Search

The role of repopulating lymphocytes after allogeneic stem cell transplantation (SCT) includes the prevention of serious infections and attacking residual tumour cells in the early post-transplant phase. Therefore, the current study analysed the role of the absolute lymphocyte count (ALC) on day 21 after SCT in predicting transplant outcomes of 82 patients in terms of the risk of opportunistic infections and recurrence of original disease. The median dose of CD34+, CD3+ and mononuclear cells (MNC) infused was 6·41 × 106/kg, 1·96 × 108/kg and 6·81 × 108/kg respectively. The high ALC group (high ALC on day 21; ≥0·35 × 109/l) was associated with the use of peripheral blood stem cells, matched sibling donors and higher cell doses of MNC, CD3+ and CD4+ cells. The high ALC group also exhibited a better overall survival (56·3% vs. 17·7%) and disease-free survival (50·1% vs. 15·9%) after 3 years and lower incidences of relapse (33·6% vs. 67·1%) and fungal infections (3·0% vs. 19·5%) after 1 year. The incidence of cytomegalovirus antigenaemia was lower in the high ALC group (47·7% vs. 73·7%). Accordingly, identifying the ALC on day 21 would appear to be a useful and simple measurement to predict those patients with a high risk of opportunistic infections and relapse after allogeneic SCT. [ABSTRACT FROM AUTHOR]

Lists the research papers to be published in the succeeding issues of the "European Journal of Biochemistry." "The structure of DNA junctions and their interaction with enzymes," by D.R. Duckett and colleagues; "CD4 gene transcription is transiently repressed during differentiation of myeloid cells to macrophage-like cells," by F.X. Pimentel-Muiñoz and colleagues; "Malonate decarboxylase of Malonomas rubra: a novel type of biotin-containing acetyl-enzyme," by H. Hilbi and colleagues.

Pulmonary fibrosis involves various types of immune cells and soluble mediators, including TGF‐β and IL‐35, a recently identified heterodimeric cytokine that belongs to the IL‐12 cytokine family. However, the effect of regulatory IL‐35 may play an important role in fibrotic diseases. The aim of this paper is to explore the immunoregulatory role of IL‐35 in the development of fibrosis in interstitial lung disease (ILD). To gain a better understanding of this issue, the concentrations of IL‐35 and different profibrotic cytokines in fibrotic (F‐ILD) and non‐fibrotic (NF‐ILD) patients by ELISA were compared to that of intracellular IL‐35 and IL‐17 on CD4+ T cells stimulated in the presence of BAL or with different ratios of recombinant IL‐35 (rIL‐35) and TGF‐β (rTGF‐β), which were evaluated by flow cytometry. We observed that BAL concentration of IL‐35 was lower in F patients (p < 0.001) and was negatively correlated with concentrations of TGF‐β (p < 0.001) and IL‐17 (p < 0.001). In supplemented cell cultures, BAL from NF but not F patients enhanced the percentage of IL‐35 + CD4+ T (p < 0.001) cells and decreased the percentage of IL‐17 + CD4+ T cells (p < 0.001). The percentage of IL‐35 + CD4+ T cells correlated positively with BAL concentration of IL‐35 (p = 0.02), but correlated negatively with BAL concentrations of IL‐17 (p = 0.007) and TGF‐β (p = 0.01). After adjusting the concentrations of recombinant cytokines to establish a TGF‐β: IL‐35 ratio of 1:4, an enhanced percentage of IL‐35 + CD4+ T cells (p < 0.001) but a decreased percentage of IL‐17 + CD4+ T cells (p < 0.001) was observed. After adding recombinant IL‐35 to the BAL from F patients until a 1:4 ratio of TGF‐β: IL‐35 was reached, a significantly increased percentage of IL‐35 + CD4+ T cells (p < 0.001) and a decreased percentage of IL‐17 + CD4+ T cells (p = 0.003) was found. These results suggest that IL‐35 may induce an anti‐fibrotic response, regulating the effect of TGF‐β and the inflammatory response on CD4+ T cells. In addition, the TGF‐β: IL‐35 ratio in BAL has been shown to be a potential biomarker to predict the outcome of F patients with ILD. [ABSTRACT FROM AUTHOR]

Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV‐1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion‐stabilized HIV‐1 envelope (Env) trimer, BG505 DS‐SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4‐binding site (CD4bs) of vulnerability. Two of the vaccine‐elicited CD4bs‐targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a‐hinge region and human IgG1‐constant region (G36×3‐IgG2a and R27×3‐IgG2a), neutralized 96% of a multiclade 208‐strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL−1, respectively. Cryo‐EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV‐1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2‐apex‐targeting broadly neutralizing antibody, CAP256V2LS. The resultant human‐llama bispecific antibody CAP256L‐R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV‐1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn‐Fc mice similar to the parent CAP256V2LS. Vaccine‐elicited llama nanobodies, when combined with V2‐apex broadly neutralizing antibodies, may therefore be able to fulfill anti‐HIV‐1 therapeutic and prophylactic clinical goals. [ABSTRACT FROM AUTHOR]

In this paper, we investigate the dynamical behaviors of three human immunodeficiency virus infection models with two types of cocirculating target cells and distributed intracellular delay. The models take into account both short-lived infected cells and long-lived chronically infected cells. In the two types of target cells, the drug efficacy is assumed to be different. The incidence rate of infection is given by bilinear and saturation functional responses in the first and second models, respectively, while it is given by a general function in the thirdmodel. Lyapunov functionals are constructed and LaSalle invariance principle is applied to prove the global asymptotic stability of all equilibria of the models. We have derived the basic reproduction number R0 for the threemodels. For the first twomodels, we have proven that the diseasefree equilibrium is globally asymptotically stable (GAS) when R0 ≤ 1, and the endemic equilibrium is GAS when R0 > 1. For the third model, we have established a set of sufficient conditions for global stability of both equilibria of the model. We have checked our theoretical results with numerical simulations. [ABSTRACT FROM AUTHOR]

Natural killer ( NK) cells provide an immediate first line of defence against viral infections. Memory responses, maintained by CD4+ T cells, require exposure to viral antigen and provide long-term protection against future infections. It is known that NK cells can promote the development of the adaptive response through cytokine production and cross-talk with antigen-presenting cells. In this paper however, we summarize a series of recent publications, in mouse models and for the first time in man, with the unifying message that rapid viral antigen control by the innate immune system limits antigen exposure to CD4+ cells thereby abrogating the development of a memory response. We discuss the significant implication of these studies on viral treatment strategies and immunization models. [ABSTRACT FROM AUTHOR]

