4-1BB co-stimulation enhances human CD8(+) T cell priming by augmenting the proliferation and survival of effector CD8(+) T cells

Interactions between 4-1BB and its ligand, 4-1BBL, enhance CD8(+) T cell-mediated antiviral and antitumor immunity in vivo. However, mechanisms regulating the priming of CD8(+) T cell responses by 4-1BB remain unclear, particularly in humans. The 4-1BB receptor was undetectable on naive or resting human CD8(+) T cells and induced in vitro by TCR triggering. Naive cord blood cells were therefore primed in vitro against peptides or cellular antigens and then co-stimulated with 4-1BBL or agonistic antibodies. Co-stimulation enhanced effector function such as IFN-gamma production and cytotoxicity by augmenting numbers of antigen-specific and effector CD8(+) T cells. OKT3 responses also showed reduced cell death and revealed that the proliferation of CD8(+) T cells required two independently regulated events. One, the induction of IL-2 production, could be directly triggered by 4-1BB engagement on CD8(+) T cells in the absence of accessory cells. The other, expression of CD25, was induced with variable efficacy by accessory cells. Thus, suboptimal accessory cells and 4-1BB co-stimulation combined their effects to enhance IL-2 production and proliferation. Reduced apoptosis observed after co-stimulation in the presence of accessory cells correlated with increased levels of Bcl-X(L) in CD8(+) T cells, while Bcl-2 expression remained unchanged. Altogether, 4-1BB enhanced expansion, survival and effector functions of newly primed CD8(+) T cells, acting in part directly on these cells. As 4-1BB triggering could be protracted from the TCR signal, 4-1BB agonists may function through these mechanisms to enhance or rescue suboptimal immune responses.     

Serum Immunoglobulin Levels in Splenectomized and Non- Splenectomized Patients with Major Beta-Thalassemia

Objective

Thalassemia is a common disease in many countries, in which several complications such as infections can occur. Although aberration in the function of the immune system could be a reason for such complication, a little is known about the status of humoral immune system in major beta thalassemia. In this study we measured serum immunoglobulins level in a group of patients with major beta thalassemia.

Methods

Ninety nine patients with major beta thalassemia were enrolled in this study divided into two groups of splenctomized and not splenctomized patients. Serum IgG, IgM and IgA levels of these patients were measured and analyzed.

Findings

Serum mean levels of IgG and IgM in patients of all ages in both groups were normal. The mean serum IgA level in the group of not splenectomized patients aged less than five years as well as in the splenectomized patients aged more than twenty years was increased. However, it was normal in other age groups.

Conclusion

Although this study could not show any defect in the humoral immune system, evaluation of immunoglobulins could be useful to understand the relmarkable high rate of infection in the patients with major beta thalassemia.     

Phenotypic expansion of POGZ‐related intellectual disability syndrome (White‐Sutton syndrome)

White‐Sutton syndrome (WHSUS) is a recently‐identified genetic disorder resulting from de novo heterozygous pathogenic variants in POGZ. Thus far, over 50 individuals have been reported worldwide, however phenotypic characterization and data regarding the natural history are still incomplete. Here we report the clinical features of 22 individuals with 21 unique loss of function POGZ variants. We observed a broad spectrum of intellectual disability and/or developmental delay with or without autism, and speech delay in all individuals. Other common problems included ocular abnormalities, hearing loss and gait abnormalities. A validated sleep disordered breathing questionnaire identified symptoms of obstructive sleep apnea in 4/12 (33%) individuals. A higher‐than‐expected proportion of cases also had gastrointestinal phenotypes, both functional and anatomical, as well as genitourinary anomalies. In line with previous publications, we observed an increased body mass index (BMI) z‐score compared to the general population (mean 0.59, median 0.9; p 0.0253). Common facial features included microcephaly, broad forehead, midface hypoplasia, triangular mouth, broad nasal root and flat nasal bridge. Analysis of the Baylor Genetics clinical laboratory database revealed that POGZ variants were implicated in approximately 0.14% of cases who underwent clinical exome sequencing for neurological indications with or without involvement of other body systems. This study describes a greater allelic series and expands the phenotypic spectrum of this new syndromic form of intellectual disability and autism.     

