LPS-binding protein and IL-6 Mark paradoxical tuberculosis immune reconstitution inflammatory syndrome in HIV patients

Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB co-infected patients initiating antiretroviral therapy (ART). The role of the innate immune system in TB-IRIS is becoming increasingly apparent, however the potential involvement in TB-IRIS of a leaky gut and proteins that interfere with TLR stimulation by binding PAMPs has not been investigated before. Here we aimed to investigate the innate nature of the cytokine response in TB-IRIS and to identify novel potential biomarkers. Methods: From a large prospective cohort of HIV-TB co-infected patients receiving TB treatment, we compared 40 patients who developed TB-IRIS during the first month of ART with 40 patients matched for age, sex and baseline CD4 count who did not. We analyzed plasma levels of lipopolysaccharide (LPS)-binding protein (LBP), LPS, sCD14, endotoxin-core antibody, intestinal fatty acid-binding protein (I-FABP) and 18 pro-and anti-inflammatory cytokines before and during ART. Results: We observed lower baseline levels of IL-6 (p = 0.041), GCSF (p = 0.036) and LBP (p = 0.016) in TB-IRIS patients. At IRIS event, we detected higher levels of LBP, IL-1RA, IL-4, IL-6, IL-7, IL-8, G-CSF (p ≤ 0.032) and lower I-FABP levels (p = 0.013) compared to HIV-TB co-infected controls. Only IL-6 showed an independent effect in multivariate models containing significant cytokines from pre-ART (p = 0.039) and during TB-IRIS (p = 0.034). Conclusion: We report pre-ART IL-6 and LBP levels as well as IL-6, LBP and I-FABP levels during IRIS-event as potential biomarkers in TB-IRIS. Our results show no evidence of the possible contribution of a leaky gut to TB-IRIS and indicate that IL-6 holds a distinct role in the disturbed innate cytokine profile before and during TB-IRIS. Future clinical studies should investigate the importance and clinical relevance of these markers for the diagnosis and treatment of TB-IRIS. Copyright: © 2013 Goovaerts et al.

IL-12RB1 deficiency and disseminated Mycobacterium tilburgii disease.

Mycobacterium tilburgii rarely causes disseminated disease. We describe a case of M. tilburgii infection in an otherwise healthy 33-year-old woman, who was found to carry bi-allelic mutations of the gene encoding the β1 chain of the IL-12 receptor.

Revisiting human IL-12Rβ1 deficiency: A survey of 141 patients from 30 countries

Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought. © 2010 Lippincott Williams & Wilkins.

Polymorphisms in the interleukin-4 and IL-4 receptor genes modify risk for chronic inflammatory arthropathies in women.

Rheumatoid and juvenile idiopathic arthritis (RA, JIA) are chronic inflammatory arthropathies with polygenic autoimmune background. We analysed the IL-4 +33 C/T and IL-4R Q551R single nucleotide polymorphisms (SNPs) in 294 RA, 72 JIA and 165 controls from Northern Ireland. Analysis of the individual phenotypes (RA or JIA) showed that both the IL-4 +33 TT (P = 0.02; OR: 0.25, 95% CI: 0.07-0.87) and the IL-4R Q551R CC genotypes (P = 0.001; OR: 0.19, 95% CI: 0.06-0.56) were exclusively decreased in female RA patients compared to female controls. Similar non-significant trends were observed in female JIA patients (OR: 0.25, 95% CI: 0.03-2.11 and OR: 0.31, 95% CI: 0.07-1.47, respectively). Analysis of the common phenotype (inflammatory arthropathy; i.e. JIA and RA combined) corroborated the unique association of these polymorphisms with female inflammatory arthropathy (P = 0.013 and 0.002, respectively). This is the first demonstration of sex-specific association of the two foremost genes of the IL-4 signalling cascade with chronic inflammatory arthropathies.

Plasma IL-6 levels correlate with clinical and ultrasound measures of arthritis in patients with systemic lupus erythematosus

ObjectiveThe objective of this paper is to elucidate the role of specific cytokines in lupus (SLE) arthritis.MethodsFifty SLE and 40 RA patients had an ultrasound (US) scan of their hand as per standardized protocols. US scores were expressed per joint and as a total 'US activity' score, (sum of power Doppler (PD) and grey-scale synovial hypertrophy scores in all joints) and a total erosion score. SLE disease activity was assessed (BILAG and SELENA-SLEDAI). Plasma levels of IL-6, TNF-alpha and BLyS were measured using sandwich ELISA kits (Quantikine kits, R & D).ResultsOn the basis of the US results SLE patients were divided into three groups: erosive arthritis (n?=?20), non-erosive arthritis (n?=?18) and those with a normal US scan (n?=?12). Across the SLE groups plasma IL-6 levels correlated with CRP (p?