Many successes have been achieved in HIV care in low- and middle-income countries (LMIC): increased number of HIV-infected individuals receiving antiretroviral treatment (ART), wide decentralization, reduction in morbidity and mortality and accessibility to cheapest drugs. However, these successes should not hide existing failures and difficulties. In this paper, we underline several key challenges. First, ensure long-term financing, increase available resources, in order to meet the increasing needs, and redistribute the overall budget in a concerted way amongst donors. Second, increase ART coverage and treat the many eligible patients who have not yet started ART. Competition amongst countries is expected to become a strong driving force in encouraging the least efficient to join better performing countries. Third, decrease early mortality on ART, by improving access to prevention, case-finding and treatment of tuberculosis and invasive bacterial diseases and by getting people to start ART much earlier. Fourth, move on from WHO 2006 to WHO 2010 guidelines. Raising the cut-off point for starting ART to 350 CD4/mm3 needs changing paradigm, adopting opt-out approach, facilitating pro-active testing, facilitating task shifting and increasing staff recruitments. Phasing out stavudine needs acting for a drastic reduction in the costs of other drugs. Scaling up routine viral load needs a mobilization for lower prices of reagents and equipments, as well as efforts in relation to point-of-care automation and to maintenance. The latter is a key step to boost the utilization of second-line regimens, which are currently dramatically under prescribed. Finally, other challenges are to reduce lost-to-follow-up rates; manage lifelong treatment and care for long-term morbidity, including drug toxicity, residual AIDS and HIV-non-AIDS morbidity and aging-related morbidity; and be able to face unforeseen events such as socio-political and military crisis. An old African proverb states that the growth of a deep-rooted tree cannot be stopped. Our tree is well rooted in existing field experience and is, therefore, expected to grow. In order for us to let it grow, long-term cost-effectiveness approach and life-saving evidence-based programming should replace short-term budgeting approach. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Dorton B, Mulindwa J, Li M, Chintu N, Chibwesha C, Mbewe F, Frenkel L, Stringer J, Chi B. CD4 cell count and risk for antiretroviral drug resistance among women using peripartum nevirapine for perinatal HIV prevention. BJOG 2011;118:495-499. To determine the association between the antenatal CD4 cell count and the development of viral drug resistance following the use of peripartum nevirapine (NVP) for perinatal HIV prevention. Secondary analysis of data from a previously conducted randomised controlled trial. Lusaka, Zambia. HIV-positive pregnant women. We analysed the data from a clinical trial of single-dose tenofovir/emtricitabine (TDF/FTC) to reduce viral drug resistance associated with peripartum NVP. The trial population was categorised according to antenatal CD4 cell count (200-350, 351-500 and >500 cells/μl). The relative risk for acquiring drug resistance, determined by consensus sequencing and oligonucleotide ligation assay (OLA), was estimated using multivariable logistic regression. Of the 397 study participants, 119 (30%) had a CD4 count of 200-350 cells/μl, 135 (34%) had a CD4 count of 351-500 cells/μl and 143 (36%) had a CD4 count of >500 cells/μl. Among women receiving no intervention, the risk for drug resistance appeared to increase as the CD4 cell count decreased. Participants with CD4 cell counts of 200-350 cells/μl randomised to the study arm had the lowest risk, suggesting a higher efficacy of the intervention within this stratum. These results were consistent at 2 and 6 weeks, regardless of how drug resistance was measured. Women with CD4 cell counts of 200-350 cells/μl may be at increased risk for viral drug resistance following the use of peripartum NVP. Given the high prevalence of NVP resistance and the clear benefits of treatment, antiretroviral therapy should be initiated among pregnant women with CD4 cell counts of ≤350 cells/μl. [ABSTRACT FROM AUTHOR]

Copyright of Tropical Medicine & International Health is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Peripheral blood CD4 CD45RO T cells activated in vitro are able to induce expression of tumour necrosis factor-α (TNF-α) in monocytes via a contact-dependent mechanism. Activation is achieved either with interleukin-2 (IL-2)/IL-6/TNF-α over an 8-day period or cross-linking CD3 using anti-CD3 antibody for 48 hr. In this paper, we show that the p38 mitogen-activated protein kinase (MAPK) signalling pathway played different roles in the generation of effector function in these two types of activated T cells. In anti-CD3 activated T cells, p38 MAPK is a negative regulator for anti-CD3 induced cell proliferation and has no significant effect on the acquisition of either the effector function (induction of monocyte-derived TNF-α) or production of T-cell cytokines. In contrast, the p38 MAPK signalling pathway is required for the acquisition of cytokine-induced effector function and promotes cell proliferation and cytokine production. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Absence of modulation of CD4+CD25high regulatory T cells in CTCL patients treated with bexarotene. Experimental Dermatology 2010; 19: e95-e102. Abstract: Cutaneous T-cell lymphoma (CTCL) are a heterogeneous group of lymphoproliferative disorders, characterized by the infiltration of the epidermis by mature and activated malignant CD4+ T-lymphocytes. Retinoids such as retinoic acid and synthetic analogues have long been used alone or in combination with other therapies for CTCL. Bexarotene, the first synthetic highly selective RXR retinoid, was approved for the treatment of all stages of CTCL in patients refractory to at least one systemic therapy. Recently, six cases in which the initiation of bexarotene therapy for CTCL was associated with the progression of internal disease despite improvement of cutaneous signs and symptoms were reported. Moreover, it has been established that retinoids promote the generation of CD4+ Foxp3+ regulatory T cells, raising the question of an induction of regulatory T-cells by bexarotene. The aim of this work was to determine if bexarotene induces an increase of functional regulatory T cells which could play a role in the development of secondary extra-cutaneous lymphomas. Regulatory T cells were studied both in cutaneous biopsy specimens using an immunohistochemical analysis of CD4, CD25 and Foxp3 and in blood where proportion and functionality of circulating CD4+CD25high T-cells were determined. The study was performed in 10 patients [five patients with Sézary syndrome (SS) and five mycosis fungoïdes (MF)], treated for 6 months with bexarotene. Four healthy donors were used as controls for phenotypic and functional analysis on PBL. We found that the frequency of CD4+CD25high Treg cells was not significantly different before starting bexarotene and after 6 months of treatment in CTCL patients. However, we observed that the frequency of CD4+CD25high Treg cells before the beginning of the treatment was significantly increased compared to healthy donors. In addition, functional assays demonstrated that Foxp3 expressing CD4+CD25high T-cells were capable of suppressing autologous CD4 + CD25− T-cell proliferation. In the present work, we detected the presence of functional circulating CD4+CD25high Foxp3+ regulatory T-cells in CTCL patients, with an increased frequency compared to healthy donors. The treatment with bexarotene does not seem to affect the regulatory T-cell compartment. [ABSTRACT FROM AUTHOR]

Listeria monocytogenes, a Gram-positive bacterium, is the causative agent for the disease called listeriosis. This pathogen utilizes host cell surface proteins such as E-cadherin or c-Met in order to invade eukaryotic cells. The invasion via c-Met depends on the bacterial protein InlB that activates c-Met phosphorylation and internalization mimicking in many regards HGF, the authentic c-Met ligand. In this paper, we demonstrate that the activation of c-Met induced by InlB is dependent on CD44v6, a member of the CD44 family of transmembrane glycoproteins. Inhibiting CD44v6 by means of a blocking peptide, a CD44v6 antibody or CD44v6-specific siRNA prevents the activation of c-Met induced by InlB. Subsequently, signalling, scattering and the entry of InlB-coated beads into host cells are also impaired by CD44v6 blocking reagents. For the entry process, ezrin, a protein that links the CD44v6 cytoplasmic domain to the cytoskeleton, is required as well. Most importantly, this collaboration between c-Met and CD44v6 contributes to the invasion of L. monocytogenes into target cells as demonstrated by a drastic decrease in bacterial invasion in the presence of blocking agents such as the CD44v6 peptide or antibody. [ABSTRACT FROM AUTHOR]

CD4 T cells play a central role in the immune response to malaria. They are required to help B cells produce the antibody that is essential for parasite clearance. They also produce cytokines that amplify the phagocytic and parasitocidal response of the innate immune system, as well as dampening this response later on to limit immunopathology. Therefore, understanding the mechanisms by which T helper cells are activated and the requirements for development of specific, and effective, T cell memory and immunity is essential in the quest for a malaria vaccine. In this paper on the CD4 session of the Immunology of Malaria Infections meeting, we summarize discussions of CD4 cell priming and memory in malaria and in vaccination and outline critical future lines of investigation. B. Stockinger and M.K. Jenkins proposed cutting edge experimental systems to study basic T cell biology in malaria. Critical parameters in T cell activation include the cell types involved, the route of infection and the timing and location and cell types involved in antigen presentation. A new generation of vaccines that induce CD4 T cell activation and memory are being developed with new adjuvants. Studies of T cell memory focus on differentiation and factors involved in maintenance of antigen specific T cells and control of the size of that population. To improve detection of T cell memory in the field, efforts will have to be made to distinguish antigen-specific responses from cytokine driven responses. [ABSTRACT FROM AUTHOR]

