Lack of Mycobacterium tuberculosis-specific interleukin-17A-producing CD4(+) T cells in active disease.

Protective immunity to Mycobacterium tuberculosis (Mtb) is commonly ascribed to a Th1 profile; however, the involvement of Th17 cells remains to be clarified. Here, we characterized Mtb-specific CD4(+) T cells in blood and bronchoalveolar lavages (BALs) from untreated subjects with either active tuberculosis disease (TB) or latent Mtb infection (LTBI), considered as prototypic models of uncontrolled or controlled infection, respectively. The production of IL-17A, IFN-γ, TNF-α, and IL-2 by Mtb-specific CD4(+) T cells was assessed both directly ex vivo and following in vitro antigen-specific T-cell expansion. Unlike for extracellular bacteria, Mtb-specific CD4(+) T-cell responses lacked immediate ex vivo IL-17A effector function in both LTBI and TB individuals. Furthermore, Mtb-specific Th17 cells were absent in BALs, while extracellular bacteria-specific Th17 cells were identified in gut biopsies of healthy individuals. Interestingly, only Mtb-specific CD4(+) T cells from 50% of LTBI but not from TB subjects acquired the ability to produce IL-17A following Mtb-specific T-cell expansion. Finally, IL-17A acquisition by Mtb-specific CD4(+) T cells correlated with the coexpression of CXCR3 and CCR6, currently associated to Th1 or Th17 profiles, respectively. Our data demonstrate that Mtb-specific Th17 cells are selectively undetectable in peripheral blood and BALs from TB patients.

Overlap Between Common Genetic Polymorphisms Underpinning Kidney Traits and Cardiovascular Disease Phenotypes: The CKDGen Consortium.

BACKGROUND: Chronic kidney disease is associated with cardiovascular disease. We tested for evidence of a shared genetic basis to these traits. STUDY DESIGN: We conducted 2 targeted analyses. First, we examined whether known single-nucleotide polymorphisms (SNPs) underpinning kidney traits were associated with a series of vascular phenotypes. Additionally, we tested whether vascular SNPs were associated with markers of kidney damage. Significance was set to 1.5×10(-4) (0.05/325 tests). SETTING & PARTICIPANTS: Vascular outcomes were analyzed in participants from the AortaGen (20,634), CARDIoGRAM (86,995), CHARGE Eye (15,358), CHARGE IMT (31,181), ICBP (69,395), and NeuroCHARGE (12,385) consortia. Tests for kidney outcomes were conducted in up to 67,093 participants from the CKDGen consortium. PREDICTOR: We used 19 kidney SNPs and 64 vascular SNPs. OUTCOMES & MEASUREMENTS: Vascular outcomes tested were blood pressure, coronary artery disease, carotid intima-media thickness, pulse wave velocity, retinal venular caliber, and brain white matter lesions. Kidney outcomes were estimated glomerular filtration rate and albuminuria. RESULTS: In general, we found that kidney disease variants were not associated with vascular phenotypes (127 of 133 tests were nonsignificant). The one exception was rs653178 near SH2B3 (SH2B adaptor protein 3), which showed direction-consistent association with systolic (P = 9.3 ×10(-10)) and diastolic (P = 1.6 ×10(-14)) blood pressure and coronary artery disease (P = 2.2 ×10(-6)), all previously reported. Similarly, the 64 SNPs associated with vascular phenotypes were not associated with kidney phenotypes (187 of 192 tests were nonsignificant), with the exception of 2 high-correlated SNPs at the SH2B3 locus (P = 1.06 ×10(-07) and P = 7.05 ×10(-08)). LIMITATIONS: The combined effect size of the SNPs for kidney and vascular outcomes may be too low to detect shared genetic associations. CONCLUSIONS: Overall, although we confirmed one locus (SH2B3) as associated with both kidney and cardiovascular disease, our primary findings suggest that there is little overlap between kidney and cardiovascular disease risk variants in the overall population. The reciprocal risks of kidney and cardiovascular disease may not be genetically mediated, but rather a function of the disease milieu itself.

Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-gamma release assay vs. tuberculin skin test.

