Risk Factors for Autoimmune Diseases Development After Thrombotic Thrombocytopenic Purpura

Autoimmune thrombotic thrombocytopenic purpura (TTP) can be associated with other autoimmune disorders, but their prevalence following autoimmune TTP remains unknown. To assess the prevalence of autoimmune disorders associated with TTP and to determine risk factors for and the time course of the development of an autoimmune disorder after a TTP episode, we performed a cross sectional study. Two-hundred sixty-one cases of autoimmune TTP were included in the French Reference Center registry between October, 2000 and May, 2009. Clinical and laboratory data available at time of TTP diagnosis were recovered. Each center was contacted to collect the more recent data and diagnosis criteria for autoimmunity. Fifty-six patients presented an autoimmune disorder in association with TTP, 9 years before TTP (median; min: 2 yr, max: 32 yr) (26 cases), at the time of TTP diagnosis (17 cases) or during follow-up (17 cases), up to 12 years after TTP diagnosis (mean, 22 mo). The most frequent autoimmune disorder reported was systemic lupus erythematosus (SLE) (26 cases) and Sjögren syndrome (8 cases). The presence of additional autoimmune disorders had no impact on outcomes of an acute TTP or the occurrence of relapse. Two factors evaluated at TTP diagnosis were significantly associated with the development of an autoimmune disorder during follow-up: the presence of antidouble stranded (ds)DNA antibodies (hazard ratio (HR): 4.98; 95% confidence interval (CI) [1.64–15.14]) and anti-SSA antibodies (HR: 9.98; 95% CI [3.59–27.76]). A follow-up across many years is necessary after an acute TTP, especially when anti-SSA or anti-dsDNA antibodies are present on TTP diagnosis, to detect autoimmune disorders early before immunologic events spread to prevent disabling complications.     

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.Metastatic melanoma is a highly aggressive cancer with a fast increasing incidence worldwide. Unless diagnosed early and surgically resected, the disease becomes metastatic and life threatening. Both chemotherapy and irradiation are ineffective. Novel therapies that target oncogenic drivers have brought some improvements, but tumor cells escape regularly (1). Melanoma is a prototypical immunogenic tumor, as shown by the occurrence of spontaneous CD8 T-cell responses that drive tumor regressions and by the identification of CD8 T cells that recognize melanoma antigens (2, 3). Although many immunotherapeutic strategies have been developed to induce such responses, clinical efficacies have been poor. More recently, “checkpoint blockade” therapies that target T-cell–inhibitory pathways mediated by CTLA4 (4) and PD1 (5) have yielded encouraging clinical results and demonstrated that spontaneous CD8 T-cell responses in tumors can be boosted to treat melanoma.The mechanisms that drive spontaneous antitumor immune responses are poorly understood. Type I IFNs (IFN-α and IFN-β) may play a role as the expression type I IFN-related genes in primary melanoma has been associated with spontaneous tumor regressions (6) and correlated to the tumor infiltration by specific CD8+ T cells (6, 7). Furthermore, the lack of type I IFN signaling or IFN-β expression inhibited the generation of tumor-specific CD8 T cells and accelerated tumor growth in a murine melanoma model (7–9).Type I IFNs are typically induced upon recognition of nucleic acids in intracellular compartments. Several cytosolic DNA receptors have been identified and include DNA-dependent activator of IFN-regulatory factors (DAI) (10), gamma-interferon-inducible protein-16 (IFI16) (11), and the helicase DEAD (Asp-Glu-Ala-Asp) box protein 41 (DDX41) (12). These cytosolic receptors trigger IFN-β production via a signaling cascade that involves the master adaptor molecule stimulator of IFN genes (STING), which binds to tank-binding kinase 1 (TBK1) and induces phosphorylation of the interferon regulatory factor 3 (IRF3) (13). STING associates weakly to dsDNA (14) but strongly binds the endogenous cyclic dinucleotide GMP-AMP (cGAMP) synthesized by the cGMP-AMP synthase (cGAS) (15, 16).Recently, spontaneous STING activation was found to be required for the spontaneous induction of antitumor immunity (17). Activation of STING occurred via tumor DNA-dependent cGAS activation and generation of endogenous cGAMP (17, 18). However, the cellular mechanism underlying this response and whether this mechanism could be exploited to generate more efficient antitumor immune responses is currently unknown.Here, we show that intratumoral injection of exogenous cGAMP enhanced STING activation and strongly promoted the generation of antitumor CD8 T-cell responses leading to efficient growth control of injected and contralateral tumors. This response was dependent on IFN-β produced by tumor endothelial cells. In fact, endothelial cells were found to be the principal producers of type I IFN in response to both spontaneous and enforced STING activation, suggesting a role of the tumor vasculature in the initiation of antitumor immunity.     

