To assess the humoral immune response to low-dose AS03-adjuvanted and standard-dose nonadjuvanted 2009 pandemic H1N1 influenza A vaccine in HIV-infected aviremic individuals receiving antiretroviral ...therapy and in uninfected individuals.
A three-arm study.
Two clinics: one at the National Institutes of Health in Bethesda, Maryland, USA; and the other at the Maple Leaf Medical Clinic in Toronto, Ontario, Canada.
HIV-infected and HIV-uninfected adults.
Single intramuscular 15 μg dose of the monovalent inactivated 2009 pandemic H1N1 influenza A vaccine without adjuvant or 3.75 μg dose of the same strain with adjuvant AS03.
Immunogenicity, as measured by hemagglutination inhibition (HAI) antibody titers and vaccine-specific memory B-cell responses.
A total of 74 participants were enrolled. Twenty-one HIV-infected individuals received the low-dose adjuvanted 2009 pandemic H1N1 influenza A vaccine. Twenty-nine HIV-infected and 24 HIV-uninfected individuals received the standard-dose nonadjuvanted vaccine. There were no significant differences in antibody responses at 9 weeks postvaccination among the three groups studied. However, the IgG memory B-cell response against the vaccine was significantly higher in the HIV-infected group that received the low-dose adjuvanted vaccine when compared to the HIV-infected and uninfected groups that received the standard-dose nonadjuvanted vaccine. Conclusions remained unchanged after regression adjustment for age, gender, CD4 T-cell count, and baseline HAI titer.
These data suggest that adjuvants could be used to expand coverage through dose sparing and improve humoral immune responses in immunocompromised individuals.
ABSTRACT
In this study we assess the genetic architecture of bread‐making quality traits in spring wheat (Triticum aestivum L.). A mapping population derived from BR34 and ‘Grandin’ was used to ...measure 20 end‐use quality traits including six kernel, seven milling and flour, four dough mixing strength, and three bread‐making traits. A total of 31 quantitative trait loci (QTL) significantly associated with all but two traits were identified. These QTL were clustered in five chromosomal regions, namely 1BS, 1DL, 4BL, 5BL, and 6AS, and explained a large proportion of trait variation with favorable alleles contributed by both parents. The 1DL cluster containing the high molecular weight glutenin gene, Glu‐D1, had a large genetic influence on dough mixing strength and bread‐making performance. Most of the QTL affecting kernel traits were clustered on 6AS. Inconsistency of QTL locations detected from different environments was observed for the flour and milling traits and was likely due to genotype × environment interaction (G × E) effects. Despite high heritabilities estimated for the 20 quality traits evaluated, no QTL were found for flour brightness and bake water absorption, suggesting that these traits may be controlled by QTL with small effects that could not be detected due to the small population size. Because of the complex inheritance of these traits, it will be necessary to validate these QTL in different spring wheat backgrounds evaluated in similar growth conditions as used in this study before the marker information can be used for breeding applications.
The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report, we present ...the histopathological and immunophenotypic features seen in the lymph nodes (
n = 16), peripheral blood (
n = 10), bone marrow (
n = 2), spleen (
n = 3), and liver (
n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-αβ CD3
+ CD4
−CD8
−(double-negative, DN) T cells that were negative for CD45RO. CD45RA
+ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by
in situdetection of DNA fragmentation and staining with MIB-1, respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA
+ T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5
+ B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS. Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin's disease, respectively).
Survivors of Ebola virus disease (EVD) may experience ocular sequelae. Comparison with antibody-negative individuals from the local population is required to characterize the disease.
To assess ...features of ophthalmic disease specific to EVD.
This baseline cross-sectional analysis of survivors of EVD and their close contacts was conducted within PREVAIL III, a 5-year, longitudinal cohort study. Participants who enrolled at John F. Kennedy Medical Center in Liberia, West Africa from June 2015 to March 2016 were included in this analysis. Close contacts were defined as household members or sex partners of survivors of EVD. Data were analyzed from July 2016 to July 2020.
All participants, both survivors and close contacts, underwent testing of IgG antibody levels against Ebola virus surface glycoprotein.
Ocular symptoms, anterior and posterior ophthalmologic examination findings, and optical coherence tomography images were compared between antibody-positive survivors and antibody-negative close contacts.
A total of 564 antibody-positive survivors (320 56.7% female; mean SD age, 30.3 14.0 years) and 635 antibody-negative close contacts (347 54.6% female; mean SD age, 25.8 15.5 years) were enrolled in this study. Survivors were more likely to demonstrate color vision deficit (28.9% vs 19.0%, odds ratio OR, 1.6; 95% CI, 1.2-2.1) and lower intraocular pressure (12.4 vs 13.5 mm Hg; mean difference, -1.2 mm Hg; 95% CI, -1.6 to -0.8 mm Hg) compared with close contacts. Dilated fundus examination revealed a higher percentage of vitreous cells (7.8% vs 0.5%; OR, 16.6; 95% CI, 5.0-55.2) and macular scars (4.6% vs 1.6%; OR, 2.8; 95% CI, 1.4-5.5) in survivors than in close contacts. Uveitis was present in 26.4% of survivors and 12.1% of close contacts (OR, 2.4; 95% CI, 1.8-3.2). Among all participants with uveitis, survivors were more likely than close contacts to have intermediate uveitis (34.2% vs 6.5% of all cases; OR, 7.8; 95% CI, 3.1-19.7) and had thicker mean central subfield thickness on optical coherence tomography (222 vs 212 μm; mean difference, 14.4 μm; 95% CI, 1.9-26.9 μm).