α2,6‐sialylation, catalyzed by α2,6‐sialyltransferase (ST6GAL1), plays a pivotal role in immune responses. However, the role of ST6GAL1 in the pathogenesis of ulcerative colitis (UC) remains unknown. ST6GAL1 mRNA is highly expressed in UC tissues compared with the corresponding adjacent normal tissues, and α2,6‐sialylation is significantly increased in the colon tissues of patients with UC. The expression of ST6GAL1 and proinflammatory cytokines, such as interleukin (IL)‐2, IL‐6, IL‐17, and interferon‐gamma, is also increased. The number of CD4+ T cells increases in UC patients. St6gal1 gene knockout (St6gal1−/‐) rats are established by clustered regularly interspaced short palindromic repeats (CRISPR)‐associated gene knockout system. St6gal1 deficiency reduces the levels of pro‐inflammatory cytokines and alleviates colitis symptoms in UC model rats. Ablation of α2,6‐sialylation inhibits the transport of the TCR to lipid rafts and suppresses CD4+ T‐cell activation. The attenuation of TCR signaling downregulates the expression of NF‐κB in ST6GAL1‐/‐ CD4+ T‐cells. Moreover, NF‐κB could bind to the ST6GAL1 promoter to increase its transcription. Ablation of ST6GAL1 downregulates the expression of NF‐κB and reduces the production of proinflammatory cytokines to relieve UC pathogenesis, which is a potential novel target for the clinical treatment of UC. [ABSTRACT FROM AUTHOR]

A systemic and local inflammatory immune imbalance is thought to be the cause of traumatic tracheal stenosis (TS). However, with CD4+ T lymphocytes being the predominant immune cells in TS, the mechanism of action and recruitment has not been described. In our research, using flow cytometry, ELISA, immunofluorescence, and Transwell chamber assays, the expression, distribution, and potential chemotactic function of CD4+ T cells in TS patients were examined before and after treatment. The results showed that the untreated group had significantly more CD4+ T cells and their secreted TGF‐β1 than the treated group. Additionally, the untreated group's CD4+ T cells showed a significant rise in CCL22 and CCL1, as well as a larger proportion of CCR4 and CCR8. CD4+ T cells and CD68+ macrophages located in TS also expressed CCL1 and CCL22. In vitro, anti‐CCL1 and anti‐CCL22 can partially block the chemoattractant effect of TS bronchoalveolar lavage (BAL) on purified CD4+ T cells. The findings of this study indicated that TS contained unbalanced CD4 immune cells that were actively recruited locally by CCR4/CCL22 and CCR8/CCL1. As a result, it is anticipated that CD4 immune rebalancing can serve as a novel treatment for TS. [ABSTRACT FROM AUTHOR]

Nucleus accumbens‐associated protein 1 (NAC1), a transcriptional cofactor, has been found to play important roles in regulating regulatory T cells, CD8+ T cells, and antitumor immunity, but little is known about its effects on T‐cell memory. In this study, we found that NAC1 expression restricts memory formation of CD4+ T cells during viral infection. Analysis of CD4+ T cells from wild‐type (WT) and NAC1‐deficient (−/−) mice showed that NAC1 is essential for T‐cell metabolism, including glycolysis and oxidative phosphorylation, and supports CD4+ T‐cell survival in vitro. We further demonstrated that a deficiency of NAC1 downregulates glycolysis and correlates with the AMPK‐mTOR pathway and causes autophagy defective in CD4+ T cells. Loss of NAC1 reduced the expression of ROCK1 and the phosphorylation and stabilization of BECLIN1. However, a forced expression of ROCK1 in NAC1−/− CD4+ T cells restored autophagy and the activity of the AMPK‐mTOR pathway. In animal experiments, adoptively transferred NAC1−/− CD4+ T cells or NAC1−/− mice challenged with VACV showed enhanced formation of VACV‐specific CD4+ memory T cells compared to adoptively transferred WT CD4+ T cells or WT mice. This memory T‐cell formation enhancement was abrogated by forcing expression of ROCK1. Our study reveals a novel role for NAC1 as a suppressor of CD4+ T‐cell memory formation and suggests that targeting NAC1 could be a new approach to promoting memory CD4+ T‐cell development, which is critical for an effective immune response against pathogens. [ABSTRACT FROM AUTHOR]

This paper describes a model of successful immunotherapy of advanced lymphoma based on the selective elimination of cycling tumour-induced suppressor T cells. It shows that a single injection of the anti-mitotic drug, vinblasting (Vb), results in complete regression of a large L5178Y lymphoma and its metastases, but not if it is growing in an immunocompetent host. Vb-induced, immunologically mediated tumour regression was dependent on the anti-tumour function of CD8+ T cells, because regression was prevented by depleting the host of this subset of T cells 24 hr after Vb was given. Regression was also prevented by infusing the host with Vb-sensitive, CD4+ T cells from a turnout-bearing donor. These and other results are in keeping with the interpretation that Vbinduced regression of the L5178Y lymphoma depends on the ability of the drug to eliminate CD4+ suppressor T ceils that are replicating, and to spare non-replicating CD8+ effector cells, it is suggested that at an advanced stage of growth of the L5178Y lymphoma the host possesses an acquired population of antigen-primed CD8+ effector T cells that are unable to become activated in response to abundant tumour antigen because of the dominant influence of CD4+ suppressor cells. Activation of these CD8+ T cells was indicated by the finding that they were rapidly converted from being cyclophosphamide (Cy) resistant to being highly Cy sensitive within 48 hr of giving Vb. [ABSTRACT FROM AUTHOR]

The leucocyte common antigen, CD45 (T200, Ly-5), exists in a number of isoforms generated by differential usage of three exons that code for an extracellular region close to the NH2 terminus. Use of antibodies to different isoforms of CD45 has lead to the identification of two subsets of CD4+ T cells in rat, man and mouse. Data on the functions of the two rat CD4+ T-cell subsets isolated on the basis of different levels of expression of exon B (and/or C) are largely concordant with those obtained from the two subsets of human CD4 + T cells defined by their levels of expression of exon A. However, results presented in this paper on the CD45 phenotype of rat T cells that produce interferon-gamma (IFN-γ) are not compatible with the human data, if it is assumed that there are only two functional subsets of CD4+ T cells. The data could, in principle, be reconciled if the expression of exons A and B defined three rather than two subsets, and this possibility has now been examined in man where monoclonal antibodies against both A and B exon products are available. The results show the presence of a third CD4+ T-cell subset and that this extra subset is contained within the population originally shown to provide memory T-cell function. [ABSTRACT FROM AUTHOR]

Variations in T lymphocytes in asthmatic patients are related to disease severity. However, the effects of natural exposure to pollens on peripheral blood T lymphocytes have not been clarified. In this paper, the effects on peripheral blood CD4 and CD8 lymphocytes from pollen-sensitive subjects and from nonatopic donors were studied during and outside the pollen season. In patients who suffer from seasonal asthma, we found an increase in the CD4/CD8 bright ratio and a decrease in the mean number of CD4 receptors per cell during the pollen season. No variation was observed in healthy subjects. These results suggest that CD4 lymphocytes may be causally linked to the pathogenesis of seasonal bronchial asthma. [ABSTRACT FROM AUTHOR]

The monocyte–macrophage system is known to play a central role in HIV infection, and expression of CD4 on the surface of monocytes/macrophages is important, since this molecule is a key factor for the entrance of HIV into susceptible cells. In this paper we evaluated the expression of CD4 in monocytes of haemophiliac patients (He) who had been infected with HIV (HIV+ He) through transfusion of contaminated plasma concentrates. Thirty seropositive patients (HIV+ He), 10 seronegative He patients (HIV- He) and 20 voluntary normal blood donors were studied. Phenotypic evaluation of monocytes was performed by flow cytometry of peripheral blood stained with anti-CD45, -CD3, -CD4 and -CD14 monoclonal antibodies. The percentage of CD4 monocytes was increased in all HIV+ patient groups, but it was highest in those belonging to Groups III and IV A of the CDC classification. Furthermore, the median of fluorescence intensity of CD4+ monocytes from individual patients was shifted to the right, indicating expression of increased numbers of CD4 molecules on the cell membrane of monocytes. This could in turn favour HIV infection and viral persistence, facilitating in vivo dissemination of the virus. [ABSTRACT FROM AUTHOR]

Background: T‐cell‐rich angiomatoid polypoid pseudolymphoma (TRAPP) and inflammatory lobular hemangioma (ILH) encompass a spectrum of cutaneous vascular lesions in which a prominent lymphoplasmacytic component may impart a pattern highly reminiscent of low‐grade cutaneous lymphoma (pseudolymphoma). Epithelioid hemangioma, including its most common variant angiolymphoid hyperplasia with eosinophilia (ALHE), is a distinct entity associated with FOS and/or FOSB expression detected by immunohistochemistry (IHC). These entities can show significant morphological overlap. Methods: We performed IHC for FOSB, FOS, and lymphoid markers in a series of TRAPP/ILH and ALHE. Results: We identified 13 cases of ILH/TRAPP, which showed a predominance in CD8+ T‐cells (CD8>CD4: 11/13) while FOSB and FOS were expressed in 36% (4/11) and 27% (3/11) of cases, respectively. ALHE (n = 9) showed a predominance in CD4+ T‐cell (67%) with FOSB and FOS co‐expression in 78% (seven of nine) of the cases. Conclusion: We showed, based on FOS and/or FOSB immunohistochemical expression, that there is a possible link between ILH/TRAPP and epithelioid hemangioma/ALHE. The use of FOS and FOSB IHC in the routine diagnostic setting of cutaneous vascular lesions will help to redefine cases of ILH/TRAPP as a subset of these may represent inflammatory variants of epithelioid hemangioma. [ABSTRACT FROM AUTHOR]

The role and potential molecular mechanism of inflammatory cells in pediatric localized scleroderma are poorly investigated. In this study, we first investigated the profiling of inflammatory cells in skin samples from pediatric localized scleroderma. Among them, CD4+ T‐cells were up‐regulated. Co‐culture dermal fibroblasts with CD4+ T‐cells promoted fibrosis of fibroblasts. Candidate lncRNAs were further explored by lncRNAs‐seq between the normal skin tissues and pediatric localized scleroderma tissues, and the lncRNAs‐seq between fibroblasts co‐cultured with CD4+ T lymphocytes and control fibroblasts. By comparing the two datasets, we identified eight up‐regulated and three down‐regulated lncRNAs, which were the potential lncRNAs for the phenotype of pediatric localized scleroderma. Here, we identified the CD4+ T‐cells infiltration in pediatric localized scleroderma and potential lncRNAs for the treatment of pediatric localized scleroderma. [ABSTRACT FROM AUTHOR]

Introduction: The frequencies and functions of T stem cell memory (TSCM) subsets vary in autoimmune diseases. We evaluated the frequencies of CD4+ and CD8+ TSCM subsets as well as their PD‐1 expression levels in patients with T1D. Methods: Blood samples were collected from new case (NC) (n = 15), and long‐term (LT) (n = 15) groups and healthy controls (n = 15). Five subsets of T cells including TCM(CD4+/CD8+ CCR7+ CD45RO+ CD95+), TCMhi (CD4+/CD8+ CCR7+ CD45ROhi CD95+), TEM(CD4+/CD8+ CCR7− CD45RO+ CD95+), TSCM(CD4+/CD8+ CCR7+ CD45RO− CD95+), and T naive (CD4+/CD8+ CCR7+ CD45RO− CD95−) were detected by flow‐cytometry. Results: The frequency of CD4+ TSCM was higher in NC patients than LT patients and controls (p <.0001 and p =.0086, respectively). A higher percentage of the CD8+ T naive cells was shown in NC patients as compared with LT and healthy individuals (p =.0003 and p =.0002, respectively). An increased level of PD‐1 expression was observed on the CD4+TCM and TCMhi cells in LT patients as compared with healthy controls (p =.0037 and p =.0145, respectively). Also, the higher PD‐1 expression was observed on the CD8+ TCM and TCMhi in NC and LT patients as compared with controls (p =.0068 and p <.0001; p =.0012 and p =.0012, respectively). Conclusion: Considering TSCMs' capacities to generate all memory and effector T cells, our results may suggest a potential association between the increased frequencies of TSCMs and T1D progression. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses the use of CD4 T cell to control tumours and influenza among indigenous Australians which won the Publication of the Year Awards 2016.

Background and Aims: Little is known about the impact of DNA methylation modifications on autoimmune hepatitis (AIH) pathogenesis and therapeutic response. We investigated the potential alterations of DNA methylation in AIH peripheral lymphocytes at diagnosis and remission. Methods: Ten AIH patients at diagnosis (time‐point 1; AIH‐tp1), 8/10 following biochemical response (time‐point 2; AIH‐tp2), 9 primary biliary cholangitis (PBC) and 10 healthy controls (HC) were investigated. Peripheral CD19(+) and CD4(+) cells were isolated. Global DNA methylation (5mC)/hydroxymethylation (5hmC) was studied by ELISAs. mRNA of DNA methylation (DNMT1/3A/3B) and their counteracting hydroxymethylation enzymes (TET1/2/3) was determined by quantitative RT‐PCR. Epigenome wide association study (EWAS) was performed in CD4(+) cells (Illumina HumanMethylation 850 K array) in AIH and HC. Total 5mC/5hmC was also assessed by immunohistochemistry (IHC) on paraffin‐embedded liver sections. Results: Reduced TET1 and increased DNMT3A mRNA levels characterized CD19(+) and CD4(+)‐lymphocytes from AIH‐tp1 compared to HC and PBC, respectively, without affecting global DNA 5mC/5hmC. In AIH‐tp1, CD4(+) DNMT3A expression was negatively correlated with serum IgG (P =.03). In remission, DNMT3A decreased in both CD19(+) and CD4(+) cells compared to AIH‐tp1 (P =.02, P =.03 respectively). EWAS in CD4(+) cells from AIH patients confirmed important modifications in genes implicated in immune responses (HLA‐DP, TNF, lnRNAs and CD86). IHC showed increased 5hmC staining of periportal infiltrating lymphocytes in AIH‐tp1 compared to HC and PBC. Conclusion: Altered TET1 and DNMT3A expressions, characterize peripheral lymphocytes in AIH. DNMT3A was associated with disease activity and decreased following remission. Gene DNA methylation modifications affect immunological pathways that may play an important role in AIH pathogenesis. [ABSTRACT FROM AUTHOR]

The pathogenic immune response in celiac disease (CeD) is orchestrated by phenotypically distinct CD4+ T cells that recognize gluten epitopes in the context of disease‐associated HLA‐DQ allotypes. Cells with the same distinct phenotype, but with elusive specificities, are increased across multiple autoimmune conditions. Here, whether sorting of T cells based on their distinct phenotype (Tphe cells) yields gluten‐reactive cells in CeD is tested. The method′s efficiency is benchmarked by parallel isolation of gluten‐reactive T cells (Ttet cells), using HLA‐DQ:gluten peptide tetramers. From gut biopsies of 12 untreated HLA‐DQ2.5+ CeD patients, Ttet+/Tphe+, Ttet−/Tphe+, and Ttet−/Tphe− cells are sorted for single‐cell T‐cell receptor (TCR)‐sequencing (n = 8) and T‐cell clone (TCC)‐generation (n = 5). The generated TCCs are TCR sequenced and tested for their reactivity against deamidated gluten. Gluten‐reactivity is observed in 91.2% of Ttet+/Tphe+ TCCs, 65.3% of Ttet−/Tphe+ TCCs and 0% of Ttet−/Tphe− TCCs. TCR sequencing reveals clonal expansion and sequence sharing across patients, features reflecting antigen‐driven responses. The feasibility to isolate antigen‐specific CD4+ T cells by the sole use of phenotypic markers in CeD outlines a potential avenue for characterizing disease‐driving CD4+ T cells in autoimmune conditions. [ABSTRACT FROM AUTHOR]

