Human FcγRIIA induces anaphylactic and allergic reactions

IgE and IgE receptors (FcεRI) are well-known inducers of allergy. We recently found in mice that active systemic anaphylaxis depends on IgG and IgG receptors (FcγRIIIA and FcγRIV) expressed by neutrophils, rather than on IgE and FcεRI expressed by mast cells and basophils. In humans, neutrophils, mast cells, basophils, and eosinophils do not express FcγRIIIA or FcγRIV, but FcγRIIA. We therefore investigated the possible role of FcγRIIA in allergy by generating novel FcγRIIA-transgenic mice, in which various models of allergic reactions induced by IgG could be studied. In mice, FcγRIIA was sufficient to trigger active and passive anaphylaxis, and airway inflammation in vivo. Blocking FcγRIIA in vivo abolished these reactions. We identified mast cells to be responsible for FcγRIIA-dependent passive cutaneous anaphylaxis, and monocytes/macrophages and neutrophils to be responsible for FcγRIIA-dependent passive systemic anaphylaxis. Supporting these findings, human mast cells, monocytes and neutrophils produced anaphylactogenic mediators after FcγRIIA engagement. IgG and FcγRIIA may therefore contribute to allergic and anaphylactic reactions in humans.     

Febrile urinary tract infection after pediatric kidney transplantation: a multicenter,prospective observational study

Background

Febrile urinary tract infections (fUTIs) are common after kidney transplantation (KTx); however, prospective data in a multicenter pediatric cohort are lacking. We designed a prospective registry to record data on fUTI before and after pediatric KTx.

Methods

Ninety-eight children (58 boys and 40 girls)?≤?18 years from 14 mid-European centers received a kidney transplant and completed a 2-year follow-up.

Results

Posttransplant, 38.7 % of patients had at least one fUTI compared with 21.4 % before KTx (p?=?0.002). Before KTx, fUTI was more frequent in patients with congenital anomalies of kidneys and urinary tract (CAKUT) vs. patients without (38 % vs. 12 %; p?=?0.005). After KTx, fUTI were equally frequent in both groups (48.7 % vs. 32.2 %; p?=?0.14). First fUTI posttransplant occurred earlier in boys compared with girls: median range 4 vs. 13.5 years (p?=?0.002). Graft function worsened (p?<?0.001) during fUTI, but no difference was recorded after 2 years. At least one recurrence of fUTI was encountered in 58 %.

Conclusion

This prospective study confirms a high incidence of fUTI after pediatric KTx, which is not restricted to patients with CAKUT; fUTIs have a negative impact on graft function during the infectious episode but not on 2-year graft outcome.

     

Short-term inhibition of DPP-4 enhances endothelial regeneration after acute arterial injury via enhanced recruitment of circulating progenitor cells

Background

Endothelial injuries regularly occur in atherosclerosis and during interventional therapies of the arterial occlusive disease. Disturbances in the endothelial integrity can lead to insufficient blood supply and bear the risk of thrombus formation and acute vascular occlusion. At present, effective therapeutics to restore endothelial integrity are barely available.We analyzed the effect of pharmacological DPP-4-inhibition by Sitagliptin on endogenous progenitor cell-based endothelial regeneration via the SDF-1α/CXCR4-axis after acute endothelial damage in a mouse model of carotid injury.

Methods and Results

Induction of a defined endothelial injury was performed in the carotid artery of C57Bl/6 mice which led to a local upregulation of SDF-1α expression. Animals were treated with placebo, Sitagliptin or Sitagliptin + AMD3100. Using mass spectrometry we could prove that Sitagliptin prevented cleavage of the chemokine SDF-1α. Accordingly, increased SDF-1α concentrations enhanced recruitment of systemically applied and endogenous circulating CXCR4 + progenitor cells to the site of vascular injury followed by a significantly accelerated reendothelialization as compared to placebo-treated animals. Improved endothelial recovery, as well as recruitment of circulating CXCR4 + progenitor cells (CD133 +, Flk1 +), was reversed by CXCR4-antagonization through AMD3100. In addition, short-term Sitagliptin treatment did not significantly promote neointimal or medial hyperplasia.

Conclusion

Sitagliptin can accelerate endothelial regeneration after acute endothelial injury. DPP-4 inhibitors prevent degradation of the chemokine SDF-1α and thus improve the recruitment of regenerative circulating CXCR4 + progenitor cells which mediate local endothelial cell proliferation without adversely affecting vessel wall architecture.     