BACKGROUND: Antitumour necrosis factor (anti-TNF) treatments may reactivate latent tuberculosis infection (LTBI). For detecting LTBI, the tuberculin skin test (TST) has low sensitivity and specificity. Interferon-gamma release assays (IGRA) have been shown to be more sensitive and specific than TST. OBJECTIVE: To compare the TST and the T-SPOT.TB IGRA for identifying LTBI in patients with psoriasis before anti-TNF treatment. METHODS: A retrospective study was carried out over a 4-year period on patients with psoriasis requiring anti-TNF treatment. All were subjected to the TST, T-SPOT.TB and chest X-ray. Risk factors for LTBI and history of bacillus Calmette-Guérin (BCG) vaccination were recorded. The association of T-SPOT.TB and TST results with risk factors for LTBI was tested through univariate logistic regression models. Agreement between tests was quantified using kappa statistics. Treatment for LTBI was started 1 month before anti-TNF therapy when indicated. RESULTS: Fifty patients were included; 90% had prior BCG vaccination. A positive T-SPOT.TB was strongly associated with a presumptive diagnosis of LTBI (odds ratio 7.43; 95% confidence interval 1.38-39.9), which was not the case for the TST. Agreement between the T-SPOT.TB and TST was poor, kappa = 0.33 (SD 0.13). LTBI was detected and treated in 20% of the patients. In 20% of the cases, LTBI was not retained in spite of a positive TST but a negative T-SPOT.TB. All patients received an anti-TNF agent for a median of 56 weeks (range 20-188); among patients with a positive TST/negative T-SPOT.TB, no tuberculosis was detected with a median follow-up of 64 weeks (44-188). One case of disseminated tuberculosis occurred after 28 weeks of adalimumab treatment in a patient with LTBI in spite of treatment with rifampicin. CONCLUSION: This study is the first to underline the frequency of LTBI in patients with psoriasis (20%), and to support the use of IGRA instead of the TST for its detection. Nevertheless, there is still a risk of tuberculosis under anti-TNF therapy, even if LTBI is correctly diagnosed and treated.

Transcriptome of a mouse kidney cortical collecting duct cell line: effects of aldosterone and vasopressin.

Aldosterone and vasopressin are responsible for the final adjustment of sodium and water reabsorption in the kidney. In principal cells of the kidney cortical collecting duct (CCD), the integral response to aldosterone and the long-term functional effects of vasopressin depend on transcription. In this study, we analyzed the transcriptome of a highly differentiated mouse clonal CCD principal cell line (mpkCCD(cl4)) and the changes in the transcriptome induced by aldosterone and vasopressin. Serial analysis of gene expression (SAGE) was performed on untreated cells and on cells treated with either aldosterone or vasopressin for 4 h. The transcriptomes in these three experimental conditions were determined by sequencing 169,721 transcript tags from the corresponding SAGE libraries. Limiting the analysis to tags that occurred twice or more in the data set, 14,654 different transcripts were identified, 3,642 of which do not match known mouse sequences. Statistical comparison (at P < 0.05 level) of the three SAGE libraries revealed 34 AITs (aldosterone-induced transcripts), 29 ARTs (aldosterone-repressed transcripts), 48 VITs (vasopressin-induced transcripts) and 11 VRTs (vasopressin-repressed transcripts). A selection of the differentially-expressed, hormone-specific transcripts (5 VITs, 2 AITs and 1 ART) has been validated in the mpkCCD(cl4) cell line either by Northern blot hybridization or reverse transcription-PCR. The hepatocyte nuclear transcription factor HNF-3-alpha (VIT39), the receptor activity modifying protein RAMP3 (VIT48), and the glucocorticoid-induced leucine zipper protein (GILZ) (AIT28) are candidate proteins playing a role in physiological responses of this cell line to vasopressin and aldosterone.

Interferon-gamma release assays for the diagnosis of tuberculosis and tuberculosis infection in HIV-infected adults: a systematic review and meta-analysis.