In this cross-sectional study, survivors of EVD had a distinct spectrum of ocular and neuro-ophthalmologic findings compared with close contacts that potentially require medical and surgical treatment.
Wegener's granulomatosis (WG) is a granulomatous vasculitis that affects the upper respiratory tract, lung, and kidney. Since T cells make up a significant proportion of cells infiltrating ...granulomatous lesions in WG, we investigated the proliferative response and cytokine profile of T cells from these patients. PBMCs were isolated from 12 patients with active WG, 7 patients with inactive disease, and 12 healthy normal donors. PBMCs from clinically active WG patients exhibited increased proliferation following stimulation with either PMA/ionomycin or anti-CD2 and anti-CD28, when compared with normal donors. In addition, these PBMCs exhibited increased secretion of IFN-gamma, but not of IL-4, IL-5, or IL-10. Furthermore, TNF-alpha production from PBMCs and CD4+ T cells isolated from patients with WG was elevated, when compared with healthy donors. In further studies, we investigated the ability of WG patients' monocytes to produce IL-12 and showed that both inactive and active patients produced increased amounts of IL-12. Finally, the in vitro IFN-gamma production by WG PBMC is inhibited in a dose-dependent manner by exogenous IL-10. These data suggest that T cells from WG patients overproduce IFN-gamma and TNF-alpha, probably due to dysregulated IL-12 secretion, and that IL-10 may therefore have therapeutic implications for this disease.
During HIV infection distinct mechanisms drive immune activation of the CD4 and CD8 T cells leading to CD4 T-cell depletion and expansion of the CD8 T-cell pool. This immune activation is polyclonal ...and extends beyond HIV-specific T cells. One consequence of this immune activation is a profound decrease in IL-7Rα (CD127) expression on memory CD8 T cells. The mechanisms leading to this are unknown and because of the potential impact of reduced IL-7 signaling in memory T cells specific to HIV and other pathogens, in the present study we examined the molecular mechanisms implicated in this downregulation of CD127.
Membrane bound (mIL7RA) and soluble (sIL7RA) mRNA expression was determined by qRT-PCR. CD127, Eomesodermin (Eomes) and T-bet expression in healthy controls and HIV-infected patients were studied by flow cytometry.
CD127 downregulation occurs at the transcriptional level for both mIL7RA and sIL7RA alternative spliced forms in the CD127 memory CD8 T cells. CD127 memory CD8 T cells exhibited increased Eomes expression and an 'effector-like' gene profile. These changes were associated with higher HIV-RNA levels. Following combination antiretroviral therapy (cART), there was an increase in CD127 expression over an extended period of time (>5 months) which was associated with decreased Eomes expression.
CD127 is downregulated at a transcriptional level in memory CD8 T cells in association with upregulation of Eomes expression.
Lymphopenia, corticosteroids, antiretroviral therapy (ART), and inflammation negatively impact bone turnover and decrease bone mineral density, but their combined effect has not been evaluated. We ...examined the association between corticosteroids on bone turnover markers in severely lymphopenic HIV-infected patients initiating ART. Levels of osteocalcin (bone formation marker) and C-terminal telopeptide (CTX; bone resorption marker) were measured at baseline, weeks 4, 12, and 48 of ART in individuals with severe lymphopenia and opportunistic infection (OI) who received (n=28) or did not receive corticosteroids (n=30) during the first year of ART, and in a control group with CD4 >200 (n=15). Wilcoxon tests were used to compare median values of variables between groups. Correlations between plasma interleukin (IL)-6 and tumor necrosis factor (TNF) levels with bone turnover marker levels were performed using Spearman's coefficient. Individuals given corticosteroids received a median of 21 days at a 35 mg prednisone-equivalent daily dose. Individuals with severe lymphopenia had lower osteocalcin levels at baseline and week 4 and higher CTX levels at ART initiation vs.
Bone turnover markers did not differ in severely lymphopenic persons according to corticosteroid receipt. In those with severe lymphopenia, higher IL-6 was associated with higher CTX levels at ART initiation only. HIV-infected patients with severe lymphopenia and OI had lower levels of bone formation and higher levels of bone resorption than those initiating ART at higher CD4. Corticosteroid use, as prescribed during OI, was not associated with bone turnover. In contrast, higher markers of systemic inflammation prior to ART were associated with greater bone resorption.
Autoimmune lymphoproliferative syndrome Sneller, Michael C; Dale, Janet K; Straus, Stephen E
Current opinion in rheumatology
15, Številka:
4
Journal Article
Odprti dostop
Autoimmune lymphoproliferative syndrome arises early in childhood in people who inherit mutations in genes that mediate lymphocyte apoptosis, or programmed cell death. In the immune system, ...antigen-induced lymphocyte apoptosis maintains immune homeostasis by limiting lymphocyte accumulation and minimizing reactions against self-antigens. In autoimmune lymphoproliferative syndrome, defective lymphocyte apoptosis manifests as chronic, nonmalignant adenopathy and splenomegaly; the expansion of an unusual population of CD4-CD8- T cells; and the development of autoimmune disease. Most cases of autoimmune lymphoproliferative syndrome involve heterozygous mutations in the lymphocyte surface protein Fas (CD95, Apo1) that impair a major apoptotic pathway. Prospective evaluations of patients and their families have revealed an ever-expanding spectrum of autoimmune lymphoproliferative syndrome and its major complications.
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