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Intracranial aneurysm (IA) is a common cerebrovascular disease. Immune system disorders and endothelial dysfunction are essential mechanisms of its pathogenesis. This study aims to explore the therapeutic effect and mechanism of Geniposide (Gen) on IA, which has a protective impact on endothelial cells and cardiovascular and cerebrovascular diseases. IA mouse models were administered intraperitoneal injections of geniposide for 2 weeks following elastase injection into the right basal ganglia of the brain for intervention. The efficacy of Gen in treating IA was evaluated through pathological testing and transcriptome sequencing analysis of Willis ring vascular tissue. The primary mechanism of action was linked to the expression of GSK3β in Th17 cells. The percentage of splenic Th17 cell differentiation in IA mice was significantly inhibited by Gen. GSK3β/STAT3, and other pathway protein expression levels were also significantly inhibited by Gen. Additionally, TNF‐α and IL‐23 cytokine contents were significantly downregulated after Gen treatment. These results indicated that Gen significantly inhibited the percentage of Th17 cell differentiation, an effect that was reversed upon overexpression of the GSK3B gene. Furthermore, Gen‐treated, Th17 differentiation‐inducing cell‐conditioned medium significantly up‐regulated the expression of tight junction proteins ZO‐1, Occludin, and Claudin‐5 in murine aortic endothelial cells. Administering the GSK3β inhibitor Tideglusib to IA mice alleviated the severity of IA disease pathology and up‐regulated aortic tight junction protein expression. In conclusion, Gen inhibits Th17 cell differentiation through GSK3β, which reduces endothelial cell injury and up‐regulates tight junction protein expression. [ABSTRACT FROM AUTHOR]

Background: The regulatory mechanisms guiding CD4 T cell differentiation are complex and are further influenced by intrinsic cell variability along with that of microenvironmental cues, such as cytokine and nutrient availability. Objective: This study aims to expand our understanding of CD4 T cell differentiation by examining the influence of intrinsic noise on cell fate. Methodology: A model based on a complex regulatory network of early signaling events involved in CD4 T cell activation and differentiation was described in terms of a set of stochastic differential equation to assess the effect of noise intensity on differentiation efficiency to the Th1, Th2, Th17, Treg, and TFH effector phenotypes under defined cytokine and nutrient conditions. Results: The increase of noise intensity decreases differentiation efficiencies. In a microenvironment of Th1-inducing cytokines and optimal nutrient conditions, noise levels of 3%, 5% and 10% render Th1 differentiation efficiencies of 0.87, 0.76 and 0.62, respectively, underscoring the sensitivity of the network to random variations. Further increments of noise reveal that the network is relatively stable until noise levels of 20%, where the resulting cell phenotypes becomes heterogeneous. Notably, Treg differentiation showed the highest robustness to noise perturbations. A combined Th1-Th2 cytokine environment with optimal nutrient levels induces a dominant Th1 phenotype; however, removal of glutamine shifts the balance towards the Th2 phenotype at all noise levels, with an efficiency similar to that obtained under Th2-only cytokine conditions. Similarly, combinations of Th1/Treg and Treg/Th17-inducing cytokines along with the removal of either tryptophan or oxygen shift the dominant Th1 and Treg phenotypes towards Treg and Th17 respectively. Model results are consistent with differentiation efficiency patterns obtained under wellcontrolled experimental settings reported in the literature. Conclusion: The stochastic CD4 T cell mathematical model presented here demonstrates a noise-dependent modulation of T cell differentiation induced by cytokines and nutrient availability. Modeling results can be explained by the network topology, which assures that the system will arrive at stable states of cell functionality despite variable levels of biological intrinsic noise. Moreover, the model provides insights into the robustness of the T cell differentiation process. [ABSTRACT FROM AUTHOR]

Conventional CD4+ T lymphocytes consist of naïve, foreign antigen-specific memory, and self-antigen-driven memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells tonically proliferate in response to self-antigens and differentiate into the T-bet+ subset in steady state. How excess proliferation and differentiation of MP cells are inhibited remains unclear. Given immunosuppressive function of regulatory T cells (Tregs), it is possible that they are also involved in inhibition of spontaneous MP cell activation. Here we show using Foxp3-diphtheria toxin receptortransgenic mice that both MP and naïve CD4+ T cells spontaneously proliferate and differentiate into Th1 cells upon acute Treg depletion. At an early time point post Treg depletion, MP as compared to naïve CD4+ T cells are preferentially activated while at a later stage, the response is dominated by activated cells originated from the naïve pool. Moreover, we argue that MP cell proliferation is driven by TCR and CD28 signaling whereas Th1 differentiation mediated by IL-2. Furthermore, our data indicate that such activation of MP and naïve CD4+ T lymphocytes contribute to development of multi-organ inflammation at early and later time points, respectively, after Treg ablation. Together our findings reveal that Tregs tonically inhibit early, spontaneous proliferation and Th1 differentiation of MP CD4+ T lymphocytes as well as late activation of naïve cells, thereby contributing to maintenance of T cell homeostasis. [ABSTRACT FROM AUTHOR]

Conventional CD4+ T lymphocytes consist of naïve, foreign antigen-specific memory, and self-antigen-driven memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells tonically proliferate in response to self-antigens and differentiate into the T-bet+ subset in steady state. How excess proliferation and differentiation of MP cells are inhibited remains unclear. Given immunosuppressive function of regulatory T cells (Tregs), it is possible that they are also involved in inhibition of spontaneous MP cell activation. Here we show using Foxp3-diphtheria toxin receptor-transgenic mice that both MP and naïve CD4+ T cells spontaneously proliferate and differentiate into Th1 cells upon acute Treg depletion. At an early time point post Treg depletion, MP as compared to naïve CD4+ T cells are preferentially activated while at a later stage, the response is dominated by activated cells originated from the naïve pool. Moreover, we argue that MP cell proliferation is driven by TCR and CD28 signaling whereas Th1 differentiation mediated by IL-2. Furthermore, our data indicate that such activation of MP and naïve CD4+ T lymphocytes contribute to development of multi-organ inflammation at early and later time points, respectively, after Treg ablation. Together our findings reveal that Tregs tonically inhibit early, spontaneous proliferation and Th1 differentiation of MP CD4+ T lymphocytes as well as late activation of naïve cells, thereby contributing to maintenance of T cell homeostasis.