Introduction: Adolescents living with HIV are subject to multiple co‐morbidities, including growth retardation and immunodeficiency. We describe growth and CD4 evolution during adolescence using data from the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) global project. Methods: Data were collected between 1994 and 2015 from 11 CIPHER networks worldwide. Adolescents with perinatally acquired HIV infection (APH) who initiated antiretroviral therapy (ART) before age 10 years, with at least one height or CD4 count measurement while aged 10–17 years, were included. Growth was measured using height‐for‐age Z‐scores (HAZ, stunting if <‐2 SD, WHO growth charts). Linear mixed‐effects models were used to study the evolution of each outcome between ages 10 and 17. For growth, sex‐specific models with fractional polynomials were used to model non‐linear relationships for age at ART initiation, HAZ at age 10 and time, defined as current age from 10 to 17 years of age. Results: A total of 20,939 and 19,557 APH were included for the growth and CD4 analyses, respectively. Half were females, two‐thirds lived in East and Southern Africa, and median age at ART initiation ranged from <3 years in North America and Europe to >7 years in sub‐Saharan African regions. At age 10, stunting ranged from 6% in North America and Europe to 39% in the Asia‐Pacific; 19% overall had CD4 counts <500 cells/mm3. Across adolescence, higher HAZ was observed in females and among those in high‐income countries. APH with stunting at age 10 and those with late ART initiation (after age 5) had the largest HAZ gains during adolescence, but these gains were insufficient to catch‐up with non‐stunted, early ART‐treated adolescents. From age 10 to 16 years, mean CD4 counts declined from 768 to 607 cells/mm3. This decline was observed across all regions, in males and females. Conclusions: Growth patterns during adolescence differed substantially by sex and region, while CD4 patterns were similar, with an observed CD4 decline that needs further investigation. Early diagnosis and timely initiation of treatment in early childhood to prevent growth retardation and immunodeficiency are critical to improving APH growth and CD4 outcomes by the time they reach adulthood. [ABSTRACT FROM AUTHOR]

MicroRNA are important regulators of CD4 T cell differentiation, altering the balance between the immunogenic and tolerogenic pathways. Studies in mice with micro RNA-deficient T cells have revealed defects in differentiation into the regulatory T cell lineage; however, the individual micro RNA responsible have remained elusive. A recent paper in The EMBO Journal uses a systematic screen to find a novel cooperative action between an inducible and a constitutive micro RNA in aiding regulatory T cell induction. [ABSTRACT FROM AUTHOR]

Bronchoalveolar lavage (BAL) as a method of sampling cells is useful in the diagnosis and differential diagnosis of sarcoidosis. However, CD4/CD8 ratio in BAL fluid (BALF) is highly variable and it generates continuous discussions about its diagnostic role. To prospectively evaluate diagnostic role of BALF CD4/CD8 ratio in pulmonary sarcoidosis manifested in different radiographic and clinical forms in the real clinical practice. The study population consisted of 318 sarcoid patients with a newly diagnosed disease. Comparator groups consisted of 55 healthy subjects and 130 patients with other disorders who underwent BAL and examination of CD4/CD8 ratio in BALF as a step of diagnostic pathway. Diagnostic accuracy of CD4/CD8 ratio in BALF using receiver-operating characteristic analysis has been calculated. The percentage of BALF lymphocytes in sarcoid patients was significantly different from comparator groups. Normal BALF cell counts were found in 7% of sarcoid patients. However, typical sarcoid BALF cellular pattern was found in 6.2% of all control subjects. We have found that optimal cutoff points for CD4/CD8 ratio are 3.5 and 4.0 for asymptomatic and symptomatic patients, respectively. Sensitivity of the optimal cutoff points of CD4/CD8 ratio was lower in asymptomatic patients compared with symptomatic patients. Sensitivity of the optimal cutoff points decreased with the increased stage of sarcoidosis. BAL is a valuable method in diagnostic pathway of pulmonary sarcoidosis. However, results of BALF examination must be interpreted considering a specific clinical case. BALF CD4/CD8 ratio depends on clinical and radiographic manifestation. Please cite this paper as: Danila E, Norkūnienė J, Jurgauskienė L and Malickaitė R. Diagnostic role of BAL fluid CD4/CD8 ratio in different radiographic and clinical forms of pulmonary sarcoidosis. The Clinical Respiratory Journal 2009; 3: 214-221. [ABSTRACT FROM AUTHOR]

Background: Characterising the clinical and immunological impact of daily cat exposure in cat‐allergic subjects with asthma who live with cats (WC) and those who do not (WoC) may provide understanding of the drivers of the allergic response. Methods: Clinical and immunological characteristics (skin prick test, spirometry, symptom assessments, immunological markers) were compared between asthmatic subjects WC (n = 10) and WoC (n = 9). Results: WC subjects had greater use of long‐acting beta agonists (p <.05) and high‐potency corticosteroids. No differences were observed in lung function, nasal and ocular symptoms, or asthma control between the groups. Cat dander‐ and Fel d 1‐specific IgG4 concentrations were higher in WC than WoC subjects (both p <.05). Total IgE and cat dander‐, Fel d 1‐ and Fel d 7‐specific IgE concentrations were similar, but Fel d 4‐sIgE was higher in WC subjects (p <.05) versus WoC. Basophil sensitivity to cat dander extract and Fel d 1 was lower in WC versus WoC subjects (p <.05) and correlated with higher IgG4 concentrations (r = 0.63; p =.009). Fel d 1‐specific CD4+ T‐cell responses polarised toward Th2A responses in WC versus WoC subjects; Fel d 1‐specific IgE correlated with surface expression of CRTH2 and CD200R (both p ≤.05). Conclusion: Immunological differences observed in WC versus WoC did not reflect clinical tolerance with natural cat exposure. The ability to live with a cat despite allergy could be driven by higher preventative medication use. This study may support design of novel therapeutics for allergy management. [ABSTRACT FROM AUTHOR]

Autumn closing date (CD) in intensive pasture‐based systems influences spring herbage availability. Little is known about the impact of earlier closing of swards in autumn on sward structure. A two‐year experiment was undertaken to investigate the impact of five CD on herbage production, leaf extension rate (LER), leaf senescence rates (LSR), sward free leaf lamina (FLL) content and the production and survival of tillers over winter and into spring. The five CD ranges were October 1–15 (CD1), October 16–30 (CD2), October 31––November 14 (CD3), November 15–29 (CD4), November 30–December 14 (CD5) and sward measurements were made on four measurement dates (MD): December 11 (MD1), January 6 (MD2), January 27 (MD3) and prior to spring defoliation (MD4). Thirty perennial ryegrass tillers were measured until the first defoliation in spring (average 1 March). Herbage mass was greatest in early CD and tillers had greater LER and LSR (4.6 and 4.5 mm tiller−1 day−1 respectively) compared to swards with a later CD (3.2 and 2.3 mm tiller−1 day−1 respectively). Early CD had greater parent and daughter tiller mortality than later CD (parent tiller mortality 1.1 and 0.3 ± 0.19 tillers; daughter tiller mortality 1.1 and 0.3 ± 0.27 tillers respectively). Early CD also had greater LER and LSR in daughter tillers (2.6 and 1.5 mm tiller−1 day−1, respectively) compared to late (1.5 and 0.5 mm tiller−1 day−1, respectively). Earlier closing of sward increased herbage mass in spring, however, there were negative implications, such as increased LSR and tiller mortality. [ABSTRACT FROM AUTHOR]

In the tumor microenvironment, T cells, B cells, and many other cells play important and distinct roles in anti‐tumor immunotherapy. Although the immune checkpoint blockade and adoptive cell transfer can elicit durable clinical responses, only a few patients benefit from these therapies. Increased understanding of tumor‐infiltrating immune cells can provide novel therapies and drugs that induce a highly specific anti‐tumor immune response to certain groups of patients. Herein, the recent research progress on tumor‐infiltrating B cells and T cells, including CD8+ T cells, CD4+ T cells, and exhausted T cells and their role in anti‐tumor immunity, is summarized. Moreover, several anti‐tumor therapy approaches are discussed based on different immune cells and their prospects for future applications in cancer treatment. [ABSTRACT FROM AUTHOR]