IL-33 attenuates the development of experimental autoimmune uveitis

Interleukin (IL)-33 is associated with several important immune-mediated disorders. However, its role in uveitis, an important eye inflammatory disease, is unknown. Here we investigated the function of IL-33 in the development of experimental autoimmune uveitis (EAU). IL-33 and IL-33 receptor (ST2) were expressed in murine retinal pigment epithelial (RPE) cells in culture, and IL-33 increased the expression of Il33 and Mcp1 mRNA in RPE cells. In situ, IL-33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in EAU mice. ST2-deficient mice developed exacerbated EAU compared with WT mice, and administration of IL-33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL-33-treated mice was accompanied by decreased frequency of IFN-γ(+) and IL-17(+) CD4(+) T cells and reduced IFN-γ and IL-17 production but with increased frequency of IL-5(+) and IL-4(+) CD4 T cells and IL-5 production in the draining lymph node and spleen. Macrophages from the IL-33-treated mice show a significantly higher polarization towards an alternatively-activated macrophage (M2) phenotype. Our results therefore demonstrate that the endogenous IL-33/ST2 pathway plays an important role in EAU, and suggest that IL-33 represents a potential option for treatment of uveitis.

Opera Workshop, Il Mondo Della Luna, November 10, 2008

Concert program for Opera Workshop, Il Mondo Della Luna, November 10, 2008

Il Mondo Della Luna, Autumn 2008

Concert program for Il Mondo Della Luna, Autumn 2008

HCV infection after liver transplantation is associated with lower levels of alloreactive CD4+CD25+CD45RO+IL-7R+high+ T cells

Aim: Expression of IL-7R discriminates alloreactive CD4 T cells (Foxp3 negative), from IL-7Rlow regulatory CD4 T cells (Foxp3 positive). Chronic hepatitis C virus infection (HCV) reduces expression of IL-7R on T cells thus promoting persistence of infection. The aim of this study was to analyze the effect of HCV infection on the expression of IL-7R of activated CD4+ T cells in liver transplant patients. Patients and methods: We analyzed PBMC from liver transplant recipients for the expression of CD4, CD25, FoxP3, IL-7R (24 HCV negative and 29 HCV-chronically infected). We compared these data with non-transplanted individuals (52 HCV-chronically infected patients and 38 healthy donors). Results: In HCV-infected liver transplant recipients, levels of CD4+CD25+CD45RO+IL-7R+ T cells were significantly reduced (10.5+/-0.9%) when compared to non-HCV-infected liver transplant recipients (17.6+/-1.4%) (P<0.001), while both groups (HCV-infected and negative transplant recipients) had significantly higher levels than healthy individuals (6.6+/-0.9%) (P<0.0001). After successful antiviral therapy (sustained antiviral response), 6 HCV-infected transplant recipients showed an increase of CD4+CD25+CD45RO+IL-7R+ T cells, reaching levels similar to that of non-HCVinfected recipients (10.73+/-2.63% prior therapy versus 21.7+/-6.3% after clearance of HCV). (P<0.05) In 4 non-responders (i.e. HCVRNA remaining present in serum), levels of CD4+CD25+CD45RO+IL-7R+ T cells remained unmodified during and after antiviral treatment (11.8+/- 3.3% versus 11.3+/-3.3% respectively). Conclusions: Overall, these data indicate that CD4+CD25+CD45RO+IL-7R+ T cells appear to be modulated by chronic HCV infection after liver transplantation. Whether lower levels of alloreactive T cells in HCV-infected liver transplant recipients are associated with a tolerogenic profile remains to be studied.

[Lettre autographe signée de Sophie Arnould à Alleaume, 11 octobre 1776]

Lettre d'affaires. - "Il me faudra aller mourir à l'hôpital"

« Harangues, remonstrances et oraisons funebres » prononcées, semble-t-il, la plupart par Achille de Harlay, de 1581 à 1611. Copies.