BackgroundThe regulatory mechanisms guiding CD4 T cell differentiation are complex and are further influenced by intrinsic cell variability along with that of microenvironmental cues, such as cytokine and nutrient availability.ObjectiveThis study aims to expand our understanding of CD4 T cell differentiation by examining the influence of intrinsic noise on cell fate.MethodologyA model based on a complex regulatory network of early signaling events involved in CD4 T cell activation and differentiation was described in terms of a set of stochastic differential equation to assess the effect of noise intensity on differentiation efficiency to the Th1, Th2, Th17, Treg, and TFH effector phenotypes under defined cytokine and nutrient conditions.ResultsThe increase of noise intensity decreases differentiation efficiencies. In a microenvironment of Th1-inducing cytokines and optimal nutrient conditions, noise levels of 3%, 5% and 10% render Th1 differentiation efficiencies of 0.87, 0.76 and 0.62, respectively, underscoring the sensitivity of the network to random variations. Further increments of noise reveal that the network is relatively stable until noise levels of 20%, where the resulting cell phenotypes becomes heterogeneous. Notably, Treg differentiation showed the highest robustness to noise perturbations. A combined Th1-Th2 cytokine environment with optimal nutrient levels induces a dominant Th1 phenotype; however, removal of glutamine shifts the balance towards the Th2 phenotype at all noise levels, with an efficiency similar to that obtained under Th2-only cytokine conditions. Similarly, combinations of Th1/Treg and Treg/Th17-inducing cytokines along with the removal of either tryptophan or oxygen shift the dominant Th1 and Treg phenotypes towards Treg and Th17 respectively. Model results are consistent with differentiation efficiency patterns obtained under well-controlled experimental settings reported in the literature.ConclusionThe stochastic CD4 T cell mathematical model presented here demonstrates a noise-dependent modulation of T cell differentiation induced by cytokines and nutrient availability. Modeling results can be explained by the network topology, which assures that the system will arrive at stable states of cell functionality despite variable levels of biological intrinsic noise. Moreover, the model provides insights into the robustness of the T cell differentiation process.

The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression. [ABSTRACT FROM AUTHOR]

The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression.

We have earlier discovered a new factor of autoimmunity downregulation, called regulatory rheumatoid factor (regRF). Being anti-idiotypic antibodies, regRF restricts the expansion of CD4+ T lymphocytes to the idiotype of which it is specific, according to the negative feedback principle. It has been shown that only activated CD4+ T lymphocytes are the target of regRF. However, it is still not clear the way regRF distinguishes activated cells from naive ones. RegRF molecules, apart from individual paratopes specific to unique sequences of B- and T-cell receptors, have a shared paratope. We assume that regRF by means of a shared paratope recognizes one of the surface activation molecules of CD4+ T lymphocytes and initiates the cell death. Programmed death-1 (PD-1) has been tested as a potential receptor of the shared regRF paratope and transmitter of the negative regRF signal into activated CD4+ T lymphocytes. The specificity of the shared regRF paratope to PD-1 was determined by ELISA. T cell activation was performed with immobilized anti-CD3ε antibodies. Flow cytometry was used to study the effect of regRF on PD-1+CD4+ lymphocytes. We found that regRF binds to PD-1. IgG Fc fragments carrying epitopes specific to the shared paratope of regRF compete with PD-1 for binding to regRF. It follows that regRF recognizes specifically PD-1 by means of a shared paratope. RegRF-containing serum reduced the number of PD-1+CD4+ lymphocytes in proportion to their increase resulting from the action of anti-CD3ε antibodies. RegRF uses PD-1 pathway to control activated CD4+ T lymphocytes. [ABSTRACT FROM AUTHOR]

Malnutrition is a common clinical problem in patients infected with HIV and causes immune suppression and depletion of CD4 T cells. The powder from the leaves of Moringa oleifera (MO) through numerous studies has shown nutritional and therapeutic virtues. Also the administration of this vitamin complex associated with mineral salts to a patient would be simple and practical than that of conventional micronutrients. The objective of this study was to measure the impact of the daily intake of Moringa oleifera leaf powder on the cells of the immune system, more particularly the CD4 T lymphocytes (CD4 LT) of people aged 18 years and over living with HIV AIDS at Notre Dame des Apôtres Maingara Hospital in Sarh / Chad. This was a comparative case-control study that took place over a period of six (06) months. The study included 100 undernourished people living with HIV / AIDS aged 18 or under followed at the level of the People Living with Human Immunodeficiency Virus (PLWHIV) department. Patients were enrolled in two groups. Each patient received 15g / day of Moringa oleifera leaf powder (group A) or NDA enriched flour (group B) during the 6 months. The patients also benefited from a clinical followup (with the measurement of the biological parameters (CBC, TCD4 lymphocytes) at inclusion and after six months. The results obtained showed that there was a nutritional recovery of 52.97 % for the groups supplemented with Moringa oleifera leaf powder versus 20.23% for the enriched flour NDA. We also observed no statistically significant difference in the mean of lymphocytes in group B (enriched flour NDA) (p0.975) The improvement in the CD4 LT count observed in patients supplemented with Moringa oleifera also reflects an improvement in the immune status of PLHIV which is normally in decline after infection with HIV oxidative stress. These micronutrients (vitamins, Mg, phycocyanin) have immuno stimulatory properties which would allow a gain or stabilization of the number of CD4 lymphocytes in groups supplemented with Moringa oleifera leaf powder. Analysis of the blood count reveals that the consumption of M. oleifera allowed a significant increase (p= 0.000) in the values of red blood cells (RBC), hemoglobin level (THb), hematocrit (Hte) and (p= 0.001) of the mean globular volume (MCV) as well as the parameters of the leukocyte line (macrophages, monocytes and dendritic cells which express this CD4 receptor) which are also major players in the immune system. In control subjects, blood count parameters did not change significantly. Moringa Oleifera leaf powder is said to offer enormous benefits in nutritional recovery (weight gain), stabilization or gain of lymphocytes thus contributing to the well-being of PLHIV. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is characterized by the loss of myelin and of myelin-producing oligodendrocytes (OLs) in the central nervous system (CNS). Pro-inflammatory CD4+ Th17 cells are considered pathogenic in MS and are harmful to OLs. We investigated the mechanisms driving human CD4+ T cell-mediated OL cell death. Using fluorescent and brightfield in vitro live imaging, we found that compared to Th2-polarized cells, Th17-polarized cells show greater interactions with primary human OLs and human oligodendrocytic cell line MO3.13, displaying longer duration of contact, lower mean speed, and higher rate of vesicle-like structure formation at the sites of contact. Using single-cell RNA sequencing, we assessed the transcriptomic profile of primary human OLs and Th17-polarized cells in direct contact or separated by an insert. We showed that upon close interaction, OLs upregulate the expression of mRNA coding for chemokines and antioxidant/anti-apoptotic molecules, while Th17-polarized cells upregulate the expression of mRNA coding for chemokines and pro-inflammatory cytokines such as IL-17A, IFN-γ, and granzyme B. We found that secretion of CCL3, CXCL10, IFN-γ, TNFα, and granzyme B is induced upon direct contact in cocultures of human Th17-polarized cells with human OLs. In addition, we validated by flow cytometry and immunofluorescence that granzyme B levels are upregulated in Th17-polarized compared to Th2-polarized cells and are even higher in Th17-polarized cells upon direct contact with OLs or MO3.13 cells compared to Th17-polarized cells separated from OLs by an insert. Moreover, granzyme B is detected in OLs and MO3.13 cells following direct contact with Th17-polarized cells, suggesting the release of granzyme B from Th17-polarized cells into OLs/MO3.13 cells. To confirm granzyme B–mediated cytotoxicity toward OLs, we showed that recombinant human granzyme B can induce OLs and MO3.13 cell death. Furthermore, pretreatment of Th17-polarized cells with a reversible granzyme B blocker (Ac-IEPD-CHO) or a natural granzyme B blocker (serpina3N) improved survival of MO3.13 cells upon coculture with Th17 cells. In conclusion, we showed that human Th17-polarized cells form biologically significant contacts with human OLs and exert direct toxicity by releasing granzyme B. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is characterized by the loss of myelin and of myelin-producing oligodendrocytes (OLs) in the central nervous system (CNS). Pro-inflammatory CD4+ Th17 cells are considered pathogenic in MS and are harmful to OLs. We investigated the mechanisms driving human CD4+ T cell-mediated OL cell death. Using fluorescent and brightfield in vitro live imaging, we found that compared to Th2-polarized cells, Th17-polarized cells show greater interactions with primary human OLs and human oligodendrocytic cell line MO3.13, displaying longer duration of contact, lower mean speed, and higher rate of vesicle-like structure formation at the sites of contact. Using single-cell RNA sequencing, we assessed the transcriptomic profile of primary human OLs and Th17-polarized cells in direct contact or separated by an insert. We showed that upon close interaction, OLs upregulate the expression of mRNA coding for chemokines and antioxidant/anti-apoptotic molecules, while Th17-polarized cells upregulate the expression of mRNA coding for chemokines and pro-inflammatory cytokines such as IL-17A, IFN-γ, and granzyme B. We found that secretion of CCL3, CXCL10, IFN-γ, TNFα, and granzyme B is induced upon direct contact in cocultures of human Th17-polarized cells with human OLs. In addition, we validated by flow cytometry and immunofluorescence that granzyme B levels are upregulated in Th17-polarized compared to Th2-polarized cells and are even higher in Th17-polarized cells upon direct contact with OLs or MO3.13 cells compared to Th17-polarized cells separated from OLs by an insert. Moreover, granzyme B is detected in OLs and MO3.13 cells following direct contact with Th17-polarized cells, suggesting the release of granzyme B from Th17-polarized cells into OLs/MO3.13 cells. To confirm granzyme B–mediated cytotoxicity toward OLs, we showed that recombinant human granzyme B can induce OLs and MO3.13 cell death. Furthermore, pretreatment of Th17-polarized cells with a reversible granzyme B blocker (Ac-IEPD-CHO) or a natural granzyme B blocker (serpina3N) improved survival of MO3.13 cells upon coculture with Th17 cells. In conclusion, we showed that human Th17-polarized cells form biologically significant contacts with human OLs and exert direct toxicity by releasing granzyme B.