Improved survival for adolescents and young adults with Hodgkin lymphoma and continued high survival for children in the Netherlands: a population-based study during 1990–2015

Population-based studies that assess long-term patterns of incidence, major aspects of treatment and survival are virtually lacking for Hodgkin lymphoma (HL) at a younger age. This study assessed the progress made for young patients with HL (<25 years at diagnosis) in the Netherlands during 1990–2015. Patient and tumour characteristics were extracted from the population-based Netherlands Cancer Registry. Time trends in incidence and mortality rates were evaluated with average annual percentage change (AAPC) analyses. Stage at diagnosis, initial treatments and site of treatment were studied in relation to observed overall survival (OS). A total of 2619 patients with HL were diagnosed between 1990 and 2015. Incidence rates increased for 18–24-year-old patients (AAPC + 1%, P = 0·01) only. Treatment regimens changed into less radiotherapy and more ‘chemotherapy only’, different for age group and stage. Patients aged 15–17 years were increasingly treated at a paediatric oncology centre. The 5-year OS for children was already high in the early 1990s (93%). For patients aged 15–17 and 18–24 years the 5-year OS improved from 84% and 90% in 1990–1994 to 96% and 97% in 2010–2015, respectively. Survival for patients aged 15–17 years was not affected by site of treatment. Our present data demonstrate that significant progress in HL treatment has been made in the Netherlands since 1990.     

The PML domain of PML–RARα blocks senescence to promote leukemia

In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein–retinoic acid receptor α (PML–RARα) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML–RARα (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19^ARF cell-cycle regulators. This induction coincides with a loss of the cancer-associated ATRX/Daxx–histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.Acute promyelocytic leukemia (APL) is characterized by chromosomal translocations involving retinoic acid receptor alpha (RARα) with a limited number of translocation partners. A common feature of APL-promoting fusion proteins is their ability to self-associate. Indeed, previous studies have shown that fusion of RARα with self-associating domains is sufficient to render RARα leukemogenic (1). In APL patients, the predominant leukemogenic protein found in 95–99% of cases is the result of the fusion of promyelocytic leukemia protein (PML) with RARα (human PML–RARα; hPR) (2, 3). RARα and PML are regulatory proteins implicated in multiple aspects of differentiation and development (4) and apoptosis and cellular senescence (5, 6), respectively. Despite speculation, the relevance of senescence in APL is not fully understood (7, 8).Current mouse models recapitulate many key features of the human disease, including a malignant promyelocytic phenotype and sensitivity to all-trans retinoic acid (ATRA), but suffer from incomplete penetrance and long latency until disease presentation (1, 9, 10). We reasoned that the relatively low leukemogenic activity of hPR in mice might be due to modest sequence identity between human and mouse PML (PML: 63% identity; RARα: 98% identity). Consistent with this notion, we have designed an “experimental oncoprotein” corresponding to the fusion of mouse PML with RARα (mPR), which produced myelocytic leukemia similar to hPR-induced murine APL (10) but with higher penetrance and shorter latency periods. Notably, expression of mPR disrupted PML nuclear bodies (PML-NBs), phenocopying hPR-induced APL (11, 12). We show here that senescence-related up-regulation of p21 and p19 is completely lost in primary murine bone marrow cells upon expression of mPR. Furthermore, we find that the assembly of the death domain associated protein (Daxx)–alpha thalassemia/mental retardation syndrome X-linked (ATRX) complex at PML-NBs is disrupted by mPR expression, implicating this PML–ATRX–Daxx (PAX) complex in cellular senescence and tumor suppressor activity for PML (13). This study provides experimental evidence for the relevance of PML-NB disruption in APL genesis.     

Impact of gender and age on risk factor distribution and health perception: evaluation in a prospective population with heart disease

Aim

Several large surveys have highlighted the inadequate risk factor control in populations at elevated cardiovascular risk. These populations would substantially benefit from risk reduction and could demonstrate increased awareness for risk factor control. Risk factor segregation by gender has been previously described, yet its analysis in the medical field frequently omits sociodemographic variables, which could act as potential confounders.

Subject and methods

We analyzed risk factor prevalence in a population of 1,559 patients with severe coronary heart disease prior to a coronary bypass graft (CABG) surgery. Univariate correlations between risk factor type and frequency and gender were explored. Following, multivariable models were fitted to account for sociodemographic aspects associated with gender. Interaction terms were incorporated as fit. Lastly, the correlation between gender-specific risk factor profiles and their association with self-perceived health status was assessed.

Results

Our study identified gender as the main segregating variable for risk factors after multiple adjustments and inclusion of interaction terms. Obesity and hypertension displayed a significant association with the female population (OR?=?1.598, p?=?0.047 and OR?=?3.737, p?=?0.006, respectively), while smoking and elevated alcohol consumption prevailed in males (OR?=?1.77, p?=?0.038 and OR?=?2.768, p?=?0.013, respectively). Additionally, gender-specific analysis of health perception according to risk factor loads revealed that male patients rate their health in overall better terms regardless of their risk profile.

Conclusions

Our study confirmed the role of gender as the primary risk profile segregator after multiple adjustments for potential sociodemographic confounders, even in a population at elevated cardiovascular risk. Subjective health perception, which displayed marked gender differences, should be further investigated as a potential adherence and outcome modulator.