Background: Despite the widespread use of interferon-gamma release assays (IGRAs), their role in diagnosing tuberculosis and targeting preventive therapy in HIV-infected patients remains unclear. We conducted a comprehensive systematic review to contribute to the evidence-based practice in HIV-infected people. Methodology/Principal Findings: We searched MEDLINE, Cochrane, and Biomedicine databases to identify articles published between January 2005 and July 2011 that assessed QuantiFERON H -TB Gold In-Tube (QFT-GIT) and T-SPOT H .TB (T-SPOT.TB) in HIV-infected adults. We assessed their accuracy for the diagnosis of tuberculosis and incident active tuberculosis, and the proportion of indeterminate results. The search identified 38 evaluable studies covering a total of 6514 HIV-infected participants. The pooled sensitivity and specificity for tuberculosis were 61% and 72% for QFT-GIT, and 65% and 70% for T-SPOT.TB. The cumulative incidence of subsequent active tuberculosis was 8.3% for QFT-GIT and 10% for T-SPOT.TB in patients tested positive (one study each), and 0% for QFT-GIT (two studies) and T-SPOT.TB (one study) respectively in those tested negative. Pooled indeterminate rates were 8.2% for QFT-GIT and 5.9% for T-SPOT.TB. Rates were higher in high burden settings (12.0% for QFT-GIT and 7.7% for T-SPOT.TB) than in low-intermediate burden settings (3.9% for QFT-GIT and 4.3% for T-SPOT.TB). They were also higher in patients with CD4 + T-cell count, 200 (11.6% for QFT-GIT and 11.4% for T-SPOT.TB) than in those with CD4 + T-cell count $ 200 (3.1% for QFT-GIT and 7.9% for T-SPOT.TB). Conclusions/Significance: IGRAs have suboptimal accuracy for confirming or ruling out active tuberculosis disease in HIV-infected adults. While their predictive value for incident active tuberculosis is modest, a negative QFT-GIT implies a very low short- to medium-term risk. Identifying the factors associated with indeterminate results will help to optimize the use of IGRAs in clinical practice, particularly in resource-limited countries with a high prevalence of HIV-coinfection.

Diagnosis of tuberculosis infection using interferon-γ-based assays

Interferon-γ-based assays, collectively known as IFN-γ release assays (IGRAs), have emerged as a reliable alternative to the old tuberculin skin test (TST) for the immunodiagnosis of tuberculosis (TB) infection. The 2 commercially available tests, the enzyme-linked immunosorbent assay (ELISA), QuantiFERON-TB Gold Intube (QFT-IT), and the enzyme-linked immunospot assay (ELISPOT), T-SPOT.TB, are more accurate than TST for the diagnosis of TB, since they are highly specific and correlate better with the existence of risk factors for the infection. According to the available data, T-SPOT.TB obtains a higher number of positive results than QFT-IT, while its specificity seems to be lower. Although the sensitivity of the IFN-γ -based assays may be impaired to some extent by cellular immunosuppression and extreme ages of life, they perform better than TST in these situations. Data from longitudinal studies suggest that IFN-γ-based tests are better predictors of subsequent development of active TB than TST; however this prognostic value has not been consistently demonstrated. This review focuses on the clinical use of the IFN-γ -based tests in different risk TB groups, and notes the main limitations and areas for future development.

Long-term close follow-up of chorioretinal lesions in presumed ocular tuberculosis.

PURPOSE: To evaluate the long-term outcome (up to 7 years) of presumed ocular tuberculosis (TB) when the therapeutic decision was based on WHO guidelines. METHODS: Twelve out of 654 new uveitic patients (1998-2004) presented with choroiditis and positive tuberculosis skin test (TST) (skin lesion diameter >15 mm). Therapy was administered according to WHO recommendations after ophthalmic and systemic investigation. The area size of ocular lesions at presentation and after therapy, measured on fluorescein and indocyanine green angiographies, was considered the primary outcome. Relapse of choroiditis was considered a secondary outcome. The T-SPOT TB test was performed when it became available. RESULTS: Visual acuity significantly improved after therapy (p=0.0357). The mean total surface of fluorescein lesions at entry was 44.8 ± 20.9 (arbitrary units) and decreased to 32.5 ± 16.9 after therapy (p=0.0165). The mean total surface of indocyanine green lesions at entry was 24.5 ± 13.3 and decreased to 10.8 ± 5.4 after therapy (p=0.0631). The T-SPOT TB revealed 2 false TST-positive results. The mean follow-up was 4.5 ± 1.5 years. Two relapses out of 10 confirmed ocular TB was observed after complete lesion healing, 2.5 years and 4.5 years after therapy, respectively. CONCLUSIONS: A decrease of ocular lesion mean size and a mean improvement of VA were observed after antituberculous therapy. Our long-term follow-up of chorioretinal lesions demonstrated relapse of ocular tuberculosis in 10% of patients with confirmed ocular TB, despite complete initial retinal scarring.