Conventional CD4 + T lymphocytes consist of naïve, foreign antigen-specific memory, and self-antigen-driven memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells tonically proliferate in response to self-antigens and differentiate into the T-bet + subset in steady state. How excess proliferation and differentiation of MP cells are inhibited remains unclear. Given immunosuppressive function of regulatory T cells (Tregs), it is possible that they are also involved in inhibition of spontaneous MP cell activation. Here we show using Foxp3-diphtheria toxin receptor-transgenic mice that both MP and naïve CD4 + T cells spontaneously proliferate and differentiate into Th1 cells upon acute Treg depletion. At an early time point post Treg depletion, MP as compared to naïve CD4 + T cells are preferentially activated while at a later stage, the response is dominated by activated cells originated from the naïve pool. Moreover, we argue that MP cell proliferation is driven by TCR and CD28 signaling whereas Th1 differentiation mediated by IL-2. Furthermore, our data indicate that such activation of MP and naïve CD4 + T lymphocytes contribute to development of multi-organ inflammation at early and later time points, respectively, after Treg ablation. Together our findings reveal that Tregs tonically inhibit early, spontaneous proliferation and Th1 differentiation of MP CD4 + T lymphocytes as well as late activation of naïve cells, thereby contributing to maintenance of T cell homeostasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Li, Yang, Kawajiri, Sato, Tayama, Ishii, Zhu and Kawabe.)

Background: Candida sp. is the most common opportunistic pathogen found during the development of Human immunodeficiency virus (HIV) & Acquired immune deficiency syndrome (AIDS) disease. The clinical severity of oral candidiasis and the prevalence profile of Candida species reflect immunological changes in HIV / AIDS patients. Objective: Evaluating the relationship between CD4 T lymphocyte cells counts and the number of Candida species. Methods: A cross-sectional analytical study was carried out at Dr. Soetomo, Surabaya, Indonesia. For identification of Candida species, culture was carried out on Chromagar media followed by culture with vitek 2. Results: There were 114 study subjects who were divided into three groups based on the number of CD4 T lymphocyte cells, with 158 isolates of Candida species growing in culture. The highest number of Candida species was Candida albicans with a total of 107 isolates (67.7%). Candida non-albicans were 51 isolates (32.3%). Statistical test results showed a significant correlation between the number of CD4 T lymphocyte cells and the number of Candida species (p <0.001). Conclusion: The decrease in CD4 lymphocyte cell counts is influenced by various types of Candida sp. in oral candidiasis patients. [ABSTRACT FROM AUTHOR]

Objectives We investigated the reciprocal relationship linking fibroblast-like synoviocytes (FLS) and T lymphocytes in the inflamed RA synovium and subsequently targeted cellular metabolic pathways in FLS to identify key molecular players in joint inflammation. Methods RA FLS were cultured with CD4 T cells or T cell conditioned medium (CD4CM); proliferation, expression of adhesion molecules and intracellular cytokines were examined by flow cytometry. FLS invasiveness and secreted cytokines were measured by transwell matrigel invasion chambers and ELISA, while metabolic profiles were determined by extracellular Seahorse flux analysis. Gene expression was quantified by real-time quantitative RT-PCR. Results Our results showed mutual activation between CD4 T cells and FLS, which resulted in increased proliferation and expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 by both CD4 T cells and FLS. Furthermore, interaction between CD4 T cells and FLS resulted in an increased frequency of TNF-α+, IFN-γ+ and IL-17A+ CD4 T cells and augmented TNF-α, IFN-γ, IL-17A, IL-6, IL-8 and VEGF secretion. Moreover, CD4CM promoted invasiveness and boosted glycolysis in FLS while downregulating oxidative phosphorylation, effects paralleled by increased glucose transporters GLUT1 and GLUT3 ; key glycolytic enzymes GSK3A , HK2 , LDHA and PFKFB3 ; angiogenic factor VEGF and MMP-3 and MMP-9. Importantly, these effects were reversed by the glycolytic inhibitor 2-DG and AMP analogue 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Conclusion This study demonstrates that CD4 T cells elicit an aggressive phenotype in FLS, which subsequently upregulate glycolysis to meet the increased metabolic demand. Accordingly, 2-DG and AICAR prevent this activation, suggesting that glycolytic manipulation could have clinical implications for RA treatment. [ABSTRACT FROM AUTHOR]

