Dendritic cells in transplant tolerance

Dendritic cells (DCs) are a heterogeneous family of professional APCs involved in priming adaptive immune responses. Donor DCs (direct pathway of allorecognition) and recipient DCs presenting processed donor major histocompatibility complex (MHC) as peptides (indirect pathway of allorecognition) participate actively in graft rejection by stimulating recipient T cell responses following organ transplantation. Recent studies have shown that DCs also play a central role in inducing and maintaining tolerance to self antigens (Ags) through deletion, anergy, and regulation mechanisms. It is easy to see how the remarkable functional plasticity of DCs renders them attractive therapeutic targets for immune modulation. Indeed, in the past few years, successful outcomes in rodent models have built the case that DC-based therapy may provide a novel approach to transplant tolerance. Ongoing research into our understanding of the mechanisms whereby DCs promote tolerance in the steady-state, together with development of biologically, pharmacologically and genetically manipulated ex vivo DCs to mimic/enhance their natural tolerogenicity, should warrant the success of these experimental DCs in establishing long-term allograft survival.     

Prenatal Origins of Poor Sleep in Children

Study Objectives:

We examined whether small body size at birth and prenatal tobacco or alcohol exposure predict poor sleep and more sleep disturbances in children.

Design:

An epidemiologic cohort study of 289 eight-year-old children born at term.

Measurements and results:

Sleep duration and efficiency were measured by actigraphy for 7 consecutive nights (mean = 7.1, SD = 1.2). We used both continuous measures of poor sleep and binary variables of short sleep and low sleep efficiency ( ≤ 10^th percentiles). Parents completed the Sleep Disturbance Scale for Children. Lower birth weight and shorter length at birth were associated with lower sleep efficiency. For every 1-SD decrease in weight and length at birth, the odds for low sleep efficiency increased by 1.7 fold (95% confidence interval [CI]: 1.1 to 2.7) and 2.2 fold (95% CI: 1.3 to 3.7), respectively. For every 1-SD decrease in ponderal index at birth, the risk of parent-reported sleep disorders increased by 1.4 fold (95% CI: 1.0 to 2.0). Moreover, children exposed prenatally to alcohol had a 2.9-fold (95% CI: 1.1 to 7.6) and 3.6-fold (95% CI: 1.3 to 10.0) increased risk for having short sleep and low sleep efficiency, respectively. The associations were not confounded by sex, gestational length, prenatal and perinatal complications, body mass index at 8 years, asthma, allergies, or parental socioeconomic status.

Conclusions:

Poor sleep in children may have prenatal origins. Possible mechanisms include alcohol consumption during pregnancy and other conditions associated with small body size at birth.

Citation:

Pesonen AK; Röaikköonen K; Matthews K; Heinonen K; Paavonen JE; Lahti J; Komsi N; Lemola S; Jöarvenpöaöa AL; Kajantie E; Strandberg T. Prenatal origins of poor sleep in children. SLEEP 2009;32(8):1086-1092.     

Loa loa Microfilariae Evade Complement Attack In Vivo by Acquiring Regulatory Proteins from Host Plasma