Prospective monitoring of a CD4(+) CD25(high) CD45RO(+) CD127(high) T cell population after first kidney transplantation following thymoglobulin or basiliximab induction

Introduction: Recent data have suggested that a population of CD4+ CD25high T cells, phenotypically characterized by the expression of CD45RO and CD127, is significantly expanded in stable liver and kidney transplant recipients and represents alloreactive T cells. Induction therapies may have an impact on this alloreactive T cell population. In this study, we prospectively analyzed CD4+ CD25high CD45RO+ CD127high T cells after induction with either thymoglobulin or basiliximab. Patients & methods: A total of twenty-seven kidney transplant recipients were prospectively enrolled; 14 received thymoglobulin induction followed by a 4-day course of steroids with tacrolimus and mycophenolate mofetil ("thymo group"), and 13 received basiliximab induction followed by standard triple immunosuppression (tacrolimus, mycophenolate mofetil and prednisone) ("BSX group"). Phenotypical analysis by flow cytometry of the expression of CD25, CD45RO and CD127 on peripheral CD4+ T cells was performed at 0, 3 and 6 months after transplantation. Twenty-four healthy subjects (HS) were studied as controls. Results: There were no differences in baseline characteristics between the groups; at 6 months, patient survival (100%), graft survival (100%), serum creatinine (thymo versus BSX group: 129 versus 125 μmol/l) and acute rejection (2/14 versus 2/13) were not significantly different. Thymo induction produced a strong CD4 T cell depletion. As compared to pre-transplantation values, an expansion of the alloreactive T cell population was observed at 3 months in both thymo (mean: from 6.38% to 14.72%) and BSX (from 8.01% to 18.42%) groups. At 6 months, the alloreactive T cell population remained significantly expanded in the thymo group (16.92 ± 2.87%) whereas it tended to decrease in the BSX group (10.22 ± 1.38%). Conclusion: Overall, our results indicate that the expansion of alloreactive T cells occurs rapidly after transplantation in patients receiving either thymo or BSX induction. Whether differences at later timepoints or whether different IS regimens may modify this alloreactive population remains to be studied.

Les conséquences rénales de l'anorexie [Anorexia nervosa and the kidney].

Anorexia nervosa (AN) is a severe and potentially lethal disease of the young woman. It is defined as an anxious disorder not to gain weight, and an obsessive behavior regarding body weight and physical appearance. Different and variable patterns of behaviour are observed. This article focuses on the renal problems observed in anorexic patients. Anorexia is often associated with severe electrolyte disturbances, such as hypokalemia and hypophosphatemia, and alterations of water metabolism with hyponatremia and edema. Hypokalemia and chronic dehydration may contribute to the development of renal failure. Even end stage renal disease can be observed in these patients. A better understanding of the pathophysiology might improve treatment of patients suffering from AN.

Apport de l'utltrasonographie dans la chirurgie d'épargne du rein et du testicule [Benefits of ultrasonography in kidney and testicular-sparing surgery].

Renal and testicular cancers account for 4% and 1% of all malignancies, respectively. Their prevalence has increased over the past years and is related to the widespread use of medical imaging and the incidental findings of small asymptomatic tumors on computed tomography scanners and ultrasounds examinations. The urologist faces the dilemma of overtreating benign asymptomatic lesions with radical surgery. Therefore, organ-sparing surgery was developed. Recent studies have shown that recurrence rates are often similar between organ-sparing and radical surgery for small kidney or testicular tumors. However, the risk of positive surgical margins consecutive to organ-sparing surgery remains a matter of debate. This article discusses the role of ex-vivo peroperative ultrasonography in predicting negative surgical margins during kidney- and testicular-sparing surgery.

Mycobacterium tuberculosis subverts innate immunity to evade specific effectors.

The macrophage is the niche of the intracellular pathogen Mycobacterium tuberculosis. Induction of macrophage apoptosis by CD4(+) or CD8(+) T cells is accompanied by reduced bacterial counts, potentially defining a host defense mechanism. We have already established that M. tuberculosis-infected primary human macrophages have a reduced susceptibility to Fas ligand (FasL)-induced apoptosis. To study the mechanisms by which M. tuberculosis prevents apoptotic signaling, we have generated a cell culture system based on PMA- and IFN-gamma-differentiated THP-1 cells recapitulating the properties of primary macrophages. In these cells, nucleotide-binding oligomerization domain 2 or TLR2 agonists and mycobacterial infection protected macrophages from apoptosis and resulted in NF-kappaB nuclear translocation associated with up-regulation of the antiapoptotic cellular FLIP. Transduction of a receptor-interacting protein-2 dominant-negative construct showed that nucleotide-binding oligomerization domain 2 is not involved in protection in the mycobacterial infection system. In contrast, both a dominant-negative construct of the MyD88 adaptor and an NF-kappaB inhibitor abrogated the protection against FasL-mediated apoptosis, showing the implication of TLR2-mediated activation of NF-kappaB in apoptosis protection in infected macrophages. The apoptosis resistance of infected macrophages might be considered as an immune escape mechanism, whereby M. tuberculosis subverts innate immunity signaling to protect its host cell against FasL(+)-specific cytotoxic lymphocytes.