Both maternal microbiota and helminth infection may alter offspring immunity but the relationship between these is underexplored. We hypothesized that maternal helminth exposure prior to pregnancy has lasting consequences on offspring intestinal microbiota and consequent immunity. Female BALB/c adult mice were infected with 500L3 Nippostrongylus brasiliensis (N brasiliensis). Infection was cleared by ivermectin treatment, and mice were mated 3 weeks post‐infection (NbM). Control mice were not infected but were exposed to ivermectin (NvM). We analysed maternal gut microbiota during pregnancy, breastmilk microbiota and offspring faecal microbiota and immunity 2 weeks after delivery. During pregnancy, NbM (Mothers previously infected with Nippostrongylus brasiliensis) displayed significantly altered stool bacterial communities (R2 =.242; P =.001), with increased abundance of Enterococcaceae versus NvM (Naive mothers). Similarly, we observed a profound impact on breastmilk microbiota in NbM vs NvM. Moreover, NbM pups showed significantly altered gut microbial communities at 14 days of age versus those born to NvM with increased relative abundance of Coriobacteriaceae and Micrococcaceae. These changes were associated with alterations in pup immunity including increased frequencies and numbers of activated CD4 T cells (CD4 + CD44hi) in NbM offspring spleens. Taken together, we show that preconception helminth infections impact offspring immunity possibly through alteration of maternal and offspring microbiota. [ABSTRACT FROM AUTHOR]

BACKGROUND: The correct interpretation of values from the quadratic deviation is useful in immunology, it is the average of the deviations; therefore, based on this, we can make decisions. OBJECTIVE: To analyze the behavior of leukocyte, total lymphocyte and CD4 values from the set theory when performing the mean square deviation, and extrapolate its utility to the clinic. MATERIAL AND METHOD: A transversal analytical study was done from January 1st to November 30th, 2018, after collecting leukocyte and total lymphocyte values from a blood count, as well as the latest CD4 values of HIV-infected patients, based on the theory of sets, we proceeded to classify by ranges of 1000 leukocytes, to form 10 ranges. Subsequently, it was classified by sets to finally perform the mean square deviation, this being the central axis of the present article. RESULTS: It was observed how the behavior of the probabilities is strongly distributed for total lymphocytes coming from the blood count and CD4 T lymphocytes in the 10 established ranges. For the AUC set, the quadratic deviations took values between 0.25 and 0.50; for the BUD set between 0.19 and 0.50, while for the set (AUC)n(BUD) the deviations were observed between 0.04 and 0.50. CONCLUSIONS: The quadratic deviation and its analysis is usually useful applied to the clinic. The behavior of the probabilities is distributed for both CD4 and general lymphocytes. [ABSTRACT FROM AUTHOR]

BACKGROUND: The prediction of CD4 T lymphocytes in patients with HIV-AIDS generates benefits in the field of public health, reduces costs in monitoring and time in decision making. OBJECTIVE: To apply the theory of the sets and probability to predict the amount of T CD4 lymphocytes that exist in peripheral blood taking into account only the values of blood count. MATERIAL AND METHOD: A prospective study was done from January to December 2018 applying the methodology described by Rodríguez et al. The values of leukocytes, lymphocytes from a blood count and previous CD4 were used, the sets A, B, C and D were determined, the probability of the appearance of specific combinations of leukocyte, lymphocyte and CD4 values was calculated, in ranges of 1000 leukocytes for all the cases. RESULTS: There were studied 232 cases. Values below 570 CD4 cells were predicted from ranges below 9000 leukocytes, with a percentage of effectiveness ranging from 91 to 100%. For ranges below 3000 leukocytes and the range of 8000 to 8999 was 100% effective. CONCLUSION: The probability theory is applicable to the Mexican population. It is effective and will reduce costs to the health system. [ABSTRACT FROM AUTHOR]

Summary: The murine monoclonal anti‐idiotypic antibody, NP30, is a potential vaccine candidate against Schistosoma japonicum. Previous studies have revealed that NP30 has an immunoregulatory effect, but the underlying mechanism for this effect remains unknown. This study shows that NP30 induces dendritic cell (DC) maturation and increases the production of pro‐inflammatory cytokines. The expression of CD86 and MHC II was upregulated in DCs following stimulation with NP30 in vitro. Moreover, NP30 induced Th17 polarization by increasing the production of IL‐6 and TGF‐β. In vivo, Th17 differentiation was induced by the production of key pro‐inflammatory cytokines, including IL‐6and TGF‐β, from DCs of NP30‐immunized mice. These results indicate that NP30 promotes Th17 polarization through DC activation, preventing serious schistosomiasis. [ABSTRACT FROM AUTHOR]

This study revises our understanding of the effectiveness of cell-mediated adaptive immunity and treatment against microsporidia using molecular detection and quantification of microsporidia in immunocompetent C57Bl/6 and immunodeficient CD4−/− and CD8−/− mice for the first time. We demonstrate an intense dissemination of microsporidia into most organs within the first weeks post-infection in all strains of mice, followed by a chronic infection characterized by microsporidia persistence in CD4−/− and C57Bl/6 mice and a lethal outcome for CD8−/− mice. Albendazole application reduces microsporidia burden in C57Bl/6 and CD4−/− mice, whereas CD8−/− mice experience only a temporary effect of the treatment. Surprisingly, treated CD8−/− mice survived the entire experimental duration despite enormous microsporidia burden. On the basis of our results, we conclude that microsporidia survive despite the presence of immune mechanisms and treatments that are currently considered to be effective and therefore that CD8 T lymphocytes represent a major, but not sole effector mechanism controlling microsporidiosis. Furthermore, the survival of mice does not correspond to spore burden, which provides new insight into latent microsporidiosis from an epidemiological point of view. [ABSTRACT FROM AUTHOR]

Host immunosuppression occurs during chronic nematode infection, partly due to effector T-cell hyporesponsiveness. The role of P-glycoprotein (P-gp), a member of the ABC transporter family, has been assessed in T-cell activity. This study assesses the possible role of P-gp in T-cell activity during nematode infection. Our findings indicate that blockade of P-gp in vivo increased protection against Heligmosomoides polygyrus nematode infection and was associated with the enhanced T-cell activity. Three P-gp-inhibitors, verapamil ( VRP), cyclosporine (CsA) and tariquidar ( XR9576), were used to determine the influence of nematode infection on the P-gp function of T cells. The influence of the nematode on the uptake, efflux and kinetics of extrusion in T-cell subsets CD4+ and CD8+ was assessed by the accumulation of Rho123 dye. The results indicate that H. polygyrus infection contributes to the inhibition of T-cell function by elevating P-gp activity. The blockade of P-gp in the T cells of infected mice led to an impressive increase in T-cell proliferation and IL-4 cytokine release through the upregulation of NF-κB activation. These results provide the first evidence that the P-gp function of T cells is altered during nematode infection to open the way for further studies aiming to explore the role of P-gp in host-parasite interactions. [ABSTRACT FROM AUTHOR]

For several decades, the leukotriene pathways have been implicated as playing a central role in the pathophysiology of asthma. The presence and elevation of numerous metabolites in the blood, sputum, and bronchoalveolar lavage fluid from asthmatics or experimental animals adds support to this notion. However, targeting of the leukotriene pathways has had, in general, limited success. The single exception in asthma therapy has been targeting of the cysteinyl leukotriene receptor 1, which clinically has proven effective but only in certain clinical situations. Interference with 5-lipoxygenase has had limited success, in part due to adverse drug effects. The importance of the LTB4-BLT1 pathway in asthma pathogenesis has extensive experimental support and findings, albeit limited, from clinical samples. The LTB4-BLT1 pathway was shown to be important as a neutrophil chemoattractant. Despite observations made more than two decades ago, the LTB4-BLT1 pathway has only recently been shown to exhibit important activities on subsets of T lymphocytes, both as a chemoattractant and on lymphocyte activation, as well as on dendritic cells, the major antigen presenting cell in the lung. The role of BLT2 in asthma remains unclear. Targeting of components of the LTB4-BLT1 pathway offers innovative therapeutic opportunities especially in patients with asthma that remain uncontrolled despite intensive corticosteroid treatment. [ABSTRACT FROM AUTHOR]

The introduction of anti-calcineurin-based therapies has led to an increase in the one-year survival as well as graft function rates in patients undergoing solid organ transplantation (SOT). Nonetheless, early cellular acute rejection (EAR) incidence still remains a major challenge that irrevocably heads to poor outcomes. The mechanisms underlying CD4 T cell activation in SOT are still under research. In this sense, CD28 co-stimulatory molecule plays a pivotal role triggering CD4 T cell activation as well as survival maintenance. Previous own studies stated the role that CD4 + CD28 + circulating T lymphocytes plays before and during EAR episodes. We assessed the percentage as well as the absolute number of CD28 molecules on CD4 + T cells as predictive surrogate biomarker of EAR in a prospective cohort of liver and kidney transplant recipients. Quantitative analysis of CD28 was carried out on whole peripheral blood samples by flow cytometry. Decreased pre-transplant expression of CD28 was associated with EAR in both study groups. Furthermore, the expression of CD28 within the rejected group, experimented an up-regulation upon transplantation. These preliminary results suggest that patients undergoing liver or kidney transplant can be stratified at high risk of EAR according to their CD28 molecule expression on peripheral CD4 + T lymphocytes. [ABSTRACT FROM AUTHOR]

While human immunodeficiency virus (HIV)-1 chemokine co-receptors 5 tropism and the GWGR motif in the envelope third variable region (V3 loop) have been associated with a slower disease progression, their influence on antiretroviral response remains unclear. The impact of baseline V3 characteristics on treatment response was evaluated in a randomised, double blind, prospective cohort study with patients initiating highly active antiretroviral therapy with lopinavir or efavirenz plus azithothymidine/3TC (1:1) over 48 weeks. Similar virological and immunological responses were observed for both treatment regimens. The 43 individuals had a mean baseline CD4 T cell count of 119 cells/mm³ [standard deviation (SD) = 99] and a mean viral load of 5.09 log10 copies/mL (SD = 0.49). The GWGR motif was not associated with a CD4 T cell response, but predicted R5 tropism by the geno2pheno[clinical20%] algorithm correlated with higher CD4 T cell levels at all monitoring points (p < 0.05). Moreover, higher false-positive rates (FPR) values from this analysis revealed a strong correlation with CD4 T cell recovery (p < 0.0001). Transmitted drug resistance mutations, documented in 3/41 (7.3%) cases, were unrelated to the assigned antiretroviral regimen and had no impact on patient outcomes. In conclusion, naÏve HIV-1 R5 infected patients exhibited higher CD4 T cell counts at baseline; this difference was sustained throughout therapy. The geno2pheno[clinical] option FPR positively correlated with CD4 T cell gain and may be useful in predicting CD4 T cell recovery.

Toxoplasma gondii infection induces a strong and long-lasting immune response that is able to prevent most reinfections but allows tissue cysts. Irradiated, sterilized T. gondii tachyzoites are an interesting vaccine, and they induce immunity that is similar to infection, but without cysts. In this study, we evaluated the cellular immune response in the blood and spleen of mice immunized with this preparation by mouth (v.o.) or intraperitoneally (i.p.) and analyzed the protection after challenge with viable parasites. BALB/c mice were immunized with three i.p. or v.o. doses of irradiated T. gondii tachyzoites. Oral challenge with ten cysts of the ME-49 or VEG strain at 90 days after the last dose resulted in high levels of protection with low parasite burden in the immunized animals. There were higher levels of specific IgG, IgA and IgM antibodies in the serum, and the i.p. immunized mice had higher levels of the high-affinity IgG and IgM antibodies than the orally immunized mice, which had more high-affinity IgA antibodies. B cells (CD19), plasma cells (CD138) and the CD4 and CD8 T cell populations were increased in both the blood and spleen. Cells from the spleen of the i.p. immunized mice also showed antigen-induced production of interleukin-10 (IL-10), interferon gamma (IFN-γ) and interleukin 4 (IL-4). The CD4 T cells, B cells and likely CD8 T cells from the spleens of the i.p. immunized mice proliferated with a specific antigen. The protection was correlated with the spleen and blood CD8 T cell, high-affinity IgG and IgM and antigen-induced IL-10 and IL-4 production. Immunization with irradiated T. gondii tachyzoites induces an immune response that is mediated by B cells and CD4 and CD8 T cells, with increased humoral and cellular immune responses that are necessary for host protection after infection. The vaccine is similar to natural infection, but free of tissue cysts; this immunity restrains infection at challenge and can be an attractive and efficient model for vaccine development in toxoplasmosis. [ABSTRACT FROM AUTHOR]

Ectromelia virus is a mouse-specific orthopoxvirus that, following footpad infection or natural transmission, causes mousepox in most strains of mice, while a few strains, such as C57BL/6, are resistant to the disease but not to the infection. Mousepox is an acute, systemic, highly lethal disease of remarkable semblance to smallpox, caused by the human-specific variola virus. Starting in 1929 with its discovery by Marchal, work with ECTV has provided essential information for our current understanding on how viruses spread lympho-hematogenously, the genetic control of antiviral resistance, the role of different components of the innate and adaptive immune system in the control of primary and secondary infections with acute viruses, and how the mechanisms of immune evasion deployed by the virus affect virulence in vivo. Here, I review the literature on the pathogenesis and immunobiology of ECTV infection in vivo. [ABSTRACT FROM AUTHOR]

Exosomes are extracellular vesicles (EVs) that play a role in intercellular communication. Stimulation of dendritic cells by the HIV-1 virus triggers their release. HIV-1 binds to dendritic cells via dendritic cell immunoreceptor (DCIR). This study shows that inhibiting the binding to DCIR significantly decreases exosome release by HIV-1-pulsed dendritic cells. In addition, exosome release from Raji-CD4 expressing DCIR cells stimulated by anti-DCIR or HIV-1 is decreased when the immunoreceptor tyrosine-based inhibition motif (ITIM) signaling motif of DCIR is mutated. Unlike the EVs released from Raji-CD4-DCIR cells after antibody stimulation, those released from HIV-1-infected cells contain the pro-apoptotic protein DAP-3. Furthermore, EVs from HIV-1 pulsed dendritic cells increase spontaneous apoptosis in uninfected CD4 T lymphocytes while they decrease it in neutrophils. This study describes for the first time that DCIR plays a role in the release of exosomes strengthening the importance of this receptor and EVs/exosomes in HIV-1 pathogenesis. [ABSTRACT FROM AUTHOR]