Loa loa is a filarial nematode that infects humans. The adults live in subcutaneous tissues and produce microfilariae that live for several weeks in the blood circulation in order to be transmitted to another person via blood meals of a dipterian vector. As microfilariae live in continuous contact with plasma, it is obvious that they evade the complement system. We studied markers of complement activation and signs of complement regulation on Loa loa microfilariae in vivo. The microfilariae were isolated from anticoagulated blood samples of a Loa loa-infected Caucasian patient. C1q and some mannose-binding lectin but only a limited amount of C3b or C4b fragments and practically no C5 or C5b-9 were present on the microfilariae. The covalently microfilaria-bound C3 and C4 depositions were mainly inactive iC3b, C3c, and iC4b fragments indicating that microfilariae had regulated complement activation in vivo. Also, in vitro deposition of C3b onto the microfilariae upon serum exposure was limited. The patient-isolated microfilariae were found to carry the host complement regulators factor H and C4b-binding protein on the outermost layer, so called sheath. The microfilaria-bound factor H was functionally active. Binding of the complement regulators to the microfilariae was confirmed in vitro using ¹²⁵I-labeled factor H and C4b-binding protein. In conclusion, our study shows that Loa loa microfilariae block complement activation and acquire the host complement regulators factor H and C4b-binding protein in blood circulation. This is the first time that binding of complement regulators onto nonviral pathogens has been demonstrated to occur in humans in vivo.Loa loa is a filarial parasite and the causative agent of human loiasis. This nematode has adapted well to its human host, as the adults can migrate in subcutaneous tissues for at least 15 years (15). During its whole adult life this helminth can produce microfilariae (MF) in peripheral blood, and these can circulate in blood for several weeks before transmission to the vector. Loiasis is transmitted by a dipteran vector (Chrysops spp.). The infective larvae can enter human subcutaneous tissues through a bite wound when the vector feeds again after the first blood meal. The larvae develop into adults and mate in subcutaneous tissues, resulting in production of sheathed MF after a minimum of 5 months. The MF are found mainly in peripheral blood (34).The prevalence of loiasis is high in the regions of endemicity in western and central Africa, where 20 to 40% of the population is microfilaremic (10). The majority of the infected individuals are asymptomatic, but a significant proportion of patients have symptoms such as calabar swellings, pruritis, secondary dermal lesions, and a subconjunctival eye passage of the adult worm (33, 37). In addition, serious sequelae such as endomyocardial fibrosis, renal complications, and encephalitis have also been reported (1).The main functions of the complement system are to eliminate foreign organisms that come in contact with plasma or other body fluids, either by direct effects or by enhancement of the acquired humoral immune response. Depending on the activator, complement can be activated through three pathways: the classical pathway (CP), the alternative pathway (AP), and the lectin pathway (LP). Upon activation, these pathways lead to the terminal pathway and formation of membrane attack complexes on the target cell (31).Complement activation is regulated by a variety of complement regulatory proteins. Most of the regulators are membrane bound, while two major regulators, complement factor H (CFH) and C4b-binding protein (C4BP), are plasma proteins found in high concentrations (12, 17, 47). All the three pathways lead to activation of C3, the central molecule of the complement cascade (8). Activation of C3 to C3b results in release of an anaphylatoxin, C3a (20, 21), while the C3b fragment can attach covalently to the target surface to start the AP amplification or to promote activation of the CP or LP (32). Inactivation of C3b to inactive C3b (iC3b) is carried out by serine protease factor I (FI), which needs a cofactor such as CFH (6, 8). In addition to the cofactor activity, CFH can also downregulate generation of C3b by two other means (11, 46).In the CP and LP, activation of the component C4 is essential. Upon activation, C4b is attached covalently to the target surface (27, 45) and can form an active C3-convertase, C4b2a, which is essential for propagation of the CP and LP (5). This step is regulated in plasma by complement regulatory protein C4BP, which acts as a cofactor for FI in degradation of C4b to inactive C4b (iC4b) or as an accelerator of the decay of C4b2a (23, 40, 44).Since MF of Loa loa are able to live and migrate in blood for weeks, they are obviously able to resist elimination by complement, but the mechanisms are largely unknown. One immune evasion mechanism of Loa loa is known to be induction of T-cell anergy (25), but nothing is known about evasion of innate or humoral immunity. A few complement resistance mechanisms have been reported for other helminths. Most of these are associated with physical barriers of macroscopic worms, but some helminths are known to have specific molecules mediating complement evasion or ligands that acquire host complement regulators on their surfaces (22). So far, two human helminth parasite structures have been shown to acquire host CFH on their surfaces, the echinococcal cyst wall and MF of a filarial nematode, Onchocerca volvulus (7, 30). So far there are no reports of acquisition of C4BP onto any pathogenic helminth. Several pathogenic bacteria and yeasts and a few viruses are known to utilize acquisition of host CFH or C4BP to evade complement attack (49). Four of these microbes, Streptococcus pyogenes, Borrelia burgdorferi, relapsing fever Borrelia, and Candida albicans, can acquire both CFH and C4BP on their surface (3, 28, 29). So far, all the reports where CFH or C4BP acquisition on microbes has been reported have been based on in vitro experiments only.The aim of our study was to analyze whether patient-derived Loa loa MF carry any markers of complement attack or signs of cessation of the complement cascade. The MF showed C1q deposits, as was expected since the patient had antifilarial antibodies. Despite that, however, only limited amounts of C3 or C4 fragments and practically no C5 or C5b-9 could be detected on MF. The covalently bound C3 or C4 fragments were mainly iC3b, C3c, or iC4b. Most importantly we show that MF had acquired CFH and C4BP on their surfaces in vivo. In conclusion, for the first time we show acquisition of soluble complement regulators on pathogenic microbes in the human body. Our results suggest that acquisition of complement regulators CFH and C4BP from human plasma on MF could at least partially explain the prolonged survival of MF in circulation.     