Fever of unknown origin in a Swiss-born child: don't miss tuberculosis!

Tuberculosis incidence is low in Switzer land. We report here on a Swiss-born toddler. Tuberculosis manifested with a fever of unknown origin, mimicking an inflammatory or autoimmune disorder triggering a high dose of corticosteroid treatment. The disease went unrecognized for several weeks until development of a miliary tuberculosis with advanced central nervous system involvement. This case highlights the difficulties encountered in diagnosing tuberculosis and in identifying the origin of this case. It reminds us that this disease must never be forgotten when facing a child with persistent fever who must be screened for, before starting immunosuppressive therapy.

Incidence of Infectious Complications in Kidney Transplant Recipients Receiving Induction with Basiliximab, Thymoglobulin or Both

Background: The possible additional risk of infection in patients receiving induction with both basiliximab (Ba) and thymoglobulin (Th) is unclear. We assessed the 1-year incidence of infectious complications in 3 groups of kidney transplant recipients according to the type of induction therapy received.Methods: We compared the incidence of infection at 1 year in 3 groups of patients at our institution: fi rst transplant recipients received Ba 20mg at days 0 and 4 (Group Ba); in case of retransplantation or if PRA was >20% patients received Th 1 mg/kg for 3-5 days (Group Th); in case of delayed graft function (DGF), Ba was discontinued and Th was initiated (Group Ba+Th) or prolonged in Group Th. Kaplan-Meier curves were used to calculate the incidence of infection. A Cox analysis was used to identify risk factors for the development of infection.Results: Over 5 years, 170 consecutive kidney transplant recipients were performed:n=113 in Group Ba, n=39 in Group Th and n=18 in Group Ba+Th. As expected, more patients in Group Th received a second transplant (p<0.001). No differences in CMV serostatus were observed between groups (p=0.9). Incidences of CMV infection, CMV disease, BK viremia, BK nephropathy and urinary tract infection (UTI) is shown in Table 1. Table 1 Group Ba (n=113) Group Th (n=38) Group Ba+Th (n=18) CMV infection 31 (27%) 20 (51%) 8 (44%) CMV disease 7 (6%) 4 (10%) 0 BK viremia 11 (8%) 5 (13%) 4 (22%) BK nephropathy 5 (4%) 1 (2%) 2 (11%) UTI 43 (38%) 23 (59%) 6 (33%) Incidences of infection according to type of induction In a multivariate model taking into account CMV serostatus, age, pretransplant dialysis, type of organ transplanted, number of transplants and type of induction, Group Ba carried a lower risk of CMV infection (OR 0.45, p=0.006), and UTI (OR=0.6, p=0.05), but there were no differences in CMV disease (p=0.38). There was a trend towards higher incidence of BK viremia, but not nephropathy in Group Ba+Th (OR 2.2, p=0.23). There were no signifi cant differences in kidney function or graft loss at 1 year between groups.Conclusion: By multivariate analysis, we observed a lower risk of CMV infection andUTI in patients receiving Ba. The group Ba+Th had a similar risk for infection than the group receiving Th alone. Larger studies are needed to clarify whether combining Ba+Th in the setting of DGF may increase the risk of infectious complications, in particular BK infection.

Acute norovirus-induced agranulocytosis in a pediatric kidney transplant recipient.

Norovirus (NoV) infection is usually limited to the gastrointestinal (GI) tract. However, in immunocompromised patients, this infection might lead to severe life-threatening complications. We herein describe a pediatric kidney transplant patient who presented with an acute NoV infection complicated by febrile agranulocytosis that resolved with improvement of her GI illness. This unusual presentation has not been described before, to our knowledge. The aim of this article is to highlight the sometimes dramatic clinical presentation of NoV infection in immunosuppressed patients, and the importance of including this infection in the differential diagnosis of neutropenia in that specific population.

Tuberculosis diagnostics and biomarkers: needs, challenges, recent advances, and opportunities.

Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics.