Induction of IL-5 expression by IL-2 is resistant to the immunosuppressive agents cyclosporin A and rapamycin

T cell cytokine expression may be induced by the cytokine IL-2 or via the TCR complex. The comparative effects of cytokine- and TCR-mediated signalling on the induction of human IL-5 mRNA were examined. Cytokine mRNA expression was analysed by RT-PCR in fresh peripheral blood mononuclear cells (PBMC) from normal individuals and in populations of activated T lymphocytes, derived from phytohaemagglutinin (PHA)- stimulated PBMC. rIL-2 induced IL-5 expression in PBMC, the kinetics of which were similar to the effects of PHA. rIL-4 induced IL-5 mRNA expression in activated T lymphocytes. IL-5 expression induced by either IL-2 or PHA was completely abolished by the protein synthesis inhibitor cycloheximide. rIL-2-induced IL-5 expression was resistant to cyclosporin A (CsA), whereas IL-5 expression elicited by PHA was inhibited by CsA, at doses as low as 10 ng/ml. Rapamycin (RAP) had no effect on rIL-2-stimulated IL-5 expression, but suppressed IL-5 expression induced by PHA. The inhibitory effect of RAP on PHA-induced IL-5 expression was more apparent at 12 and 24 h after stimulation than at earlier times. The resistance of IL-2 receptor (IL-2R) signalling to CsA and RAP indicates that the IL-2R and the TCR are associated with different pathways regulating IL-5 expression.      

Nationwide Implementation of Hello World: A Dutch Email-Based Health Promotion Program for Pregnant Women

Background

In November 2006, an email-based health promotion program for pregnant women was implemented nationally in the Netherlands. The program consisted of emails containing quizzes with pregnancy-related questions tailored to the number of weeks of pregnancy. Emails were sent out once every 4 weeks, up to a maximum of nine emails.

Objectives

The aims of the study were (1) to assess the recruitment of participants and their representativeness of the Dutch population and (2) to study differences in recruitment, program use, and program appreciation among women with different levels of education.

Methods

Data from 13,946 pregnant women who enrolled during the first year of the program were included. Upon registration, participants were asked how they found out about the program and subsequently received an email questionnaire to assess demographic, lifestyle, and Internet characteristics. Program use was tracked, and participants were classified into five user groups (inactive to very active). Program appreciation (low, intermediate, and high) was assessed twice with an email questionnaire that was sent after the woman had received her third and sixth quiz email. Information about pregnant women and their characteristics was obtained from Dutch registries to assess representativeness of the study population.

Results

About 8% of the pregnant women in the Netherlands enrolled in the program. Immigrants were underrepresented, and women with a low level of education seemed to be slightly underrepresented. Most women knew about the program from a promotional email sent by the organization (32%), followed by the Internet (22%) and midwives (16%). Women with little education were more often inactive users of the program than were highly educated women (15% vs 11%, P < .001), whereas highly educated women were more often very active users compared with women with little education (25% vs 20%, P< .001). However, women with less education were more likely than women with more education to have a high appreciation of the program after receiving three quiz emails (52% vs 44%, P = .001).

Conclusions

In this real-life setting, pregnant women can be reached through an email-based health promotion program. Selective engagement by education level remains a challenge.     

Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation

The association between lymphopenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28⁻CD57⁺), highly proliferative (Ki67⁺), oligoclonal, memory-like CD4 and CD8 T cells (CCR7⁻CD45RA⁻ or CCR7⁻CD45RA⁺) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopenic than their nonautoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopenia-associated autoimmunity in humans.The anti-CD (cluster of differentiation molecule) 52 monoclonal antibody alemtuzumab has proven efficacy in relapsing remitting multiple sclerosis (RRMS) (1–3). Each cycle of alemtuzumab leads to profound panlymphopenia, but relatively infrequent dosing allows reconstitution to occur: B cells recovery rapidly, whereas CD4 and CD8 cells take 35 and 20 mo, respectively, to reach normal values (4). For 5 y after alemtuzumab and maximally, at 2 y, secondary autoimmune conditions may develop: 30% of individuals experience thyroid autoimmunity, and 1% of individuals have idiopathic thrombocytopenic purpura (ITP); there are rare cases of autoimmune hemolytic anemia, autoimmune neutropenia, and Goodpasture syndrome (1–3). One-third of patients develop asymptomatic autoantibodies.An association between lymphopenia and autoimmunity is recognized; in humans, T lymphopenia is a feature of systemic lupus erythematosus, rheumatoid arthritis, and Crohn and Sjogren syndromes (5), and animal models of autoimmunity often involve the induction of lymphopenia. The mechanism driving autoimmunity in these situations is unclear. In some cases it has been attributed to loss of regulatory cells; however, although treatment of lymphopenic hosts with CD4⁺CD25⁺ Tregs can abrogate autoimmunity induced by cotransferred CD25⁻ cells, depletion of Tregs from T-replete animals rarely evokes autoimmunity (6).Recovery from T lymphopenia may occur by (i) thymopoiesis resulting in clonally diverse naive cells or (ii) homeostatic proliferation (HP) of cells that have escaped depletion. Much of what we know about HP comes from experiments in which T cells are adoptively transferred into irradiated or immune-deficient animals. These studies show that HP is driven by cytokines and in part, by recognition of self-MHC/peptide ligands (7, 8). Because homeostatically proliferating T cells acquire the characteristics of effector memory cells (9–11), it has been proposed that this process may lead to the breakdown of self-tolerance. However, only two studies (both in mice) have directly shown a role for HP in autoimmunity [promoting diabetes in the nonobese diabetic mouse driven by IL-21 in one study (12) and inducing autoimmune pancreatitis after transfer of T cells expressing hemagglutinin (HA)-specific T cell receptors (TCRs) into sublethally irradiated InsHA transgenic mice (which express HA in the beta cells of the pancreas) in another study (13)].Although informative, these complex models cannot be assumed to accurately reflect the process that drives human autoimmunity. Therefore, we take advantage of our unique patient population here to characterize T-cell reconstitution and the development of autoimmunity after lymphocyte depletion directly in humans.     