Dental fear affects adolescent perception of interaction with dental staff

The main purpose of this study was to explore whether subjective perception of interaction with dental staff is associated with dental fear in a population‐based sample of 18‐yr‐old adolescents (n = 773). The interaction was measured using the Patient Dental Staff Interaction Questionnaire (PDSIQ), validated with exploratory and confirmatory factor analyses, which yielded the factors of ‘kind atmosphere and mutual communication’, ‘roughness’, ‘insecurity’, ‘trust and safety’, and ‘shame and guilt’. Dental fear was measured using the Modified Dental Anxiety Scale (MDAS). Gender and sense of coherence (SOC) were included as potential confounding variables. Adolescents with high dental fear more often perceived their interaction with dental staff negatively and more often felt insecure than others. This difference persisted after adjustment for gender and SOC. In conclusion, adolescents with high dental fear may perceive their interaction with dental staff more positively if the staff succeed in creating a positive, trusting, approving, and supportive atmosphere with kindness, calmness, and patience. The communication and interaction skills of dental staff may play a particularly important role when encountering highly fearful dental patients.     

Circumspect descent prevails in solving random constraint satisfaction problems

We study the performance of stochastic local search algorithms for random instances of the K-satisfiability (K-SAT) problem. We present a stochastic local search algorithm, ChainSAT, which moves in the energy landscape of a problem instance by never going upwards in energy. ChainSAT is a focused algorithm in the sense that it focuses on variables occurring in unsatisfied clauses. We show by extensive numerical investigations that ChainSAT and other focused algorithms solve large K-SAT instances almost surely in linear time, up to high clause-to-variable ratios alpha; for example, for K = 4 we observe linear-time performance well beyond the recently postulated clustering and condensation transitions in the solution space. The performance of ChainSAT is a surprise given that by design the algorithm gets trapped into the first local energy minimum it encounters, yet no such minima are encountered. We also study the geometry of the solution space as accessed by stochastic local search algorithms.     

THE EFFECTS OF HYPNOSIS AND HYPNOTIC SUGGESTIONS ON THE MISMATCH NEGATIVITY IN HIGHLY HYPNOTIZABLE SUBJECTS

The neural mechanisms associated with hypnosis were investigated in a group of 9 high hypnotizable subjects by measuring the mismatch negativity (MMN) component of the auditory event-related potential (ERP). ERPs were recorded using a passive oddball paradigm to sinusoidal standard and deviant tone stimuli of 500 and 520 Hz, respectively, in four conditions: prehypnosis, neutral hypnosis, hypnotic suggestion for altering the tone perception, and posthypnotic conditions. Earlier studies have indicated that hypnosis and hypnotic suggestions might have an effect on MMN, but the results of our study contradict these results: No statistically significant differences were found between the conditions in the MMN amplitudes.     

Onchocerca volvulus microfilariae avoid complement attack by direct binding of factor H

The filarial parasite Onchocerca volvulus is the causative agent of river blindness. The adult worms produce microfilariae (mf), which are responsible for the disease pathogenesis; mf activate the complement system, but the activation stops before the formation of terminal complement complexes. Because of the arrest of complement activation, this study analyzed binding of the main alternative pathway regulator, factor H (fH), to the mf. The mf bound fH after incubation in nonimmune human serum or with purified radiolabeled fH. In the presence of factor I, mf-bound fH promoted the cleavage of complement 3 molecule b (C3b) to iC3b. An analysis with recombinant constructs of fH showed that the C-terminal short consensus repeats (SCRs) 8-20 of fH bound to mf, whereas the N-terminal SCRs 1-7 containing the complement-regulatory domains in SCRs 1-5 did not. Thus, mf of the nematode O. volvulus may evade human complement by binding fH and by promoting inactivation of C3b into iC3b.