Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation

Cumulative T-cell receptor signal strength and ensuing T-cell responses are affected by both antigen affinity and antigen dose. Here we examined the distinct contributions of these parameters to CD4 T-cell differentiation during infection. We found that high antigen affinity positively correlates with T helper (Th)1 differentiation at both high and low doses of antigen. In contrast, follicular helper T cell (T_FH) effectors are generated after priming with high, intermediate, and low affinity ligand. Unexpectedly, memory T cells generated after priming with very low affinity antigen remain impaired in their ability to generate secondary Th1 effectors, despite being recalled with high affinity antigen. These data challenge the view that only strongly stimulated CD4 T cells are capable of differentiating into the T_FH and memory T-cell compartments and reveal that differential strength of stimulation during primary T-cell activation imprints unique and long lasting T-cell differentiation programs.Following infection, T-cell receptor (TCR) interactions with foreign peptide/MHC (pMHC) drive the rapid clonal expansion and differentiation of T cells into distinct effector subsets specialized against different classes of microbes. An early bifurcation in CD4 T-cell responses results in the generation of T helper (Th)1 effectors, which regulate innate cell microbicidal function and follicular helper T (T_FH) cells, which migrate to B-cell follicles to regulate germinal center (GC) responses and antimicrobial antibody production (1). After pathogen is cleared, T cells undergo a contraction phase during which the majority of effectors die by apoptosis, leaving behind a population of long-lived memory cells to provide protection upon subsequent reinfection. The decision to differentiate into Th1 and T_FH lineages appears to occur very early in the immune response (2, 3). Initial T-cell priming by dendritic cells (DCs) is sufficient to induce fate-committed Th1 and T_FH cells as early as 3 d after infection, whereas maintenance and further expansion of the T_FH compartment depends on T-cell interactions with B cells (2). Similarly, memory T-cell differentiation occurs very early after infection and is critically dependent on B-cell interactions for optimal priming (4, 5). Importantly, CD4 T-cell differentiation is coupled to division, and unlike CD8 T-cell differentiation, requires constant antigen recognition (6, 7).Although the strength of TCR–pMHC interactions has been shown to directly modulate T-cell expansion and clonal dominance within the Th cell compartment (8, 9), how this influences CD4 T-cell fate is not well understood. Cumulative TCR signaling can be influenced by both antigen affinity and antigen dose (10). In terms of proliferation, higher antigen dose can compensate for lower antigen affinity to some extent, but several reports have shown independent effects on T-cell responses both in vitro and in vivo (10–12). These data indicate that antigen affinity and antigen dose may promote qualitatively distinct TCR signals. Recently, modulation of the overall TCR signal by varying either TCR affinity or antigen dose was shown to influence the pattern of effector T-cell differentiation, with higher affinity ligands or higher antigen dose promoting T_FH generation (13–15). However, another study examining high and low avidity CD4 T-cell responses during viral infection found significant differences in Th1 but not T_FH generation (16). Sustained TCR–pMHC interactions have also been shown to promote memory T-cell differentiation, which is associated with increased TCR avidity (17, 18). These studies, however, have focused on the development of the Th1 memory compartment, which is phenotypically and functionally distinct from the T_FH memory compartment (19, 20). Thus, although strong TCR signals resulting from high antigen affinity or high antigen dose can clearly affect the extent and quality of T-cell differentiation, whether or not T cells can discriminate these signals, and how this contributes to T-cell differentiation during infection, has not been determined.To address this question, we infected mice with varying concentrations of Listeria expressing either high or low affinity antigens for the TCR. By normalizing the degree of proliferation induced by high and low affinity antigens we were able to discern distinct influences of antigen affinity and antigen dose on Th cell differentiation. We observed a strong positive correlation between antigen affinity and Th1 differentiation that occurs early and is dose independent. Importantly, high antigen dose does not compensate for the low efficiency of Th1 differentiation induced by low affinity antigen. In contrast, early T_FH effector generation was observed after priming with high, intermediate, and low affinity antigen, but was not maintained at later time points under conditions of low antigen dose. In addition, we found that T cells activated by either high or low affinity antigen are equally capable of memory T-cell differentiation. Surprisingly, memory T cells generated by either low antigen affinity or low antigen dose maintained their biased effector lineages following recall activation with high affinity antigen. These data indicate that differential strength of stimulation during primary T-cell activation can imprint unique and long lasting T-cell differentiation programs.     

