P2RX7, a mediator of IL-1β and IL-18 processing and release, is a ligand-gated cation channel that is expressed by macrophages. In experimental Crgn, P2RX7 deficiency attenuates renal injury, but the underlying mechanism is unknown. Here, we show that P2RX7 levels and the expression of several genes belonging to the Nlrp3-inflammasome pathway are up-regulated in the macrophages of the WKY rat, a strain uniquely susceptible to macrophage-dependent NTN. Importantly, following P2RX7 activation, WKY BMDMs produce markedly increased levels of active caspase-1, IL-1β, and IL-18 when compared with the NTN-resistant LEW rat BMDMs. P2RX7 and active IL-1β, IL-18, and caspase-1 protein levels were markedly increased in the WKY nephritic glomeruli 4 days following induction of NTN, and the use of a P2RX7 antagonist reduced the levels of secreted active IL-1β. Interestingly, the post-translational control of P2RX7-mediated inflammasome activation is under the genetic regulation of two previously identified Crgn quantitative trait loci in the BMDMs and nephritic glomeruli of the WKY rat. In conclusion, we propose a novel mechanism, whereby genetically determined P2RX7 levels in macrophages regulate Nlrp3-inflammasome activation and susceptibility to Crgn.
Summary. Background: Recent studies have shown that a low clinical pretest probability may be adequate for excluding heparin‐induced thrombocytopenia. However, for patients with intermediate or high pretest probability, laboratory testing is essential for confirming or refuting the diagnosis. Rapid assessment of anti‐PF4/heparin‐antibodies may assist clinical decision‐making. Objectives: To evaluate the performance of rapid ID‐H/PF4‐PaGIA. In particular, we verified reproducibility of results between plasma and serum specimens, between fresh and frozen samples, and between different ID‐H/PF4‐polymer lots (polystyrene beads coated with heparin/PF4‐complexes). Patients/Methods: The samples studied were 1376 plasma and 914 corresponding serum samples from patients investigated for suspected heparin‐induced thrombocytopenia between January 2000 and October 2008. Anti‐PF4/heparin‐antibodies were assessed by ID‐H/PF4‐PaGIA, commercially available ELISAs and heparin‐induced platelet aggregation test. Results: Among 914 paired plasma/serum samples we noted discordant results (negative vs. low‐titre positive) in nine instances (1%; 95%CI, 0.4–1.6%). Overall, agreement between titres assessed in plasma vs. serum was highly significant (Spearman correlation coefficient, 0.975; P < 0.0001). Forty‐seven samples tested both fresh and after freezing/thawing showed a good agreement, with one discordant positive/negative result (Spearman correlation coefficient, 0.970; P < 0.0001). Among 1376 plasma samples we noted a strikingly variable incidence of false negative results (none – 82%; 95%CI, 66–98%), depending on the employed ID‐H/PF4‐polymer lot. Faulty lots can be recognized by titrating commercial positive controls and stored samples of HIT‐patients. Conclusion: Laboratories performing the assay should implement stringent internal quality controls in order to recognize potentially faulty ID‐H/PF4‐polymer lots, thus avoiding false negative results.
SummaryMonocyte subsets with differing functional properties have been defined by their expression of CD14 and CD16. We investigated these subsets in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and determined their surface expression of ANCA autoantigens. Flow cytometry was performed on blood from 14 patients with active AAV, 46 patients with AAV in remission and 21 controls. There was no change in the proportion of monocytes in each subset in patients with AAV compared with healthy controls. The expression of CD14 on monocytes from patients with active AAV was increased, compared with patients in remission and healthy controls (P < 0Á01).Patients with PR3-ANCA disease in remission also had increased monocyte expression of CD14 compared with controls (P < 0Á01); however, levels in patients with MPO-ANCA disease in remission were lower than active MPO-ANCA patients, and not significantly different from controls. There was a correlation between CD14 and both PR3 and MPO expression on classical monocytes in AAV patients (r 5 0Á79, P < 0Á0001 and r 5 0Á42, P < 0Á005, respectively). In conclusion, there was an increase in monocyte CD14 expression in active AAV and PR3-ANCA disease in remission. The correlation of CD14 expression with ANCA autoantigen expression in AAV may reflect cell activation, and warrants further investigation into the potential for increased CD14 expression to trigger disease induction or relapse.
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist.1. Green SM, Krauss BS. The numeric scoring of pain: this practice rates a zero out of ten.
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