Introduction: Persistence of HIV‐1, causing chronic immune activation, is a key determinant of premature senescence. Early antiretroviral therapy (ART) has been associated with a reduced HIV‐1 reservoir in children with perinatally acquired HIV‐1 (PHIV), but its impact on the senescence process is an open question. We investigated the association between HIV‐1 reservoir and biological and immune ageing profile in PHIV enrolled in the multicentre cross‐sectional study CARMA (Child and Adolescent Reservoir Measurements on early suppressive ART) conducted within the EPIICAL (Early treated Perinatally HIV Infected individuals: Improving Children's Actual Life) consortium. Methods: Between September 2017 and June 2018, CARMA enrolled 40 PHIV who started ART before 2 years of age and had undetectable viremia for at least 5 years before sampling date. Samples from 37 children with a median age of 13.8 years were available for this study. HIV‐1 DNA copies on CD4 cells, relative telomere length (marker of cellular senescence) and levels of T‐cell receptor rearrangement excision circle (TREC, marker of thymic output) on CD4 and CD8 cells were quantified by qPCR. Immunological profile was assessed by flow cytometry. Associations between molecular and phenotypic markers, HIV‐1 reservoir and age at ART initiation were explored using a multivariable Poisson regression. Results: Higher HIV‐1 reservoir was associated (p<0.001) with telomere shortening (incidence rate ratio [IRR] = 0.15 [0.13–0.17]), immunosenescence (CD28–CD57+, IRR = 1.23 [1.21–1.26]) and immunoactivation (CD38+ HLADR+, IRR = 7.29 [6.58–8.09]) of CD4 cells. Late ART initiation (after 6 months of age) correlated with higher HIV‐1 reservoir levels (552 [303–1001] vs. 89 [56–365] copies/106 CD4 cells, p = 0.003) and percentage of CD4 senescent cells (2.89 [1.95–6.31] vs. 1.02 [0.45–2.69, p = 0.047). TREC levels in CD8 cells were inversely associated with HIV‐1 reservoir (IRR = 0.77 [0.76–0.79]) and were significantly lower in late treated PHIV (1128 [486–1671] vs. 2278 [1425–3314], p = 0.042). Conclusions: Later ART initiation is associated with higher HIV‐1 reservoir size, which correlates with increased telomere shortening and senescence of CD4 cells. Timing of ART initiation in infancy has long‐term consequences on the immune and biological ageing profile of children with perinatally acquired HIV‐1. [ABSTRACT FROM AUTHOR]

Objectives: To assess the effect of protease inhibitor (PI)‐based dual therapy on CD4/CD8 ratio during the first year of therapy in antiretroviral therapy (ART)‐naïve patients using data from randomized controlled clinical trials. Methods: We pooled data from the GARDEL and ANDES studies, both randomized controlled clinical trials that recruited ART‐naïve people living with HIV and randomly assigned them to receive PI‐based dual therapy (DT) or triple therapy (TT) aiming to compare viral efficacy. We compared median CD4/CD8 ratios and the proportion of patients with CD4/CD8 ratio > 1 at 48 weeks after ART initiation in both treatment arms using the Mann–Whitney U‐test and the χ2 test. We performed subgroup analysis for patients > 50 years old, with baseline CD4 counts ≤ 200 cells/μL, viral load > 100 000 HIV RNA copies/mL, and ritonavir‐boosted lopinavir‐based therapy. Results: We analysed data from 571 patients: 292 on DT and 279 on TT. No differences were observed in CD4/CD8 ratio (0.632 vs. 0.617, P = 0.729) or in the proportion of patients with CD4/CD8 ratio > 1 (17.9% vs. 19.3%, P = 0.678) 48 weeks after ART initiation. Subgroup analysis showed no further differences. Conclusion: The impact of PI‐based DT regimens on the CD4/CD8 ratio during the first year of treatment for ART‐naïve patients is similar to that of TT. [ABSTRACT FROM AUTHOR]

Background: Interleukin‐27 (IL‐27) modulates CD4+ T‐cell differentiation and function. The aim of this study is to investigate the effect and molecular mechanisms of IL‐27 on the development of asthma. Methods: IL‐27 was intranasally administered in an ovalbumin‐induced asthma model, and lung mononuclear cells and different Th cell classes were detected by fluorescence‐activated cell sorting. The effect and mechanisms of IL‐27 on human bronchial epithelial (HBE) cells were investigated by measuring changes in chemotactic factors, cytokines, transcription factors, and signaling pathways. Results: We found that intranasal administration of IL‐27 could attenuate airway inflammation and hyperresponsiveness, upregulate the type 1 T helper (Th1)‐T memory (Tm) cells and regulatory T (Treg) cells subgroups of lung tissue lymphocytes, and diminish the levels of type 2 T helper (Th2) cytokines. IL‐27 upregulated the expression of C‐C motif chemokine ligand 2 (CCL2), CCL3, and CCL4 in HBE cells and promoted the production of chemotactic factors to attract monocyte recruitment. Recruited monocytes secondarily secreted IL‐27 to influence HBE cells in a positive feedback cycle. After IL‐27 intervention, signal transducer and activator of transcription 1 (STAT1) phosphorylation increased, while STAT4 and STAT6 phosphorylation declined. Conclusions: Preventative intranasal administration of IL‐27 can recruit more IL‐27‐secreted monocytes to the airway and change the different T‐cell classes in lung. The improved Th1 environment helps to alleviate Th2‐mediated allergic asthma by repairing the STAT1 pathway but not the STAT4 pathway. Preventative intranasal administration of interleukin‐27 (IL‐27) can recruit more IL‐27‐secreted monocytes to the airway and change the different T‐cell classes in lung. The improved type 1 T helper (Th1) environment helps to alleviate type 2 T helper (Th2)‐mediated allergic asthma by repairing the signal transducer and activator of transcription 1 (STAT1) pathway but not the STAT4 pathway. [ABSTRACT FROM AUTHOR]

Acquired immune deficiency syndrome is an epidemic infectious disease which is caused by the human immunodeficiency virus (HIV) and that has proliferated across worldwide. It has been a matter of concern for the scientific community to develop an antiretroviral therapy, which will prompt a rapid decline in viral abundance. With this motivation, this study proposes the design of a robust super twisting sliding mode controller based on output information for an uncertain HIV infection model. The control objective is to decrease the concentration of infected CD4+ T cells to a specified level by drug administration using only the output information of the uncertain HIV infection model which is total CD4+ T cell concentration. The robust output-feedback controller has been developed in combination with a robust exact differentiator, functioning as an observer. The reported analysis demonstrates that the approach proposed here is capable of ensuring robust performance under several operating conditions, measurement and modelling error, parametric uncertainties and external disturbances and the simulation results prove the proficiency of the controller proposed. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by an immune mediated decrease in platelet number. Disturbance of CD4+ T‐cell homeostasis with simultaneous decrease of CD4+CD25+Foxp3+ regulatory T cells (Tregs) as well as unrestricted proliferation and activation of peripheral CD4+ effector T cells underpin the pathophysiology of ITP. Indirubin is an active ingredient of a traditional Chinese herb called Indigofera tinctoria L. which is clinically used for the treatment of ITP patients. Whether indirubin targets the Tregs/effector T cell‐axis to restore platelet number is unknown. In our in vitro studies, Indirubin could significantly enhance the number and function of Tregs and meanwhile dampen the activation of effector T cells in a dose‐dependent manner. Indirubin was observed to restore the expression of programmed cell‐death 1 (PD1) and phosphatase and tensin homolog (PTEN) on the CD4+ T cells of ITP patients, leading to the subsequent attenuation of the AKT/mTOR pathway. Furthermore, these observations were recapitulated in an active murine model of ITP with a prominent platelet response. Thus, our results identified a potentially novel mechanism of the therapeutic action of indirubin in the treatment of ITP through regulating the homeostasis of CD4+ T cells in a PD1/PTEN/AKT signalling pathway. [ABSTRACT FROM AUTHOR]

