A stepwise breakdown of B-cell tolerance occurs within renal allografts during chronic rejection

Autoantibodies detected after kidney transplantation may contribute to chronic rejection. We and others have previously described the organization of immune effectors into functional intragraft tertiary lymphoid tissue, a site where breakdown of B-cell tolerance may occur. To test this, we performed a comprehensive analysis of 26 chronically rejected kidney grafts. Antibodies were screened by indirect immunofluorescence on HEp2 cells, a procedure that detects antibodies to intracellular antigens, and monkey kidney sections, which detects kidney tissue autoantigens. The incidence of anti-HEp2 autoantibodies was significantly higher in graft explant culture supernatants than in patient sera. Reactivity against monkey kidney sections was detected in almost half of culture supernatants with anti-HEp2 autoantibodies. A local enrichment in T helper 17 and B-cell-activating factor (CD257) correlated with intragraft production of anti-HEp2 antibodies. A decrease in Tregs and a symmetric increase of activated OX40 (CD134)-expressing CD4+ T cells were found in grafts in which anti-kidney autoantibodies were produced. Thus, a stepwise breakdown of B-cell tolerance occurs within the graft during chronic rejection. Hence, the intragraft microenvironment interferes with peripheral deletion of autoreactive immature B cells that, in turn, produce antibodies against intracellular autoantigens. When intragraft immune regulation is insufficient, spreading of the local response against kidney autoantigens is favored.     

Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir,Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients

Triple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P = 0.5), but there was a significant difference in the 50% effective concentrations (EC₅₀) (P = 0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P = 0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day⁻¹) and was higher in patients who subsequently eradicated HCV (P = 0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients.     

Meningeal Rosai–Dorfman disease mimicking meningioma

Rosai–Dorfman disease of the central nervous system is extremely rare and difficult to diagnose also for pathologists. We describe three unusual cases of meningeal Rosai–Dorfman disease and illustrate the difficulties of preoperative and pathological diagnosis. We retrospectively analyzed three patients who underwent surgery for a suspected meningioma for whom the final diagnosis was Rosai–Dorfman disease of the central nervous system. Pathological initial diagnosis was schwannoma, lymphoplasmacyte-rich meningioma, or inflammatory tumor, but final diagnosis in all cases was Rosai–Dorfman disease. These cases underline the preoperative and pathological difficulties of such diagnosis. Pathologists and physicians should be aware of the occurrence of such rare localization of this disease and should think about this differential diagnosis in lymphocyte-rich meningeal tumors mimicking, clinically and radiologically, a meningioma. Communication of significant previous medical history to pathologists and careful examination of slides with appropriate medical history and the use of S100 antibody in the diagnosis of meningeal tumors mimicking Rosai–Dorfman disease could lower the rate of misdiagnosis.     

Impact of liver disease severity and etiology on the occurrence of diabetes mellitus in patients with liver cirrhosis

The association between liver cirrhosis (LC) and diabetes mellitus (DM) is well known. However, the impact of the severity or etiology of LC on the occurrence of DM is relatively unknown. We aimed to determine the prevalence and clinical correlates of DM in a large cohort of patients with cirrhosis. A total of 1,068 patients with LC were included in this cross sectional study (CIRCE study). The diagnosis of cirrhosis irrespective of its etiology was based on histological confirmation by liver biopsy or, in the absence of biopsy, on typical clinical, morphological and biological data. Data related to the cirrhosis etiology: alcohol, viral markers of hepatitis B, C, iron load parameters and autoimmune markers were collected for each patient. Venous blood samples were taken in the morning after 12-h overnight fasting. There were 383 patients with cirrhosis associated with hepatocellular carcinoma (HCC). DM was found in 412 (39.7 %) patients. Patients with DM were older and more likely to be overweight and male, with a family history of DM and a diagnosis of HCC. DM was not associated with a history of stroke or myocardial infarction. Cirrhosis secondary to hepatitis infection was less strongly associated with DM than with NASH or alcoholic cirrhosis. The severity of LC was not associated with DM. In multivariate analysis, the factors associated with DM were age, BMI, a family history of DM, and statin use. There was a significant interaction between HCC and cirrhosis etiology for the risk of DM. Cirrhosis secondary to hepatitis was associated with a lesser presence of DM only in patients with HCC (interaction p = 0.0015). LC was strongly associated with DM, with around 40 % of diabetic patients. In the group of patients with LC without HCC, diabetes was not associated with the etiology of cirrhosis.     