Myxoid mesenchymal tumors of uterus: endometrial stromal and smooth muscle tumors, myxoid variant

Four myxoid variant of uterine mesenchymal tumors are reported. One was a low grade stromal sarcoma with infiltrative margins and the others were well circumscribed tumors corresponding to an endometrial stromal nodule and two leiomyomas. They were hypocellular neoplasms composed of stellated cells with an abundant Alcian Blue positive myxoid matrix. The myxoid nature of the neoplasms obscured their cellular nature and made the distinction between smooth muscle and endometrial stromal tumors difficult. Endometrial stromal tumors, showed very focal areas of small basophilic cells, characteristic of endometrial stroma. The diagnosis was based on the presence of a spiral arteriolar network, a CD10 positivity as well as the absence of h-caldesmon and desmin expression. The two myxoid leiomyomas showed more spindle cells and a desmin expression while h-caldesmon was negative and CD10 focally positive in both cases. Myxoid variant of endometrial stromal tumors does not necessarily exhibit the typical morphology of endometrial stroma. They may demonstrate morphological features of smooth muscle tumors in the uterus. Also, myxoid changes in uterin smooth muscle tumors may modify the classical immunoreactivity of smooth muscle markers in these tumors and make it difficult to distinguish between benign and malignant neoplasms. An immunohistochemical panel of antibodies including CD10, h-caldesmon and desmin may help in establishing the correct diagnosis.     

Association of waterpipe smoking and road traffic crashes

Background  

The purpose of this research was to examine whether waterpipe smokers experience increased risk of motor vehicle crashes.     

PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor

1-(2-Chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195) is a prototypic ligand of the peripheral benzodiazepine receptor (PBR), a mitochondrial outer membrane protein. PK11195 can be used to chemosensitize tumor cells to a variety of chemotherapeutic agents, both in vitro and in vivo. PK11195 has been suggested to exert this effect via inhibition of the multiple drug resistance (MDR) pump and by direct mitochondrial effects which could be mediated by the PBR. Here, we established a model system in which PK11195 and another PBR ligand, 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro5-4864), sensitize to nutrient depletion-induced cell death. In this MDR-independent model, PK11195 and Ro5-4864 are fully active even when the PBR is knocked down by small interfering RNA. Cells that lack PBR possess low-affinity binding sites for PK11195 and Ro5-4864. The starvation-sensitizing effects of PK11195 are not due to a modulation of the adaptive response of starved cells, namely autophagy and NF-kappaB activation. Rather, it appears that the combination of PK11195 with autophagy or NF-kappaB inhibitors has a potent synergistic death-inducing effect. Starved cells treated with PK11195 exhibit characteristics of apoptosis, including loss of the mitochondrial transmembrane potential, mitochondrial cytochrome c release, caspase activation and chromatin condensation. Accordingly, stabilization of mitochondria by overexpression of Bcl-2 or expression of the viral mitochondrial inhibitor (vMIA) from cytomegalovirus inhibits cell death induced by PK11195 plus starvation. Thus, PK11195 potently sensitizes to apoptosis via a pathway that involves mitochondria, yet does not involve the PBR.     

Responsibility attitude in a sample of Iranian obsessive-compulsive patients

BACKGROUND: The study of distorted beliefs about responsibility attitude and interpretation has become the central theme in Salkovskis' (1985) and Rachman and Hodgson's (1980) models of Obsessive-Compulsive Disorder (OCD). AIMS: The aim of this research is to assess the responsibility attitude in Iranian OCD patients. METHODS: Twenty OCD patients were selected through available sampling from the case referred to psychology clinics. Two other patient groups comprised of 20 non-OCD anxiety disorder patients and 20 non-clinical participants were also chosen as comparison groups. All participants completed the Responsibility Attitude Scale (RAS) and Responsibility Interpretation Questionnaire (RIQ). RESULTS: Analyses revealed statistically significant differences between OCD group and comparison groups on both RAS and RIQ. In addition, both RAS and RIQ scores were associated with the severity of OCD assessed by the Yale-Brown scale. CONCLUSIONS: These findings suggest that responsibility attitude and interpretations are the prominent features of OCD in Iranian patients and are associated with the severity of illness.