LN and correlated with fibrinoid necrosis lesions (ß = 0.63, P = 0.002). In transfection studies, miR-422a was found to directly target kallikrein-related peptidase 4 (KLK4) mRNA. Concordantly, KLK4 mRNA was significantly reduced in the kidneys of human and murine LN and correlated inversely with miR-422a levels. Immunohistochemistry confirmed reduced KLK4 protein expression in renal mesangial and tubular epithelial cells in human and murine LN. CONCLUSIONS: KLK4, a serine esterase with putative renoprotective properties, is down-regulated by miR-422a in LN kidney suggesting that, in addition to immune activation, local factors may be implicated in the disease.

Recent progress in the treatment of lupus nephritis.

The treatment of lupus nephritis has seen significant advances during the past decade mainly due to the publication of well-designed randomized clinical trials (RCTs). The choice of treatment is guided by the histopathologic classification but is also influenced by demographic, clinical, and laboratory characteristics that allow for the identification of patients at risk for more aggressive disease. For the induction arm, low-dose cyclophosphamide regimens and mycophenolate mofetil have been validated as alternatives to the established National Institutes of Health regimen of high-dose cyclophosphamide; for the maintenance phase, azathioprine and mycophenolate compete for treatment of first choice. Rituximab is efficacious in real-life clinical practice but ineffective in clinical trials. The role of recently approved belimumab in lupus nephritis eagerly awaits further documentation. Aggressive management of comorbid conditions, such as hypertension and dyslipidemia, is of utmost importance. Here, we review the latest advances in lupus nephritis therapy with a focus on recent RCTs as well as new biologic agents under development. Furthermore, we propose a therapeutic algorithm in an effort to facilitate clinical decision-making in this gradually changing landscape. Upcoming European and American recommendations should provide further clarification.

Development of lepromatous leprosy following etanercept treatment for arthritis.

We present a case of a patient treated with etanercept (TNF-a antagonist) for psoriatic arthritis, who then developed clinical symptoms of lepromatous leprosy. She presented with multiple erythematous plaques on trunk, face and extremities, saddle nose deformity, alopecia, articular deformities of the feet and peroneal neuropathy. The clinical suspicion of Hansen's Disase was confirmed by the biopsy findings (lepromatous leprosy). On further questioning, the patient stated that her father was diagnosed with leprosy 70 years ago and had spent some years in a leper colony in Spinalonga island in Southern Greece in the 1940s. This first report of Hansen's disease after administration of etanercept highlights the need of careful risk assessment of patients for whom antiTNF treatment is planned.

STAT4 is not associated with type 2 diabetes in the genetically homogeneous population of Crete.

Current classifications of diabetes distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D). However, recent evidence highlights overlap between T1D and T2D. In a recent study, we have suggested for the first time that STAT4 gene polymorphism is associated with increased risk for the development of T1D in the island of Crete, a well-defined area with genetically homogeneous population. The objective of this study was to investigate the putative association of STAT4 polymorphism with T2D. STAT4 encodes a transcription factor that transmits signals induced by several key cytokines, including interleukin-12 (IL-12) and interferon-gamma, a key indicator of T-cell differentiation into type 1 helper T (Th1) cells. Mutated allele T was more common in controls than in individuals with T2D (odds ratio [OR] = 1.59, 95% confidence interval [CI] = 1.022-2.470, p = 0.039). Mutated genotype G/T was more common in nondiabetic individuals than in T2D patients (OR = 1.735, 95% CI = 1.077-2.793, p = 0.024). Our results indicate that whilst allele T of the STAT4 rs7574865 gene polymorphism is associated with susceptibility to T1D, it is not associated with increased risk for and T2D, and thus does not represent a common genetic factor for diabetes.

Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous population.

Rheumatoid arthritis (RA) is a multifactorial disease that is increasing in incidence worldwide. It is associated with a complex mode of inheritance, with many genes being involved in the development and progression of the disease. Genome-wide association studies in different populations have recently revealed a significant association between a TRAF1/C5 and a STAT4 polymorphism and the development of RA. In the present study we performed a case-control study in the population of the island of Crete, Greece, aiming to replicate the former findings in a genetically homogeneous cohort of patients. We found that mutated allele A or genotypes A/A and G/A of the TRAF1/C5 rs10818488 SNP were more common in individuals with RA than in control individuals (odds ratio [OR]=1.7, 95% confidence interval [CI]=1.35-2.15, and OR=2.22, 95% CI=1.61-3.05, respectively). Similarly, mutated allele T or genotypes T/T and G/T of the STAT4 rs7574865 SNP were also associated with susceptibility to RA (OR=1.9, 95% CI=1.46-2.50, and OR=2.37, 95% CI 1.73-2.25, respectively). Thus, we conclude that mutant alleles or genotypes of both polymorphisms examined are associated with the development of RA in our population.