Despite extensive research, influenza A virus (IAV) remains a major cause of morbidity, mortality, and healthcare expenditure. Emerging pandemics from highly pathogenic IAV strains such as H5N1 and pandemic H1N1 highlight the need for universal, cross-protective vaccines. Current vaccine formulations generate strain-specific neutralizing antibodies primarily against the outer coat proteins hemagglutinin and neuraminidase. In contrast to these highly mutable proteins, internal proteins of IAV are more conserved and are a favorable target for developing vaccines that induce strong T cell responses in addition to humoral immunity. Here, we found that intranasal administration with a single dose of CpG and inactivated x31 (H3N2) reduced viral titers and partially protected mice from a heterosubtypic challenge with a lethal dose of PR8 (H1N1). Early after immunization, vaccinated mice showed increased innate immune activation with high levels of MHCII and CD86 expression on dendritic cells in both the draining lymph nodes and lungs. Three days after immunization, CD4 and CD8 cells in the lung upregulated CD69, suggesting that activated lymphocytes are present at the site of vaccine administration. The ensuing effector Th1 responses were capable of producing multiple cytokines and were present at least 30 days after immunization. Furthermore, functional memory responses were observed, as antigen specific IFN-γ+ and GrB+ cells were detected early after lethal infection. Together, this work provides evidence for using pattern recognition receptor agonists as a mucosal vaccine platform for inducing robust T cell responses capable of protecting against heterologous IAV challenges. [ABSTRACT FROM AUTHOR]

Leishmaniasis covers a broad spectrum of diseases with distinct, and sometimes overlapping, characteristics. The common thread in all forms of leishmaniasis is the infection by the parasite Leishmania belonging to the genus Leishmania. Upon infection of humans, there can be at least three outcomes, (i) control of Leishmania by the host immune response resulting in asymptomatic disease, (ii) patent infection and development of a relatively mild form of leishmaniasis and (iii) patent infection and development of severe clinical forms. The factors that determine the outcome of an initial inoculation with Leishmania are many, with the species of Leishmania representing one of the strongest predictive factors for the development of a given clinical form of disease. This is seen with L. braziliensis and L. amazonensis, infection leading mostly to tegumentary forms of disease, and L. infantum with the potential to induce visceral disease. However, it is also clear that the host immune response is a key factor in disease progression, not only responsible for control of Leishmania, but also playing an important role in disease progression and pathology. This duality between protective and pathogenic immune responses in individuals infected with Leishmania in the Americas is the focus of this review. [ABSTRACT FROM AUTHOR]

Poor CD4 lymphocyte recovery on antiretroviral therapy (ART) is associated with reduced function of the thymus. Palifermin (keratinocyte growth factor), by providing support to the thymic epithelium, promotes lymphopoiesis in animal models of bone marrow transplantation and graft-versus-host disease.In AIDS Clinical Trials Group A5212, a randomized, double-blind, placebo-controlled study, 99 HIV-infected patients on ART with plasma HIV-1 RNA levels 200 copies per milliliter for ≥6 months and CD4 lymphocyte counts <200 cells per cubic milliliter were randomized 1:1:1:1 to receive once daily intravenous administration of placebo or 20, 40, or 60 μg/kg of palifermin on 3 consecutive days.The median change in the CD4+ T-cell count from baseline to week 12 was not significantly different between the placebo arm [15 (-16, 23) cells/mm3] and the 20-μg/kg dose [11 (2, 32) cells/mm3], the 40-μg/kg dose [12 (-2, 25) cells/mm3], or the 60-μg/kg dose arm [8 (-13, 35) cells/mm3] of palifermin. No significant changes were observed in thymus size or in the number of naive T cells or recent thymic emigrants.Palifermin in the doses studied was not effective in improving thymic function and did not raise CD4 lymphocyte counts in HIV-infected patients with low CD4 cell counts despite virologically effective ART. [ABSTRACT FROM AUTHOR]

Allergic asthma is a complex and chronic inflammatory airway disease. Interleukin-17 is a pro-inflammatory cytokine which plays critical role in the pathogenesis of allergic asthma. It has been reported that β-arrestin2 regulated the development of allergic asthma at a proximal step in the inflammatory cascade. In this study, the influence of β-arrestin2 on Interleukin-17 production and expression of CD4+ T lymphocytes in a murine asthma model was investigated. Splenic CD4+ T lymphocytes from wild-type mice and those from a murine asthma model were purified. CD4+ T lymphocytes from a murine asthma model were transfected with siRNAs targeting the β-arrestin2 or were pretreated with the ERK1/2 inhibitor,PD98059. After stimulation, the protein expression of β-arrestin2、phosphorylated- ERK1/2 and IL-17 were detection by Western blot; the mRNA expression of IL-17 were detected by real-time PCR; the accumulation of IL-17 in supernatants were detected by ELISA. We found that β-arrestin2、phosphorylated-ERK1/2 and IL-17 expression in CD4+ T lymphocytes from a murine asthma model was increased compared with those from wild- type mice(p

Abstract: Due to the high degree of sequence identity between Orthopoxvirus species, the specific B and T cell responses raised against these viruses are largely cross-reactive and poorly selective. We therefore searched for CD4 T cell epitopes present in the conserved parts of the Vaccinia genome (VACV) but absent from Variola viruses (VARV), with a view to identifying immunogenic sequences selective for VACV. We identified three long peptide fragments from the B7R, B10R and E7R proteins by in silico comparisons of the poxvirus genomes, and evaluated the recognition of these fragments by VACV-specific T cell lines derived from healthy donors. For the 12 CD4 T cell epitopes identified, we assessed their binding to common HLA-DR allotypes and their capacity to induce peptide-specific CD4 T-cell lines. Four peptides from B7R and B10R displayed a broad binding specificity for HLA-DR molecules and induced multiple T cell lines from healthy donors. Besides their absence from VARV, the two B10R peptide sequences were mutated in the Cowpox virus and completely absent from the Monkeypox genome. This work contributes to the development of differential diagnosis of poxvirus infections. [Copyright &y& Elsevier]

Abstract: A calf model was used to determine if the depletion of CD4 T cells prior to inoculation of Mycobacterium avium subsp. paratuberculosis (Map) would delay development of an immune response to Map and accelerate disease progression. Ileal cannulas were surgically implanted in 5 bull calves at 2 months of age. Two calves were depleted of CD4 T cells by intravenous injection of anti-bovine CD4 antibody administered 24h prior to inoculation with Map. The two CD4-depleted calves and one non-depleted calf were inoculated via ileal cannula with 1×108 cfu live Map every 3 days for a total of 4 inoculations. Two additional calves served as non-depleted and uninfected controls. Injection with the anti-CD4 mAb reduced the frequency of CD4 T cells from a pre-depletion average of 15% to less than 1% in PBMC at 24h. However, a consistent proliferative response dominated by CD4 T cells, developed in both treated and untreated calves over the course of the 6-month study period. Recovery of Map from serial biopsies obtained from the CD4-depleted and non-depleted calves after Map infection did not differ. In addition, CD4 depletion did not increase the level of Map shed in the feces over the non-depleted animal. [Copyright &y& Elsevier]