Moderate acute exercise (70% VO2 peak) induces TGF‐β, α‐amylase and IgA in saliva during recovery

Strenuous exercise promotes changes in salivary IgA and can be associated with a high incidence of upper respiratory tract Infections. However, moderate exercise enhances immune function. The effect of exercise on salivary IgA has been well studied, but its effect on other immunological parameters is poorly studied. Thus, this study determined the effect of moderate acute exercise on immunological salivary parameters, such as the levels of cytokines (TGF‐β and IL‐5), IgA, α‐amylase and total protein, over 24 h. Ten male adult subjects exercised for 60 min at an intensity of 70% VO₂ peak. Saliva samples were collected before (‘basal’) and 0, 12 and 24 h after an exercise session. The total salivary protein was lower after 12 and 24 h than immediately after exercise, whereas α‐amylase increased at 12 and 24 h after exercise compared with basal levels. The IgA concentration was increased at 24 h after exercise relative to immediately after exercise, and there was no difference in the IL‐5 while TGF‐β concentration increased in recovery. In conclusion, 70% VO₂ peak exercise does not induce changes immediately after exercise, but after 24 h, it produces an increase in salivary TGF‐β without changing IL‐5.     

Research committee

The JCAH move to evaluate clinical outcomes as part of its ongoing accreditation process has significant implications for infection control, APIC, and research. Through a concerted, progressive plan to address this issue, APIC can be a pathfinder in helping to prepare its members for this change. A proactive approach to both continued input into the process and the initiation of research to establish the groundwork are clearly indicated.     

mGluR5 and GABAA receptor‐specific parametric PET atlas construction—PET/MR data processing pipeline,validation, and application

The glutamate and γ‐aminobutyric acid neuroreceptor subtypes mGluR₅ and GABA_A are hypothesized to be involved in the development of a variety of psychiatric diseases. However, detailed information relating to their in vivo distribution is generally unavailable. Maps of such distributions could potentially aid clinical studies by providing a reference for the normal distribution of neuroreceptors and may also be useful as covariates in advanced functional magnetic resonance imaging (MR) studies. In this study, we propose a comprehensive processing pipeline for the construction of standard space, in vivo distributions of non‐displaceable binding potential (BP _ND), and total distribution volume (V _T) based on simultaneously acquired bolus‐infusion positron emission tomography (PET) and MR data. The pipeline was applied to [¹¹C]ABP688‐PET/MR (13 healthy male non‐smokers, 26.6 ± 7.0 years) and [¹¹C]Flumazenil‐PET/MR (10 healthy males, 25.8 ± 3.0 years) data. Activity concentration templates, as well as V _T and BP _ND atlases of mGluR₅ and GABA_A, were generated from these data. The maps were validated by assessing the percent error δ from warped space to native space in a selection of brain regions. We verified that the average δ_ABP = 3.0 ± 1.0% and δ_FMZ = 3.8 ± 1.4% were lower than the expected variabilities σ of the tracers (σ_ABP = 4.0%–16.0%, σ_FMZ = 3.9%–9.5%). An evaluation of PET‐to‐PET registrations based on the new maps showed higher registration accuracy compared to registrations based on the commonly used [¹⁵O]H₂O‐template distributed with SPM12. Thus, we conclude that the resulting maps can be used for further research and the proposed pipeline is a viable tool for the construction of standardized PET data distributions.     

La santé des pasteurs mobiles au Sahel – Bilan de 15 années de recherches et développement

Dans le Sahel, entre la Mauritanie et la Somalie incluant le Nord Kenya, environ 20 à 30 millions de personnes vivent en transhumance. Le rythme de leur migration suit l’évolution saisonnière du climat et la disponibilité des ressources, telle que l'eau, le pâturage et le sel. Malgré une exposition élevée à certaines maladies comme les zoonoses et les problèmes conditionnés liés au climat, les pasteurs mobiles sont parmi les populations quasiment exclues du système de santé, car la mise à disposition des services sociaux adaptés à un mode de vie mobile est difficile. Suivant l'objectif de recherche d'un meilleur accès aux soins des pasteurs mobiles, l'Institut Tropical et de Santé Publique Suisse, en partenariat avec plusieurs institutions dans la région, est actif au Sahel depuis 15 ans, aussi bien dans le domaine de la recherche, que celui des actions de développement. Basées sur une approche orientée vers les besoins des pasteurs mobiles pour leur développement, des recherches interdisciplinaires ont contribué à mieux comprendre la situation et les problèmes des éleveurs. En relation de la proximité entre l'homme et son bétail, une approche unissant la santé humaine et animale s'est avérée bonne et la valeur ajoutée d'une meilleure collaboration entre médecine humaine, animale et l'environnement a été démontrée. Ces approches utiles devraient être poursuivies et consolidées dans les recherches et le développement des actions futurs.     

