Gene profiling in white blood cells predicts infliximab responsiveness in rheumatoid arthritis

As indicators of responsiveness to a tumour necrosis factor (TNF)α blocking agent (infliximab) are lacking in rheumatoid arthritis, we have used gene profiling in peripheral blood mononuclear cells to predict a good versus poor response to infliximab. Thirty three patients with very active disease (Disease Activity Score 28 >5.1) that resisted weekly methotrexate therapy were given infliximab at baseline, weeks 2 and 6, and every 8th week thereafter. The patients were categorized as responders if a change of Disease Activity Score 28 = 1.2 was obtained at 3 months. Mononuclear cell RNAs were collected at baseline and at three months from responders and non-responders. The baseline RNAs were hybridised to a microarray of 10,000 non-redundant human cDNAs. In 6 responders and 7 non-responders, 41 mRNAs identified by microarray analysis were expressed as a function of the response to treatment and an unsupervised hierarchical clustering perfectly separated these responders from non-responders. The informativeness of 20 of these 41 transcripts, as measured by qRT-PCR, was re-assessed in 20 other patients. The combined levels of these 20 transcripts properly classified 16 out of 20 patients in a leave-one-out procedure, with a sensitivity of 90% and a specificity of 70%, whereas a set of only 8 transcripts properly classified 18/20 patients. Trends for changes in various transcript levels at three months tightly correlated with treatment responsiveness and a down-regulation of specific transcript levels was observed in non-responders only. Our gene profiling obtained by a non-invasive procedure should now be used to predict the likely responders to an infliximab/methotrexate combination

Lipocalin Genes and Their Evolutionary History

Producción CientíficaAs extensively detailed elsewhere in this book, lipocalins exibit three characteristic features, which include: (i) an unusually low amino acid sequence similarity (typically 15-25% between paralogs) (ii) a highly conserved protein tertiary structure, and (iii) a similar arrangement of exons and introns in the coding sequence of their genes. These shared protein and gene features are overwhelming arguments for the existence of a single lipocalin ancestral gene that once extended into a family. The ancestral gene appears to have arisen in a group of bacteria, and possibly was inherited by eukaryotes as a result of genome fusion (see Chapter 4). Given this hypothetical beginning, lipocalins are expected to be found in all descendants of the eukaryotic common ancestor. Currently, and aside of prokaryotes, bona fide lipocalin have been recovered from a protoctist, a fungus, several plants, a nematode, several arthropods, a tunicate, a cephalochordate, and many examples of chordates. This review will first focus on the structure of lipocalin genes in eukaryotes, and then on our current view of the evolutionary hostory of this family