Effectively introducing a new meningococcal A conjugate vaccine in Africa: the Burkina Faso experience

A new Group A meningococcal (Men A) conjugate vaccine, MenAfriVac?, was prequalified by the World Health Organization (WHO) in June 2010. Because Burkina Faso has repeatedly suffered meningitis epidemics due to Group A Neisseria meningitidis special efforts were made to conduct a country-wide campaign with the new vaccine in late 2010 and before the onset of the next epidemic meningococcal disease season beginning in January 2011. In the ensuing five months (July-November 2010) the following challenges were successfully managed: (1) doing a large safety study and registering the new vaccine in Burkina Faso; (2) developing a comprehensive communication plan; (3) strengthening the surveillance system with particular attention to improving the capacity for real-time polymerase chain reaction (PCR) testing of spinal fluid specimens; (4) improving cold chain capacity and waste disposal; (5) developing and funding a sound campaign strategy; and (6) ensuring effective collaboration across all partners. Each of these issues required specific strategies that were managed through a WHO-led consortium that included all major partners (Ministry of Health/Burkina Faso, Serum Institute of India Ltd., UNICEF, Global Alliance for Vaccines and Immunization, Meningitis Vaccine Project, CDC/Atlanta, and the Norwegian Institute of Public Health/Oslo). Biweekly teleconferences that were led by WHO ensured that problems were identified in a timely fashion. The new meningococcal A conjugate vaccine was introduced on December 6, 2010, in a national ceremony led by His Excellency Blaise Compaore, the President of Burkina Faso. The ensuing 10-day national campaign was hugely successful, and over 11.4 million Burkinabes between the ages of 1 and 29 years (100% of target population) were vaccinated. African national immunization programs are capable of achieving very high coverage for a vaccine desired by the public, introduced in a well-organized campaign, and supported at the highest political level. The Burkina Faso success augurs well for further rollout of the Men A conjugate vaccine in meningitis belt countries.     

Adverse events following immunization during mass vaccination campaigns at first introduction of a meningococcal A conjugate vaccine in Burkina Faso, 2010

MenAfriVac? is a new meningococcal A conjugate vaccine developed to prevent meningitis outbreaks in Africa. It was first introduced during the last quarter of 2010 in three West African countries. We report on the monitoring of adverse events following immunization (AEFI) in Burkina Faso where more than 11 million people aged 1-29 years were vaccinated. Vaccine pharmacovigilance relied on stimulated passive AEFI surveillance countrywide and active surveillance for 12 clinical conditions in one sentinel district (Ziniaré) with 97,715 people eligible for vaccination. All AEFI occurring during the 10 days of mass campaign or the 42 subsequent days were to be notified. Serious AEFI were submitted to a national expert committee (NEC) for causality assessment. A total of 11,466,950 people were vaccinated with 1471 vaccinees reported to have experienced at least one AEFI (12.83 cases per 100,000). 1444 AEFI were minor; the most common of which were fever, headache, gastro-intestinal disorders and local reactions (2-7 cases per 100,000). Of 27 serious AEFI reported, four cases were classified by the NEC as related to vaccine (1 case per 3 million vaccinated) including one case each of exanthematous pustulosis, angioedema, bronchospasm and severe vomiting. Active surveillance identified 71 cases of the 12 conditions of interest. Convulsions, urticaria and bronchospasm were more frequently reported. Attack rates for those conditions were similar to the baseline rates recorded in the same population, over the same time period, a year earlier. With the exception of convulsions in the days following vaccination the distribution of time intervals between vaccination and the occurrence of symptoms did not reveal any temporal clustering. The monitoring of AEFI of MenAfriVac? in Burkina Faso did not suggest special concern regarding the vaccine safety. However, reported possible hypersensitivity reactions to vaccine components would require further review to rule out any anaphylactic reaction.     

Comparing acquired angioedema with hereditary angioedema (types I/II): findings from the Icatibant Outcome Survey

Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1‐INH‐HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1‐INH‐AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1‐INH‐AAE and compare disease characteristics with those with C1‐INH‐HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6‐month intervals during patient follow‐up visits. In the icatibant‐treated population, 16 patients with C1‐INH‐AAE had 287 attacks and 415 patients with C1‐INH‐HAE types I/II had 2245 attacks. Patients with C1‐INH‐AAE versus C1‐INH‐HAE types I/II were more often male (69 versus 42%; P = 0·035) and had a significantly later mean (95% confidence interval) age of symptom onset [57·9 (51·33–64·53) versus 14·0 (12·70–15·26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1‐INH‐AAE versus C1‐INH‐HAE types I/II (mean 12·3 months versus 118·1 months; P = 0·006). Patients with C1‐INH‐AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0·064). Overall, angioedema attacks were more severe in patients with C1‐INH‐HAE types I/II versus C1‐INH‐AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0·001). Median total attack duration was 5·0 h and 9·0 h for patients with C1‐INH‐AAE versus C1‐INH‐HAE types I/II, respectively.     

Unraveling the pathogenesis of Hoyeraal–Hreidarsson syndrome,a complex telomere biology disorder

Hoyeraal–Hreidarsson (HH) syndrome is a multisystem genetic disorder characterized by very short telomeres and considered a clinically severe variant of dyskeratosis congenita. The main cause of mortality, usually in early childhood, is bone marrow failure. Mutations in several telomere biology genes have been reported to cause HH in about 60% of the HH patients, but the genetic defects in the rest of the patients are still unknown. Understanding the aetiology of HH and its diverse manifestations is challenging because of the complexity of telomere biology and the multiple telomeric and non‐telomeric functions played by telomere‐associated proteins in processes such as telomere replication, telomere protection, DNA damage response and ribosome and spliceosome assembly. Here we review the known clinical complications, molecular defects and germline mutations associated with HH, and elucidate possible mechanistic explanations and remaining questions in our understanding of the disease.