Contient : 1 à 14 « Harangues aux roys Henry III, Henry IV et Louys XIII » ; 1 « Harangue de M. le premier president DE HARLAY au roy Henry III, venant en son lict de justice pour faire publier 28 edicts, l'an 1581 » ; 2 Harangue « au roy Henry III, au parlement, l'an 1584 », en juillet, « sur la publication d'aucuns edicts » ; 3 Harangue au « roy Henry III, de la part du parlement, au Louvre, l'an 1587 », en « may, sur l'arrest des deniers destinez au payement des rentes constituées sur l'Hostel de Ville » ; 4 « Harangue au roy Henry III, tenant son lict de justice, l'an 1585 », en « juillet, sur l'abolition de l'edict de pacification » ; 5 « Harangue au roy Henry III, apres la desfaicte des reistres, conduicts par le baron de Donau » ; 6 « Harangue de Mr le premier president D'HARLAY au roy Henry le Grand, au retour du siege de Vendosme, sur son nouvel advenement à la couronne, à Tours, l'an 1589 », en « novembre » ; 7 « Harangue au roy Henry le Grand, venu à Tours, l'an 1593, janvier, contre les ligueurs » ; 8 « Harangue au roy Henry le Grand, lequel auroit voulu que la cour de parlement deputast aucuns de la compaignée pour assister à son sacre à Chartres, l'an 1594 » ; 9 « Harangue au roy Henry le Grand, au Louvre, l'an 1595, febvrier », sur les bénéfices ecclésiastiques et sur les rentes de l'Hôtel de Ville » ; 10 « Harangue au roy Henry le Grand, à son retour de Sedan, au Louvre, en apvril 1606 » ; 11 « Harangue au roy Louis XIII, tenant son lict de justice, au couvent des Augustins, le 15 may 1610, le lendemaiu du tres cruel et tres inhumain parricide, commis en la personne sacrée du feu roy Henry le Grand » ; 12 « Harangue à la royne Marie de Medicis, femme du roy Henry le Grand, à son advenement à la couronne. Au Louvre ». 1601 ; 13 « Responce faicte à la royne regente [Marie de Médicis], pour l'arrest de la cour contre le livre de Belarmin, qui maintient que le pape peut instituer et deposer les roys, en cas de foiblesse et incapacité d'esprit. Au Louvre » ; 14 « Harangue à M. le prince de Condé, venu en parlement apres son retour en France, apres le deceds du roy Henry le Grand » ; 15 à 40 « Remonstrances à messieurs du parlement » ; 41 à 63 « Remonstrances aux gens du roy » ; 64 à 93 « Remonstrances aux advocats et procureurs de la cour » ; 94 à 104 « Oraisons funebres d'aucuns de messieurs du parlement » ; 94 « Oraison aux funerailles de Mr le chancelier de Birague, l'an 1583, decembre » ; 95 « Oraison aux funerailles de M. Prevost, president au parlement, l'an 1585, septembre » ; 96 « Oraison aux funerailles de M. de Pibrac, president au parlement, l'an 1584, juillet » ; 97 « Oraison aux funerailles de M. Faye, president au parlement, à Tours, l'an 1590 » ; 98 « Oraison aux funerailles de M. Brulart, president des enquestes, l'an 1584, novembre » ; 99 « Oraison aux funerailles de M. Anjorant, doyen des conseillers de la cour, l'an 1585, mars » ; 100 « Oraison aux funerailles de M. Le Sueur, doyen des conseillers clercs, l'an 1584, mars » ; 101 « Oraison aux funerailles de M. Duval, conseiller au parlement, l'an 1584, aoust » ; 102 « Oraison aux funerailles de M. Florette, conseiller au parlement » ; 103 « Oraison aux funerailles de M. Pardessus, conseiller clerc en la grand chambre, l'an 1585, may » ; 104 « Oraison aux funerailles de M. de Vignolles, conseiller clerc au parlement, l'an 1584, mars » ; 105 à 108 « Responces faictes à ceux de l'Université » ; 105 « Responce au recteur de l'Université de Paris, offrant un cierge de la part de lad. Université ». En latin ; 106 « Responce aux theologiens de Sorbonne », qui sont « exhortez à lire la Bible ». En latin ; 107 « Responce aux medecins de Paris, qui sont exhortez à fuyr toutes contentions entre eux ». En latin ; 108 « Responce à la harangue des medecins, prononcée par M. Duret, l'an 1584, juin ». En latin ; 109 à 112 « Extraicts de plusieurs passaiges de CASSIODORE et autres autheurs »