Myeloid marker S100A8/A9 and lymphocyte marker, soluble interleukin 2 receptor: biomarkers of hidradenitis suppurativa disease activity?

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory and debilitating disease of the skin. No biomarkers for this disease exist. OBJECTIVES: We set out to test whether angiotensin-converting enzyme (ACE), lysozyme, soluble interleukin 2 receptor (sIL-2R) and S100A8/A9 (calprotectin) are elevated in patients with HS. METHODS: Serum was collected from 29 patients with HS at different stages of the disease, and from 51 controls. ACE, lysozyme, sIL-2R and S100A8/A9 levels were measured. Clinical observation of disease activity was scored according to the Hurley grading system and by a physician global score (PGS) of disease severity. RESULTS: Serum levels of lysozyme and ACE were not increased above the normal reference values in controls or patients with HS. Levels of sIL-2R and S100A8/A9 were significantly higher in patients with HS than in controls (P<0·001 for both sIL-2R and S100A8/A9). Based on the receiver operating characteristic curves, the optimum sIL-2R and S100A8/A9 cut-off values were 375 U mL(-1) and 680 ng mL(-1), respectively, with a sensitivity of 0·79 and specificity of 0·78 for sIL-2R, and 0·86 and 0·88, respectively, for S100A8/A9. No correlations with Hurley classification scores were found. However, when using PGS of disease activity to categorize patients, levels of S100A8/A9, but not sIL-2R, tended to be higher in patients with more active disease. CONCLUSIONS: Levels of S100A8/A9 and sIL-2R, but not ACE or lysozyme, are elevated in the serum of patients with HS. However, there is no correlation between S100A8/A9 or sIL-2R levels and disease stage according to the Hurley classification system. Further research is needed to study the potential of S100A8/A9 to score disease activity in larger cohorts of patients and to predict disease flares.

Mechanical ventilation and the titer of antibodies as risk factors for the development of transfusion-related lung injury.

Purpose. Onset of transfusion-related acute lung injury (TRALI) is suggested to be a threshold-event. Data is lacking on the relation between titer of antibodies infused and onset of TRALI. We determined whether onset of TRALI is dependent on the titer of MHC-I antibodies infused in a combined model of ventilator-induced lung injury and antibody-induced TRALl. Methods. BALB/c mice were ventilated for five hours with low (7.5 ml/kg) or high (15 ml/kg) tidal volume. After three hours of MV, TRALI was induced by infusion of 0.5 mg/kg, 2.0 mg/kg or 4.5 mg/kg MHC-I antibodies. Control animals received vehicle. After five hours of MV, animals were sacrificed. Results. MV with high tidal volumes resulted in increased levels of all markers of lung injury compared to animals ventilated with low tidal MV. In ventilator-induced lung injury, infusion of 4.5 mg/kg of antibodies further increased pulmonary wet-to-dry ratio, pulmonary neutrophil influx and pulmonary KC levels, whereas infusion of lower dose of antibodies did not augment lung injury. In contrast, mice ventilated with low tidal volumes did not develop lung injury, irrespective of the dose of antibody used. Conclusions. In the presence of injurious MV, onset of TRALI depends on the titer of antibodies infused.

Host defence during Klebsiella pneumonia relies on haematopoietic-expressed Toll-like receptors 4 and 2.

In this study, the relative roles of Toll-like receptor (TLR)2 and TLR4 were investigated independently and together. Moreover, we studied the role of haematopoietic compartment in anti-Klebsiella host defence. We infected TLR2 and TLR4 single-, and TLR2×4 double knockout (KO) animals with different doses of Klebsiella pneumoniae. In addition, bone marrow chimeric mice were created and infected. TLR4 played a more prominent role in antibacterial defence than TLR2, considering that only TLR4 KO mice demonstrated enhanced bacterial growth in lungs and spleen 24 h after infection with 3×10³ colony-forming units of Klebsiella compared with wild-type (WT) mice. In late-stage infection or after exposure to a higher infectious dose, bacterial counts in lungs of TLR2 KO animals were elevated compared with WT mice and TLR2×4 KO animals were more susceptible to infection than TLR4 KO mice. TLR signalling in cells of haematopoietic origin is of primary importance in host defence against K. pneumoniae. These data suggest that: 1) TLR4 drives the antibacterial host response after induction of pneumonia with relatively low Klebsiella doses; 2) TLR2 becomes involved at a later phase of the infection and/or upon exposure to higher bacterial burdens; and 3) haematopoietic TLR2 and TLR4 are important for an adequate host response during Klebsiella pneumonia.

The mannose cap of mycobacterial lipoarabinomannan does not dominate the Mycobacterium-host interaction.

Pathogenic mycobacteria have the ability to persist in phagocytic cells and to suppress the immune system. The glycolipid lipoarabinomannan (LAM), in particular its mannose cap, has been shown to inhibit phagolysosome fusion and to induce immunosuppressive IL-10 production via interaction with the mannose receptor or DC-SIGN. Hence, the current paradigm is that the mannose cap of LAM is a crucial factor in mycobacterial virulence. However, the above studies were performed with purified LAM, never with live bacteria. Here we evaluate the biological properties of capless mutants of Mycobacterium marinum and M. bovis BCG, made by inactivating homologues of Rv1635c. We show that its gene product is an undecaprenyl phosphomannose-dependent mannosyltransferase. Compared with parent strain, capless M. marinum induced slightly less uptake by and slightly more phagolysosome fusion in infected macrophages but this did not lead to decreased survival of the bacteria in vitro, nor in vivo in zebra fish. Loss of caps in M. bovis BCG resulted in a sometimes decreased binding to human dendritic cells or DC-SIGN-transfected Raji cells, but no differences in IL-10 induction were observed. In mice, capless M. bovis BCG did not survive less well in lung, spleen or liver and induced a similar cytokine profile. Our data contradict the current paradigm and demonstrate that mannose-capped LAM does not dominate the Mycobacterium-host interaction.