Interleukin-6 and tumour necrosis factor-α differentially regulate lincRNA transcripts in cells of the innate immune system in vivo in human subjects with rheumatoid arthritis.

lincRNAs recently have been discovered as evolutionary conserved transcripts of non-coding DNA sequences and have been implicated in the regulation of cellular differentiation. In humans, molecular studies have suggested a functional role for lincRNAs in cancer development. The aim of the present study was to examine whether these novel molecules are specifically regulated by different cytokines in cells of the innate immune system in humans in vivo and whether lincRNAs thereby might be involved in the pathophysiology of rheumatoid arthritis (RA). Therefore, CD14(+) monocytes were isolated from RA patients before and after anti-IL-6R (tocilizumab) or anti-TNF-α (adalimumab) therapy and lincRNA transcription was analysed by a microarray based experiment. As expected, we found lincRNAs to be present in CD14(+) monocytes of RA patients. However, of the total number of 7.419 lincRNAs examined in this study only a very small number was significantly regulated by either IL-6 or TNF-α (85 lincRNAs, corresponding to 1.1%). The numbers of lincRNAs regulated was higher due to TNF-α compared to IL-6. Interestingly, none of the identified lincRNAs was influenced by both, IL-6 and TNF-α, suggesting the regulation of lincRNA transcription to be highly specific for distinct cytokines. Taken together, our results suggest (1) that lincRNAs are novel intracellular molecular effectors of specific cytokines in cells of the innate immune system in humans in vivo and (2) that lincRNAs might be involved in the molecular pathophysiology of RA.

FabryScan: a screening tool for early detection of Fabry disease.

Fabry disease, an X-linked lipid storage disorder, is associated early morbidity and mortality. Since enzyme replacement therapy is available, accurate detection of unrecognized cases is important. Characteristic early symptoms are recurrent episodes of burning and lancinating pain in the distal extremities associated with small fiber neuropathy. The aim was to develop and validate an easy diagnostic questionnaire in combination with three simple bedside tests, the "FabryScan", for the detection of Fabry disease in patients with chronic extremity pain. Questions related to relevant clinical characteristics of Fabry disease (mainly related to pain) were compiled by Fabry specialists and pain experts. Furthermore, three bedside tests assessing sensory small and large fiber function were established. The provisional version was tested in a prospective multicenter trial of 138 patients with chronic extremity pain due to Fabry disease (n = 55), painful polyneuropathy (n = 40), and rheumatoid arthritis (n = 43). Identification of the most discriminant combinations of items for Fabry disease and their calculation of sensitivity and specificity were based on multivariate analyses. We retained only 10 questions and three bedside tests for the final version of the FabryScan. A cut-off score of 12/33 (corresponding to the number of positive points) resulted in a high proportion of correctly identified patients (76 %) with a sensitivity of 88 % and a specificity of 87 %. The FabryScan is a combination of a brief and simple questionnaire with three simple bedside tests with good discriminative value for the identification of Fabry patients in patients with chronic extremity pain.

Biologics as treatment for systemic lupus: great efforts, sobering results, new challenges.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by specific organ manifestations and the production of autoantibodies to nuclear antigens. SLE can induce severe organ damage and carries the risk of fatal outcome. During recent years, no major progress has been made regarding new treatment options except for the introduction of mycophenolate mofetil. Therefore, the results of several large clinical trials using biological agents for treatment of SLE were hopefully awaited. Yet, the application of abatacept, belimumab and rituximab, respectively, to non-renal or renal lupus patients surprisingly has not been successful. Other studies using different agents have not been completed yet. Nevertheless, the results available so far will have a significant impact on the design of future clinical trials and will stimulate the debate on new targets for treatment of SLE.

Differential signaling by CpG DNA in DCs and B cells: not just TLR9.

CpG-containing oligodeoxynucleotides (CpG ODNs) act on Toll-like receptor 9 (TLR9) that is expressed on B cells and plasmacytoid dendritic cells (pDCs) to stimulate the innate immune system, however, different types of CpG ODNs induce distinct responses. Recent papers suggest some CpG ODNs could require a second receptor or cofactor to signal. The different signaling complexes assembled might impact on the affinity with which CpG ODNs signal to TLR9 or activate additional pathways that lead to distinct immune responses.

Influence of stimulatory and suppressive DNA motifs on host susceptibility to inflammatory arthritis.

OBJECTIVE: To examine whether systemic administration of immunostimulatory and immunosuppressive oligodeoxynucleotides (ODNs) alter host susceptibility to inflammatory arthritis. METHODS: Normal BALB/c mice were treated systemically with CpG ODNs or suppressive ODNs, and then challenged intraarticularly with CpG DNA. The onset and magnitude of the resulting inflammatory response was monitored. RESULTS: Systemic delivery of CpG ODNs significantly increased susceptibility to local inflammation, whereas systemic treatment with suppressive ODNs reduced this susceptibility. CD11c+ cells played a key role in mediating host sensitivity to arthritis. These cells were the dominant source of tumor necrosis factor alpha production in CpG-stimulated animals and transferred resistance to arthritis from mice treated with suppressive ODNs. CONCLUSION: Systemic exposure to immunostimulatory and immunosuppressive DNA influences host susceptibility to local inflammatory challenge. Current findings raise the possibility that suppressive ODNs may be useful in the prevention/treatment of proinflammatory diseases.

Reduction of CpG-induced arthritis by suppressive oligodeoxynucleotides.

OBJECTIVE: Bacterial DNA contains immunostimulatory CpG motifs that cause inflammation when injected into the knee joints of normal mice. We examined whether synthetic oligodeoxynucleotides (ODN) that suppress CpG-induced immune responses prevent CpG-induced arthritis. METHODS: CpG, suppressive, and/or control ODN were injected into the knees of BALB/c mice. Joint swelling and inflammation were evaluated by physical measurement, by histologic analysis of joint tissue, and by magnetic resonance imaging. RESULTS: Immunostimulatory CpG DNA induced local arthritis, characterized by swelling of the knee joints, the presence of inflammatory cell infiltrates, the perivascular accumulation of mononuclear cells, and hyperplasia of the synovial lining. Administering suppressive (but not control) ODN reduced the manifestations and severity of arthritis up to 80%. CONCLUSION: Suppressive ODN may be useful for the prevention or treatment of arthritis induced by bacterial DNA.