How to manage osteoporosis after the menopause

Many women seek advice about bone health at the time of the menopause. Although fracture probability is low in the majority, treatment may be cost-effective if targeted at those at highest risk. Optimal selection of individuals for intervention is based on a case-finding approach, fracture probability being estimated using a combination of bone mineral density and clinical risk factors. A variety of therapeutic interventions is available for the prevention of osteoporotic fractures in postmenopausal women. Hormone replacement therapy (HRT) is a second-line option in most, although it has a place in the management of perimenopausal women with menopausal symptoms who are at risk from fracture and in other postmenopausal women who express a preference for HRT over other options, after being fully informed about known risks and benefits.     

<Emphasis Type="Italic">TCF7L2</Emphasis>variant genotypes and type 2 diabetes risk in Brazil: significant association,but not a significant tool for risk stratification in the general population

Background  

Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.     

Lack of effect of intravenous pamidronate on fracture incidence and bone mineral density after orthotopic liver transplantation

BACKGROUND/AIMS: Increased rates of bone loss and fracture have been reported after liver transplantation. The aim of this study was to investigate the effects of a pre-transplant infusion of pamidronate on fracture incidence and bone loss during the first year after transplantation. METHODS: Ninety-nine adults awaiting orthotopic liver transplantation (OLT) were randomised to pamidronate or no treatment. Spinal X-rays were obtained at baseline and after 12 months. Bone mineral density (BMD) was measured at the lumbar spine (L1-4) and femoral neck at baseline, and 3, 6, and 12 months after OLT. RESULTS: The incidence of fractures in the first year after OLT was 8%, four patients within the pamidronate treated group and two in the untreated group developing fractures (P=0.40). No significant spinal bone loss occurred in either group during the first year. However, significant and sustained bone loss occurred at the femoral neck in both groups. No significant differences were seen between pamidronate treated or untreated groups at either site. CONCLUSIONS: Pamidronate in the regimen used had no significant effect on fracture rate or BMD post-transplant. The low incidence of fracture and absence of spinal bone loss indicate that bone disease after liver transplantation may be less common than previously reported.     

18F-fluoride Positron Emission Tomography Measurements of Regional Bone Formation in Hemodialysis Patients with Suspected Adynamic Bone Disease

¹⁸F-fluoride positron emission tomography (¹⁸F-PET) allows the assessment of regional bone formation and could have a role in the diagnosis of adynamic bone disease (ABD) in patients with chronic kidney disease (CKD). The purpose of this study was to examine bone formation at multiple sites of the skeleton in hemodialysis patients (CKD5D) and assess the correlation with bone biopsy. Seven CKD5D patients with suspected ABD and 12 osteoporotic postmenopausal women underwent an ¹⁸F-PET scan, and bone plasma clearance, K _i, was measured at ten skeletal regions of interest (ROI). Fifteen subjects had a transiliac bone biopsy following double tetracycline labeling. Two CKD5D patients had ABD confirmed by biopsy. There was significant heterogeneity in K _i between skeletal sites, ranging from 0.008 at the forearm to 0.028 mL/min/mL at the spine in the CKD5D group. There were no significant differences in K _i between the two study groups or between the two subjects with ABD and the other CKD5D subjects at any skeletal ROI. Five biopsies from the CKD5D patients had single tetracycline labels only, including the two with ABD. Using an imputed value of 0.3 μm/day for mineral apposition rate (MAR) for biopsies with single labels, no significant correlations were observed between lumbar spine K _i corrected for BMAD (K _i/BMAD) and bone formation rate (BFR/BS), or MAR. When biopsies with single labels were excluded, a significant correlation was observed between K _i/BMAD and MAR (r = 0.81, p = 0.008) but not BFR/BS. Further studies are required to establish the sensitivity of ¹⁸F-PET as a diagnostic tool for identifying CKD patients with ABD.     

The morbidity of multiple sclerosis.

Although the clinical course of multiple sclerosis is benign in up to one-third of patients, it is important to recognize the high rate of morbidity in others. Most individuals pass through a remitting phase but in a significant proportion the clinical manifestations subsequently recur, persist or slowly progress, and disability accumulates with time. Here we describe the frequency and spectrum of morbidity in a population based cohort of patients with multiple sclerosis. These statistics will guide those providing health care resources and planning services for patients with multiple sclerosis.