Abstract: CD4+ memory is critical for successful protection against pathogenic challenge. As such, understanding the heterogeneity of cells that arise and survive after initial stimulation of naïve CD4+ T cells will aid in the design of more successful vaccines. In previous studies, in vivo experimental systems have been extensively used to generate functional memory responses by lymphocytes. Here, we have attempted to develop an in vitro experimental system to generate memory CD4+ T lymphocytes. CD4+ T cells stimulated through the antigen receptor complex were examined for their memory-like characteristics after 3 weeks of cell culture. A subset of surviving cells expressed high levels of CD44 and low levels of CD45RB (CD44hiCD45lo), a phenotype that is similar to bonafide memory CD4+ T cells. In vitro generated memory-like CD4+ T cells secreted higher levels of IFN-γ, with rapid kinetics, upon re-stimulation than their naïve counterparts. In addition, these memory-like CD4+ T cells did not produce either IL-2 or IL-4 but readily proliferated when cultured in the presence of IL-7 and IL-4. These observations suggest that CD4+ cells surviving the expansion phase of immune response produce a Th1-signature cytokine and retain responsiveness to IL-4, a Th-2 cytokine, as well as to a well described survival factor, interleukin-7. [Copyright &y& Elsevier]

Abstract: Effector CD4+ T lymphocytes generated in response to antigens produce endogenous opioids. Thus, in addition to their critical role in host defenses against pathogens, effector CD4+ T lymphocytes contribute to relieving inflammatory pain. In this study, we investigated mechanisms of opioid release by antigen-experienced effector CD4+ T cells that leave draining lymph nodes and come back into the inflammatory site. Effector antigen-primed CD4+ T lymphocytes generated in vitro were intravenously injected into nude mice previously immunized with either cognate or irrelevant antigens in complete Freund adjuvant (CFA). CFA-induced mechanical hyperalgesia was only reduced in mice immunized with cognate antigen. Thus, antinociceptive activity of effector CD4+ T cells requires the presence of the antigen for which they are specific within the inflammatory site. Accordingly, analgesia was inhibited by neutralizing cognate T cell receptor-mediated interaction between effector CD4+ T lymphocytes and antigen-presenting cells at the site of inflammation. Analgesia was observed by transferring effector CD4+ T lymphocytes with Th1 or Th2 phenotype, suggesting that antinociceptive activity is a fundamental property of effector CD4+ T lymphocytes irrespective of their effector functions. Based on the use of agonists and antagonists selective for each of the opioid receptor subclasses, we showed that analgesia induced by T cell-derived opioids is elicited via activation of δ-type opioid receptors in the periphery. Thus, the antinociceptive activity is a fundamental property associated with the effector phase of adaptive immunity, which is driven by recognition of the cognate antigen by effector CD4+ T lymphocytes at the inflammatory site. [Copyright &y& Elsevier]

CD4 T lymphocytes of patients with chronic kidney disease (CKD) are characterized by reduced levels of crucial surface antigens and changes in the cell cycle parameters. Recombinant human erythropoietin (rhEPO) normalizes their altered phenotype and proliferative capacity. Mechanisms leading to the deficient responses of T lymphocytes are still not clear but it is postulated that immunological changes are deepened by hemodialysis (HD). Study of activation parameters of CD4 T lymphocytes in hemodialyzed and predialysis CKD patients could bring insight into this problem. Two groups of patients, treated conservatively (predialysis, PD) and hemodialyzed (HD), as well as healthy controls, were included into the study; neither had received rhEPO. Proportions of main CD4CD28, CD4CD25, CD4CD69, CD4CD95, and CD4HLA-DR lymphocyte subpopulations and proliferation kinetic parameters were measured with flow cytometry, both ex vivo and in vitro. No differences were seen in the proportions of main CD4 lymphocyte subpopulations (CD4CD28, CD4CD25, CD4HLA-DR, CD4CD69, CD4CD95) between all examined groups ex vivo. CD4 T lymphocytes of HD patients exhibited significantly decreased expression of co-stimulatory molecule CD28 and activation markers CD25 and CD69 after stimulation in vitro when compared with PD patients and healthy controls. HD patients showed also decreased percentage of CD4CD28 lymphocytes proliferating in vitro; these cells presented decreased numbers of finished divisions after 72 h of stimulation in vitro and had longer G0→G1 time when compared to healthy controls. CD4 T lymphocytes of PD patients and healthy controls were characterized by similar cell cycle parameters. Our study shows that repeated hemodialysis procedure influences phenotype and proliferation parameters of CD4 T lymphocytes. [ABSTRACT FROM AUTHOR]

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Abstract: CD4+ T cells are critical for effective immune responses against HIV, but they are also the main cell type targeted by the virus. To investigate the key factors that could protect these cells from infection, we evaluated the capacity of HIV gp120-specific human CD4+ T cells to produce chemokines that inhibit HIV and determined their contribution in suppressing infection in the cells. Antigen stimulation of the CD4+ T cells elicited production of high amounts of CCR5 chemokines MIP-1α (CCL3), MIP-1β (CCL4), and RANTES (CCL5). Production of these CCR5 ligands was more readily and reproducibly detected than that of IFN-γ or IL-2. Importantly, in association with secretion of the CCR5 ligands, antigen stimulation made these CD4+ T cells more resistant to CCR5-tropic HIV-1. Conversely, in the absence of antigen stimulation, the cells were readily infected by the virus, and after infection, their capacity to produce MIP-1β and IFN-γ rapidly declined. Thus, vaccines that trigger HIV-specific CD4+ T cells to elicit robust and rapid production of anti-viral chemokines would be advantageous. Such responses would protect virus-specific CD4+ T cells from HIV infection and preserve their critical functions in mounting and maintaining long-lasting immunity against the virus. [Copyright &y& Elsevier]

The article reports on the effects of antiretroviral therapy on HIV-infected patients. The patients administered with increase in plasma IL-7 levels showed T-cell pool decrease progressively in HIV-infected patients. The cell surface expression of CD127 was measured ex vivo in CD4 and CD8 T lymphocytes drawn from 3 groups of HIV patients. The reason for the dysfunctional of IL-7 receptor in HIV patients are due to the abnormal activation of the immune system of the individual.