Objectives: The reported prevalence of chronic obstructive pulmonary disease (COPD) in people living with HIV (PLWHIV) varies widely. Our objective was to estimate the prevalence of airflow obstruction and COPD in unselected PLWHIV and identify characteristics that increase the risk of nonreversible airflow obstruction in order to guide case finding strategies for COPD. Methods: All adults attending the Chronic Viral Illness Service were invited to participate in the study, regardless of smoking status or history of known COPD/asthma. Individuals underwent spirometric testing both before and after use of a salbutamol bronchodilator. Airflow obstruction was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.7 post‐bronchodilation, whereas COPD was defined as FEV1/FVC < 0.7 post‐bronchodilation and Medical Research Council (MRC) score > 2. Multivariate logistic regression was used to evaluate risk factors associated with airflow obstruction, reported as adjusted odds ratios (aORs). Results: Five hundred and three participants successfully completed spirometry testing. The median (Q1; Q3) age was 52 (44; 58) years. The median (Q1; Q3) CD4 count was 598 (438; 784) cells/μL and the median (Q1; Q3) nadir CD4 count was 224 (121; 351) cells/μL. There were 119 (24%) current smokers and 145 (29%) former smokers. Among those screened, 54 (11%) had airflow obstruction whereas three (1%) of the participants had COPD. Factors that were associated with airflow obstruction included a history of smoking [aOR 2.2; 95% confidence interval (CI) 1.1; 4.7], older age (aOR 1.6; 95% CI 1.2; 2.2), and lower CD4 count (aOR 0.8; 95% CI 0.7; 1.0). Conclusions: Airflow obstruction was relatively uncommon. Our findings suggest that PLWHIV who are ≥50 years old, smokers and those with nadir CD4 counts ≤ 200 cells/μL could be targeted to undergo spirometry to diagnose chronic airflow obstruction. [ABSTRACT FROM AUTHOR]

The CD7 antigen is a member of the immunoglobulin superfamily that expresses on the surface of all thymocytes, a majority of mature T cells, and also natural killer cells. Interestingly, under physiological and different pathological conditions, the loss of CD7 antigen occurred in the subset of CD4+ memory T cells. Various functions have been proposed for CD7, including its role in the activation and intercellular adhesiveness of T cells. Several studies indicate that the number of CD4+CD7− T cells increases in diseases such as chronic inflammation and T‐cell malignancies, these being skin inflammatory lesions. Therefore, this can be useful for the diagnosis of cancer cells, especially with reference to blood origin, treatment monitoring, and establishment of new therapies. Therefore, a comprehensive review could be useful to increase our knowledge about the clinical importance of these cells in human disease. In this review, we first focus on the clinical importance of CD4+CD7− T cells in human disease and also explain the possible function of these cells. Secondly, we also investigate if the CD4 +CD7− T cells are resistant to apoptosis. [ABSTRACT FROM AUTHOR]

Sustained adaptive immunity to pathogens provides effective protection against infections, and effector cells located at the site of infection ensure rapid response to the challenge. Both are essential for the success of vaccine development. To explore new vaccination approach against Mycobacterium tuberculosis (M.tb) infection, we have shown that Rv3615c, identified as ESX‐1 substrate protein C of M.tb but not expressed in BCG, induced a dominant Th1‐type response of CD4+ T cells from patients with tuberculosis pleurisy, which suggests a potential candidate for vaccine development. But subcutaneous immunization with Rv3615c induced modest T‐cell responses systemically, and showed suboptimal protection against virulent M.tb challenge at the site of infection. Here, we use a mouse model to demonstrate that intranasal immunization with Rv3615c induces sustained capability of adaptive CD4+ T‐ and B‐cell responses in lung parenchyma and airway. Rv3615c contains a dominant epitope of mouse CD4+ T cells, Rv3615c41‐50, and elicits CD4+ T‐cell response with an effector–memory phenotype and multi‐Th1‐type cytokine coexpressions. Since T cells resident at mucosal tissue are potent at control of infection at early stage, our data show that intranasal immunization with Rv3615c promotes a sustained regional immunity to M.tb, and suggests a potency in control of M.tb infection. Our study warranties a further investigation of Rv3615c as a candidate for development of effective vaccination against M.tb infection. [ABSTRACT FROM AUTHOR]

Summary: Upon encounter with their cognate antigen, naive CD4 T cells become activated and are induced to differentiate into several possible T helper (Th) cell subsets. This differentiation depends on a number of factors including antigen‐presenting cells, cytokines and co‐stimulatory molecules. The strength of the T‐cell receptor (TCR) signal, related to the affinity of TCR for antigen and antigen dose, has emerged as a dominant factor in determining Th cell fate. Recent studies have revealed that TCR signals of high or low strength do not simply induce quantitatively different signals in the T cells, but rather qualitatively distinct pathways can be induced based on TCR signal strength. This review examines the recent literature in this area and highlights important new developments in our understanding of Th cell differentiation and TCR signal strength. [ABSTRACT FROM AUTHOR]

Abstract: As a proinflammatory cytokine, CD137 (4‐1BB, TNFRSF9) is present in membrane‐bound and soluble forms. Increased expression of CD137 was recently found in T cells in human atherosclerotic plaques. However, the exact role of CD137 in ischemic stroke is not clear. In this study we analyzed the protein levels of soluble CD137 (sCD137) and the expression of CD137 on CD4+ T cells in the peripheral blood of patients with acute atherothrombotic stroke by using the cytometry beads array (CBA) and flow cytometry. Within 24 hours of onset, the stroke patients showed elevated levels of sCD137 (2.7 pg/ml) and CD137 expression on CD4+ T cells (4.9 ± 3.2%) compared with normal controls (1.1 pg/ml, P < 0.01; 1.3 ± 1.0%, P < 0.01). Alterations in CD137 expression may enhance ischemia‐induced inflammatory responses via bidirectional signaling and, consequently, aggravate brain injury in early stages of this disorder. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Modelling suggests that early diagnosis and immediate antiretroviral therapy (ART) among key populations would have a substantial impact in reducing HIV transmission and mortality in Vietnam. An implementation research project of “test‐and‐treat” among people who inject drugs (PWID) was developed to inform effective roll‐out of such interventions. Methods: “Test‐and‐treat” was offered to PWID in two high burden provinces, Thai Nguyen and Thanh Hoa. The interventions comprised the offer of biannual HIV testing and immediate ART, irrespective of CD4 count. PWID were enrolled between April 2014 and July 2015 and followed up for 12 months, and retention, HIV viral load (VL) and risk behaviours were assessed. Retention in care of this prospective cohort was compared with the retention among men enrolled in care in the preceding period (April 2012 to March 2013) at the same clinics when ART was initiated at CD4 cell count ≤350 cells/mm3. Results: In total, 287 HIV positive PWID started immediate ART. The majority (98%) were men; median age was 34; and median (interquartile range) CD4 count was 199 (50 to 402) cells/mm3. After 12 months, 238 participants (83%) were retained on ART, and 205 achieved viral suppression (<1000 copies/mL) (92% among those in whom VL was measured, 71% overall). Baseline CD4 count ≤100 cells/mm3 and history of imprisonment were associated with lower retention and viral suppression, while engagement in methadone maintenance was associated with higher retention. Retention in care was higher in the “test‐and‐treat” cohort (83%) compared with men enrolled in care in the preceding period (78%), primarily because lost‐to‐follow‐up during pre‐ART care was eliminated. No decline in consistent condom use and clean needle use was observed. Conclusions: Early ART initiation resulted in successful treatment outcomes among PWID, with no observed increase in self‐reported risk behaviours, suggesting feasibility and potential effectiveness of “test‐and‐treat” approach. The results also call for differentiated care for PWID, including promoting early diagnosis and engagement in methadone maintenance therapy while enhancing care for those with advanced HIV disease and history of imprisonment. [ABSTRACT FROM AUTHOR]