Quantitative elastography of renal transplants using supersonic shear imaging: a pilot study

Purpose

To evaluate the reliability of quantitative ultrasonic measurement of renal allograft elasticity using supersonic shear imaging (SSI) and its relationship with parenchymal pathological changes.

Materials and methods

Forty-three kidney transplant recipients (22 women, 21 men) (mean age, 51?years; age range, 18–70?years) underwent SSI elastography, followed by biopsy. The quantitative measurements of cortical elasticity were performed by two radiologists and expressed in terms of Young’s modulus (kPa). Intra- and inter-observer reproducibility was assessed (Kruskal-Wallis test and Bland-Altman analysis), as well as the correlation between elasticity values and clinical, biological and pathological data (semi-quantitative Banff scoring). Interstitial fibrosis was evaluated semi-quantitatively by the Banff score and measured by quantitative image analysis.

Results

Intra- and inter-observer variation coefficients of cortical elasticity were 20?% and 12?%, respectively. Renal cortical stiffness did not correlate with any clinical parameters, any single semi-quantitative Banff score or the level of interstitial fibrosis; however, a significant correlation was observed between cortical stiffness and the total Banff scores of chronic lesions and of all elementary lesions (R?=?0.34, P?=?0.05 and R?=?0.41, P?=?0.03,respectively).

Conclusion

Quantitative measurement of renal cortical stiffness using SSI is a promising non-invasive tool to evaluate global histological deterioration.

Key Points

? Supersonic shear imaging elastography can measure cortical stiffness in renal transplants ? The level of cortical stiffness is correlated with the global degree of tissue lesions ? The global histological deterioration of transplanted kidneys can be quantified using elastography     

Vaccinia virus-induced smallpox postvaccinal encephalitis in case of blood-brain barrier damage

Smallpox vaccination is the only currently effective mean to combat the threat of variola virus used as a bioterrorism agent, although it is responsible for a rare but serious complication, the postvaccinal encephalitis (PVE). Development of safer vaccines therefore is a high priority as the PVE physiopathology is not well understood to date. If vaccinia virus (VACV) is responsible for PVE by central nervous system (CNS) dissemination, trans-migration of the VACV across the blood-brain barrier (BBB) would be supposed to be essential. Given the complexity of the pathogenesis of vaccinia neurovirulence, an in vitro BBB model was used to explore the mechanism of VACV to induce BBB permeability. Two VACV strains were studied, the neurovirulent Western Reserve strain (VACV-WR) and the vaccine reference Lister strain (VACV-List). A mouse model was also developed to study the ability of these two viral strains to propagate in the brain from the blood compartment, their neurovirulence and their neuropathogenesis. In vitro, the loss of permeability resulted from the tight-junctions disruption was induced by virus replication. The ability of VACV to release infectious particles at the abluminal side suggests the capacity of both VACV strains to migrate across the BBB from the blood to the CNS. In vivo, the virus replication in mice CNS was strain-dependent. The VACV-WR laboratory strain proved to be neuroinvasive and neurovirulent, whereas the VACV-List strain is safe in physiological conditions. Mice PVE was observed only with VACV-WR in the co-infection model, when BBB opening was obtained by lipopolysaccharide (LPS) treatment. This study suggests that VACV is able to cross the BBB but encephalitis occurs only in the presence of a co-infection by bacteria. So, a model of co-infection, mimicked by LPS treatment, could have important implication towards the assessment of neurovirulence of new vaccines.     