Objective To study the determinants of immunological and virological response to highly active antiretroviral therapy (HAART) in naïve patients, adjusting for time since HIV-1 seroconversion. Design Data from HIV-cohort studies where dates of seroconversion have been reliably estimated. Methods In previously untreated patients, short- and long-term marker responses from HAART initiation (three or more antiretroviral drugs) to the end of follow-up or any treatment modification were considered using mixed effects models accounting for undetectable HIV viral load and informative dropout. Results In total, 943 patients were treated with a first HAART regimen for a median of 29 months. In adjusted analyses, compared with a reference group of homosexual men without AIDS initiating treatment 4 years after seroconversion, injecting drug users (IDUs) were treated at similar CD4 and HIV RNA levels but had poorer short-term virological response (2.54 vs 2.13 log10 HIV-1 RNA copies/mL at 1.5 months, P=0.03) and poorer long-term immunological response (522 vs 631 cells/μL at 24 months, P<0.0001). Although individuals with AIDS at HAART initiation had lower CD4 counts (206 vs 382 cells/μL, P<0.0001), their immunological responses were similar to those of individuals without AIDS. Similarly, individuals further from seroconversion started HAART at lower CD4 counts (e.g. 311 vs 382 cells/μL at vs before 9 years from seroconversion, P<0.0001), but had similar CD4 responses. However, they experienced poorer long-term virological response (0.67 log10 copies/mL/year smaller decline, P<0.0001) compared to those treated before 9 years from seroconversion. Conclusion Taking into account the time elapsed since seroconversion, this study suggests that careful choices of initial treatment should be made and intensive follow-up carried out in high-risk subgroups such as IDUs who have poorer responses. [ABSTRACT FROM AUTHOR]

Summary Human immunodeficiency virus (HIV) infection leads to a profound T cell dysfunction well before the clinical onset of acquired immunodeficiency syndrome (AIDS). We have been accumulating evidence that one of the mechanisms responsible for this T cell deficiency may be the dysregulation of signal transduction via the interleukin (IL)-2/IL-2 receptor (R) complex. In CD4 T cells, we have observed previously that viral envelope (env) glycoproteins induce IL-2 unresponsiveness and the down-regulation of the three chains making up the IL-2R (α , β , γ ) in vitro . We have now established further that this disruption of the IL-2/IL-2R system manifests itself in defective signal propagation via the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) pathway in response to IL-2. The treatment of CD4 T cells with HIV env or surface ligation of CD4 with anti-CD4 monoclonal antibodies inhibited the IL-2-induced activation of Jak-1 and Jak-3, as well as their targets, STAT5a and STAT5b. This Jak/STAT deficiency may contribute to the crippling of CD4 T cell responses to a cytokine central to the immune response by HIV. [ABSTRACT FROM AUTHOR]

A dermatophytoma is a mass of hyphae that is observed at direct examination, it responds poorly to treatment with antifungal drugs, some authors have proposed that it is actually a biofilm. This pathology is underdiagnosed, and its true incidence is unknown. This study presents the clinical findings of dermatophytoma in HIV/AIDS patients from Colombia presenting onychomycosis. A transversal observational descriptive study was carried out in a third level university hospital. One hundred thirty HIV positive patients diagnosed using ELISA and Western Blot that presented nail lesions on their hands and/or feet compatible with onychomycosis were included. Samples taken from affected nails were observed in direct examination with KOH and seeded onto Sabouraud agar, mycosel agar and dextrose-potato agar. Molds were identified based on macroscopic and microscopic characteristics. Six (4.6%) individuals presented dermatophytoma. Average age was 43 years (range 33–50); nails more commonly affected (5/6) were on the toes, principally the hallux. Clinical manifestations included a yellow or white, rounded or linear dense area on the nail. Superficial white onychomycosis was present in 83.3% of the patients. Fungal cultures were obtained in only 5 patients; Trichophyton mentagrophytes complex was found in 2 individuals while T. rubrum, T. tonsurans and Epidermophyton floccosum were in the other 3. Average cell count for CD4+ T lymphocytes was 86.8 cells/mm3 (range 9–282). This is the first report in Colombia of dermatophytoma in HIV/AIDS patients, most of them had a CD4+ T lymphocytes count less than 200 cells/mm3. Several clinical forms of onychomycosis were observed, the most frequent was the white superficial onychomycosis. [ABSTRACT FROM AUTHOR]

The proliferative response of CD4 and CD8 T lymphocytes obtained from C3H/HeN mice chronically infected with Trypanosoma cruzi strains that differ in virulence, tropism and immunogenicity, was assayed against skeletal muscle, sciatic nerve and spinal cord homogenates. Although both CD4 and CD8 T lymphocytes from mice infected with the RA strain strongly proliferated against the nervous system, no response against skeletal muscle anhigens was detected. DD4 and CD8 T lymphocytes from mice infected with the K-98 clone ifrom CA-I strain) showed low proliferative response against all the antigens assayed. To determine whether the proliferation patients showed correlation with T cell- mediated neuromuscular damage, passive veil transfer studies were performed. Fifteen days after transfer of CD4 T cells from RA-infected donors (CD4-RA), normal syngeneic recipients displayed exclusively nervous tissue damage, such as perineural, endoneural and for meningeal inflammatory infiltrates, with predominance of CD4 T cells. Fifteen days alter transfer of CD4 T lymphocytes from mice infected with K-98 (CD4-K98), recipients showed inflammatory infiltrates only in skeletal muscle, where CD4 T lymphocytes and macrophages were predominant cells. Recipients of CD8 T cells front RA-infected mice (CD8-RA) showed lesions in both spinal cord and sciatic nerves. Higher percentages of CD8 T cells were observed in comparison with the recipients of CD4-RA or CD4-K98. In contrast, CD8 T cells front K-98-infected donors (CD8-K98) did not induce tissue damage. These results provide evidence that mice infected with T. cruzi populations that differ in their biological characteristics show diverse immune mechanisms that may be involved in the pathogenesis of peripheral nervous system damage. [ABSTRACT FROM AUTHOR]

To determine whether adhesion of peripheral blood lymphocytes (PBL) of patients with juvenile rheumatoid arthritis (JRA) may been enhanced, adhesion of PBL of children with JRA, children with seronegative spondyloarthropathies (SSA), age-appropriate and adult controls, to human umbilical vein endothelial cells (HUVEC) was assessed in vitro. B and CD4 T lymphocytes in initial, adherent, and non-adherent cell fractions were identified by flow cytometry. B lymphocytes of all the younger subjects combined had a higher adherence to activated HLJVEC compared with B lymphocytes of the adult donors, Except for greater adherence of HLA-DR+ CD4 T cells, lymphocytes of children with JRA showed no enhanced adhesion lo either unactivated or activated HUVEC. The percentage of B cells adherent to activated HUVEC in each of the subject groups was 1.5-3.6-fold higher than adherent CD4 T lymphocytes. Surface analyses indicated higher percentages of CD49d (α4) + and CD29 (β1) + CD4 T lymphocytes in adherent cells, but less of a differential in CD49 (α4) + and no differences in CD29 (β1) + B lymphocytes. There were fewer Leu-8 (L-selectin) + B and Leu-8+ CD4 T cells among adherent cells. The data suggest a greater adhesive capacity of B lymphocytes compared with CD4 T lymphocytes which is unrelated to disease, and the possibility that B lymphocytes may utilize adhesion molecules distinct from those of CD4 T lymphocytes. Only a small subset of T cells of patients with JRA may have an enhanced capacity for adhesion to endothelium. [ABSTRACT FROM AUTHOR]