Summary: Although regulatory T‐cells (Tregs) have been shown to be expanded in acute dengue, their role in pathogenesis and their relationship to clinical disease severity and extent of viraemia have not been fully evaluated. The frequency of Tregs was assessed in 56 adult patients with acute dengue by determining the proportion of forkhead box protein 3 (FoxP3) expressing CD4+ CD25+T‐cells (FoxP3+ cells). Dengue virus (DENV) viral loads were measured by quantitative real‐time polymerase chain reaction (PCR) and DENV‐specific T‐cell responses were measured by ex‐vivo interferon (IFN)‐γ enzyme‐linked immunospot (ELISPOT) assays to overlapping peptide pools of DENV‐NS3, NS1 and NS5. CD45RA and CCR4 were used to phenotype different subsets of T‐cells and their suppressive potential was assessed by their expression of cytotoxic T lymphocyte‐antigen 4 (CTLA‐4) and Fas. While the frequency of FoxP3+ cells in patients was significantly higher (P < 0·0001) when compared to healthy individuals, they did not show any relationship with clinical disease severity or the degree of viraemia. The frequency of FoxP3+ cells did not correlate with either ex‐vivo IFN‐γ DENV‐NS3‐, NS5‐ or NS1‐specific T‐cell responses. FoxP3+ cells of patients with acute dengue were predominantly CD45RA+ FoxP3low, followed by CD45RA‐FoxP3low, with only a small proportion of FoxP3+ cells being of the highly suppressive effector Treg subtype. Expression of CCR4 was also low in the majority of T‐cells, with only CCR4 only being expressed at high levels in the effector Treg population. Therefore, although FoxP3+ cells are expanded in acute dengue, they predominantly consist of naive Tregs, with poor suppressive capacity. [ABSTRACT FROM AUTHOR]

Copyright of Tropical Medicine & International Health is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: The Streamlined Antiretroviral Therapy Initiation Strategy (START-ART) study found that a theory-based intervention using opinion leaders to inform and coach health care providers about the risks of treatment delay, provision of point of care (POC) CD4 testing machines (PIMA) and reputational incentives, led to rapid rise in ART initiation. We used qualitative research methods to explore mechanisms of provider behaviour change. Methods: We conducted in-depth interviews (IDIs) with 24 health care providers and nine study staff to understand perceptions, attitudes and the context of changes in ART initiation practices. Analyses were informed by the Theoretical Domains Framework. Results: Rapid dissemination of new practices was enabled in the environmental context of an existing relationship based on communication, implementation and accountability between Makerere University Joint AIDS Program (MJAP), a Ugandan University-affiliated organization that provided technical oversight for HIV service delivery at the health facilities where the intervention was implemented, and a network of health facilities operated by the Uganda Ministry of Health. Coaching carried out by field coordinators from MJAP strengthened influence and informal accountability for carrying out the intervention. Frontline health workers held a pre-existing strong sense of professional identity. They were proud of attainment of new knowledge and skills and gratified by providing what they perceived to be higher quality care. Peer counsellors, who were not explicitly targeted in the intervention design, effectively substituted some functions of health care providers; as role models for successful ART uptake, they played a crucial role in creating demand for rapid ART initiation through interactions with patients. Point of care (POC) CD4 testing enabled immediate action and relieved providers from frustrations of lost or delayed laboratory results, and led to higher patient satisfaction (due to reduced costs because of ability to initiate ART right away, requiring fewer return trips to clinic). Conclusions: Qualitative data revealed that a multicomponent intervention to change provider behaviour succeeded in the context of strong institutional and individual relationships between a University-affiliated organization, government facilities, and peer health workers (who acted as a crucial link between stakeholders) and the community. Fostering stable institutional relationships between institutional actors (non-governmental organization (NGOs) and ministry-operated facilities) as well as between facilities and the community (through peer health workers) can enhance uptake of innovations targeting the HIV cascade in similar clinical settings. [ABSTRACT FROM AUTHOR]

Transendothelial migration (TEM) of Th1 and Th17 cells across the blood-brain barrier (BBB) has a critical role in the development of experimental autoimmune encephalomyelitis (EAE). How cytokines produced by inflammatory Th1 and Th17 cells damage the endothelial BBB and promote transendothelial migration of immune cells into the central nervous system (CNS) during autoimmunity is not understood. We therefore investigated the effect of various cytokines on brain endothelial cells. Among the various cytokines tested, such as Th1 (IFN-γ, IL-1α, IL-1β, TNF-α, IL-12), Th2 (IL-3, IL-4, IL-6 and IL-13), Th17 (IL-17A, IL-17F, IL-21, IL-22, IL-23, GM-CSF) and Treg-specific cytokines (IL-10 and TGF-β), IFN-γ predominantly showed increased expression of ICAM-1, VCAM-1, MAdCAM-1, H2-Kb and I-Ab molecules on brain endothelial cells. Furthermore, IFN-γ induced transendothelial migration of CD4+ T cells from the apical (luminal side) to the basal side (abluminal side) of the endothelial monolayer to chemokine CCL21 in a STAT-1-dependent manner. IFN-γ also favored the transcellular route of TEM of CD4+ T cells. Multicolor immunofluorescence and confocal microscopic analysis showed that IFN-γ induced relocalization of ICAM-1, PECAM-1, ZO-1 and VE-cadherin in the endothelial cells, which affected the migration of CD4+ T cells. These findings reveal that the IFN-γ produced during inflammation could contribute towards disrupting the BBB and promoting TEM of CD4+ T cells. Our findings also indicate that strategies that interfere with the activation of CNS endothelial cells may help in controlling neuroinflammation and autoimmunity. [ABSTRACT FROM AUTHOR]

Inherited mutations in lipopolysaccharide-responsive beige-like anchor (LRBA) cause a recessive human immune dysregulation syndrome with memory B-cell and antibody deficiency (common variable immunodeficiency), inflammatory bowel disease, enlarged spleen and lymph nodes, accumulation of activated T cells and multiple autoimmune diseases. To understand the pathogenesis of the syndrome, C57BL/6 mice carrying a homozygous truncating mutation in Lrba were produced using CRISPR/Cas9-mediated gene targeting. These mice revealed that LRBA has a critical, cell-autonomous role in promoting cytotoxic T-lymphocyte antigen-4 (CTLA-4) accumulation within CD4 effector T cells and FOXP3+ T-regulatory cells (Tregs). In young mice, or in chimeric mice where only half of the T cells are LRBA deficient, low CTLA-4 was the only detectable abnormality in Tregs, whereas in old mice FOXP3 was also decreased. Low CTLA-4 did not translate into increased CD86 on B cells unless the LRBA-deficient mice were immunised, and neither immunisation nor chronic lymphocytic choriomeningitis virus infection precipitated immune dysregulation. LRBA deficiency did not alter antigen-specific B-cell activation, germinal centre (GC) formation, isotype switching or affinity maturation. Paradoxically, CD86 was decreased on GC B cells in LRBA-deficient mice, pointing to compensatory mechanisms for controlling CD86 in the face of low CTLA-4. These results add to the experimental rationale for treating LRBA deficiency with the CTLA4-Ig fusion protein, Abatacept, and pose questions about the limitations of laboratory experiments in mice to reproduce human disease in natura. [ABSTRACT FROM AUTHOR]

CD4 T cells help immune responses, but knowledge of how memory CD4 T cells are regulated and how they regulate adaptive immune responses and induce immunopathology is limited. Using adoptive transfer of virus-specific CD4 T cells, we show that naive CD4 T cells undergo substantial expansion following infection, but can induce lethal T helper type 1-driven inflammation. In contrast, memory CD4 T cells exhibit a biased proliferation of T follicular helper cell subsets and were able to improve adaptive immune responses in the context of minimal tissue damage. Our analyses revealed that type I interferon regulates the expansion of primary CD4 T cells, but does not seem to play a critical role in regulating the expansion of secondary CD4 T cells. Strikingly, blockade of type I interferon abrogated lethal inflammation by primary CD4 T cells following viral infection, despite that this treatment increased the numbers of primary CD4 T-cell responses. Altogether, these data demonstrate important aspects of how primary and secondary CD4 T cells are regulated in vivo, and how they contribute to immune protection and immunopathology. These findings are important for rational vaccine design and for improving adoptive T-cell therapies against persistent antigens. [ABSTRACT FROM AUTHOR]