Prior treatment with alpha interferon does not adversely affect the outcome of allogeneic transplantation for chronic myeloid leukaemia

Summary. The timing of transplantation in chronic myeloid leukaemia is still debated and previous treatment with interferon (IFN) alpha has been reported to be deleterious. We have analysed the outcome of 438 allogeneic transplants performed between 1984 and 1995 and reported to the Société Française de Greffe de Moelle (SFGM) registry. One hundred and two patients (group I) received IFN for more than 6 weeks (median = 9 months) before transplant. Their outcome was compared with 336 other patients (group II) not pretreated with IFN. There were no significant differences between the groups for engraftment and chronic graft‐versus‐host disease (GVHD) incidence. However, other significant differences included the incidence of acute GVHD ≥ 2 at 3 months which was higher in group I (65 ± 10%) than in group II (38 ± 5%; P = 0·01). Moreover, disease‐free survival (DFS) and overall survival (OS) at 5 years were significantly shorter for group I than for group II (33 ± 10% vs. 41 ± 6%; P = 0·005)(95% CI) and (41 ± 10% vs. 55 ± 6%; P = 0·002)(95% CI) respectively. After adjustment for patient and transplant covariables in a multivariate analysis, prior IFN was not found to adversely affect transplant outcome.     

Multiple microthrombi on a papillary fibroelastoma of the aortic valve

We report the case of a cardiac papillary fibroelastoma of the aortic valve resected by simple shaving the pedicle. The macroscopic view showed a jelly-like aspect, with the classical appearance of a sea anemone under water, with multiple slender fronds and numerous little submillimetric thrombi disseminated among the branches of the tumor.     

Evaluation of a Supervised Adapted Physical Activity Program Associated or Not with Oral Supplementation with Arginine and Leucine in Subjects with Obesity and Metabolic Syndrome: A Randomized Controlled Trial

Background: In patients with obesity and metabolic syndrome (MetS), lifestyle interventions combining diet, in particular, and physical exercise are recommended as the first line treatment. Previous studies have suggested that leucine or arginine supplementation may have beneficial effects on the body composition or insulin sensitivity and endothelial function, respectively. We thus conducted a randomized controlled study to evaluate the effects of a supervised adapted physical activity program associated or not with oral supplementation with leucine and arginine in MetS-complicated patients with obesity. Methods: Seventy-nine patients with obesity and MetS were randomized in four groups: patients receiving arginine and leucine supplementation (ALs group, n = 20), patients on a supervised adapted physical activity program (APA group, n = 20), patients combining ALs and APA (ALs+APA group, n = 20), and a control group (n = 19). After the baseline evaluation (m0), patients received ALs and/or followed the APA program for 6 months (m6). Body composition, MetS parameters, lipid and glucose metabolism markers, inflammatory markers, and a cardiopulmonary exercise test (CPET) were assessed at m0, m6, and after a 3-month wash-out period (m9). Results: After 6 months of intervention, we did not observe variable changes in body weight, body composition, lipid and glucose metabolism markers, inflammatory parameters, or quality of life scores between the four groups. However, during the CPET, the maximal power (Pmax and Ppeak), power, and O₂ consumption at the ventilatory threshold (P(VT) and O₂(VT)) were improved in the APA and ALs+APA groups (p < 0.05), as well as the forced vital capacity (FVC). Between m6 and m9, a gain in fat mass was only observed in patients in the APA and ALs+APA groups. Conclusion: In our randomized controlled trial, arginine and leucine supplementation failed to improve MetS in patients with obesity, as did the supervised adapted physical activity program and the combination of both. Only the cardiorespiratory parameters were improved by exercise training.