Potential effectiveness of stored cord blood (non-frozen) for emergency use

Bone marrow has been used for a number of years to assist patients who have accidentally received potentially lethal levels of irradiation. The intent of the transplant is to replace the victim's own bone marrow that has been injured from the irradiation or to act as temporary support to allow the patient's own marrow to recover. Following the Chernobyl disaster, some victims received bone marrow that was HLA matched or partially matched. However, donor marrows were difficult to obtain in adequate numbers; as a substitute for bone marrow, frozen fetal liver cells were used as a source of hematopoietic stem cells. The use of fetal livers, however, was unsuccessful. Human umbilical cord blood, currently considered an excellent source of hematopoietic stem cells, was not used at Chernobyl. For several years, we have been able experimentally to keep SJL/J mice alive with the use of human umbilical cord blood after the animals received lethal levels of irradiation. This finding suggests that under certain conditions human cord blood does not have to be HLA matched to facilitate rescue from irradiation. In addition, there are reports of unmatched HLA cord blood being used successfully for marrow transplantation. If human cord blood does not have to be matched for HLA, there may be emergency cataclysmic circumstances where the availability of umbilical cord blood may be of considerable value. To simulate a clinical situation such as a nuclear accident, in which human cord blood might serve as a source of stem cells for marrow transplantation, we attempted to rescue immunocompetent mice after 900 cGY of irradiation with the use of (nonfrozen) human cord blood stored in a blood bank. The blood was stored under routine conditions (3–6 °C) for 5 and 7 days in special bags that allow transmission of oxygen. Following lethal levels of irradiation, the cord blood was administered to the animals and a significant survival rate was obtained.     

Are lasers superior to lights in the photoepilation of Fitzpatrick V and VI skin types? – A comparison between Nd:YAG laser and intense pulsed light

Background and objectives: There are no large volume comparative studies available to compare the efficacy of lasers over lights for hair removal in Fitzpatrick V and VI skin types. This study is designed to compare the efficacy of Nd:YAG laser versus IPL in the darker skin types. Study design/materials and methods: Thirty-nine patients included in Group-1 were treated with Nd:YAG and 31 in Group-2 with IPL. Both groups received 5 sessions of treatment. The hair counts were assessed using digital photography and manual counting method before and after treatment and the results were analysed. Patient satisfaction scores and pain scores were recorded in each session and compared. Results: Mean hair reduction in the IPL group was 25.70 and Nd:YAG group was 24.12 (95% CI). In the Nd:YAG group, 59% of subjects had burning sensation while the figure was 32.3% in IPL group. Burning was less in IPL group (p < 0.023). There were no statistically significant differences noticed regarding hyperpigmentation in both the groups (p < 0.115). Conclusion: Both Nd:YAG and IPL are equally effective for epilation of the darker skin types. Nd:YAG is associated with mild burning sensation in a significant number of patients. Patient satisfaction scores were comparable in both the groups.     

Histopathologic and Microbiologic Aspects of Ventilator-associated Pneumonia

Background: The relationship between microbiology and histology in patients with ventilator-associated pneumonia has been sparsely described.

Methods: Twenty-five patients who died in the intensive care unit after their lungs had been mechanically ventilated for 72 h were studied. Twenty of the 25 died with clinical suspicion of pulmonary infection. A total of 375 immediate postmortem pulmonary biopsies were obtained after death and processed for quantitative microbiology and histology. Four evolutionary stages of pneumonia were defined: early, intermediate, advanced, and resolution.

Results: At least one specimen with histologic evidence of pneumonia was found in all but two patients (92%). Histologic pneumonia was a widespread and frequent process (46% of biopsies examined) involving predominantly the lower lobes (55% of all biopsies with pneumonia) and showing different histopathologic stages of progression coexisting in the same lung lobes. Lung cultures were frequently polymicrobial (149 of 375, 40% of the pulmonary biopsy cultures, and 20 of 25, 80% of the cases) and not always yielding the same pathogen (19 microorganisms) when comparing one lung to the other. Histopathology and microbiologic biopsy cultures showed a weak relationship (28% and 49% of species had counts greater or equal to 103 cfu/g in samples without pneumonia from patients with and without prior antibiotic treatment, respectively). Histopathologic evolutionary stages were not associated with any differences in quantitative culture results of pulmonary biopsies, independently of prior administration of antibiotics. Higher bacterial concentrations of biopsy cultures were associated with the absence of prior antibiotic treatment.     

A case of complete double aortic arch visualized by transthoracic echocardiography

A case of double aortic arch that was well visualized using transthoracic echocardiography is reported. A 38‐year‐old man underwent transthoracic echocardiography for the evaluation of dyspnea. A suprasternal view of transthoracic echocardiography showed the ascending aorta bifurcate to left and right aortic arches, with blood flow from the ascending aorta to bilateral aortic arches. The diagnosis of right side–dominant double aortic arch was made, and the patient's symptom was conceivably related to compression of the trachea due to a vascular ring. This report indicates the potential usefulness of transthoracic echocardiography for noninvasive detection of double aortic arch in adults.