Involvement of dendritic cells in autoimmune diseases in children

Dendritic cells (DCs) are professional antigen-presenting cells that are specialized in the uptake of antigens and their transport from peripheral tissues to the lymphoid organs. Over the last decades, the properties of DCs have been intensely studied and much knowledge has been gained about the role of DCs in various diseases and health conditions where the immune system is involved, particularly in cancer and autoimmune disorders. Emerging clues in autoimmune diseases, suggest that dendritic cell dysregulation might be involved in the development of various autoimmune disorders in both adults and children. However, studies investigating a possible contribution of DCs in autoimmune diseases in the pediatric population alone are scanty. The purpose of this review is to give a general overview of the current literature on the relevance of dendritic cells in the most common autoimmune conditions of childhood.     

Sexual assault and other types of sexual harassment by workplace personnel: a comparison of antecedents and consequences

Although sexual assault by workplace personnel is widely viewed as a type of sexual harassment, little is known about whether these overlapping constructs may possess some unique characteristics. This article compares the theoretical antecedents and consequences of sexual assault by workplace personnel and other types of sexual harassment among 22,372 women employed in the U.S. military. Path analysis revealed that low sociocultural and organizational power are associated with an increased likelihood of both types of victimization. Organizational climate and job gender context are directly associated with sexual harassment but are only indirectly associated with sexual assault by workplace personnel. Both types of victimization are associated with a variety of negative outcomes, but the pattern of negative consequences differs.     

Influences of chorion type on measurements of the corpus callosum in adult monozygotic male twins?

MRI imaging was used to estimate volumes of corpus callosum structure in 45 pairs of identical (monozygotic, MZ) twins from the National Heart, Lung, and Blood Institute (NHLBI) twin study. Age range of the study subjects was from 68–78 years. Finger, palm, and footprint data (dermatoglyphics) collected at previous examinations of the NHLBI twin study were available for 39 pairs. The dermatoglyphics were scored for an index to retrospectively assess chorion type in MZ twin‐pairs. The results indicated an association between variability in various structures of the corpus callosum with some of these dermatoglyphic traits, suggesting greater structural variation within pairs with dichorionic placentas. In contrast, total intracranial volume, which has similar heritability estimates as a result of shared genetic effects with the corpus callosum, was unrelated to the dermatoglyphic traits. The results provide indirect evidence that the intrauterine environment may influence twin‐pair similarity of corpus callosum measures in adults. Am. J. Hum. Biol. 14:338–346, 2002. © 2002 Wiley‐Liss, Inc.     

Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons

Mast cells that are in close proximity to autonomic and enteric nerves release several mediators that cause neuronal hyperexcitability. This study examined whether mast cell tryptase evokes acute and long-term hyperexcitability in submucosal neurons from the guinea-pig ileum by activating proteinase-activated receptor 2 (PAR2) on these neurons. We detected the expression of PAR2 in the submucosal plexus using RT-PCR. Most submucosal neurons displayed PAR2 immunoreactivity, including those colocalizing VIP. Brief (minutes) application of selective PAR2 agonists, including trypsin, the activating peptide SL-NH₂ and mast cell tryptase, evoked depolarizations of the submucosal neurons, as measured with intracellular recording techniques. The membrane potential returned to resting values following washout of agonists, but most neurons were hyperexcitable for the duration of recordings (> 30 min–hours) and exhibited an increased input resistance and amplitude of fast EPSPs. Trypsin, in the presence of soybean trypsin inhibitor, and the reverse sequence of the activating peptide (LR-NH₂) had no effect on neuronal membrane potential or long-term excitability. Degranulation of mast cells in the presence of antagonists of established excitatory mast cell mediators (histamine, 5-HT, prostaglandins) also caused depolarization, and following washout of antigen, long-term excitation was observed. Mast cell degranulation resulted in the release of proteases, which desensitized neurons to other agonists of PAR2. Our results suggest that proteases from degranulated mast cells cleave PAR2 on submucosal neurons to cause acute and long-term hyperexcitability. This signalling pathway between immune cells and neurons is a previously unrecognized mechanism that could contribute to chronic alterations in visceral function.     

Human and Murine Immune Responses to a Novel Leishmania major Recombinant Protein Encoded by Members of a Multicopy Gene Family

Vaccination of BALB/c mice with Leishmania major promastigote culture filtrate proteins plus Corynebacterium parvum confers resistance to infection with L. major. To define immunogenic components of this protein mixture, we used sera from vaccinated mice to screen an L. major amastigote cDNA expression library. One of the immunoreactive clones thus obtained encoded a novel protein of L. major with a molecular mass of 22.1 kDa. The predicted amino acid sequence of this clone exhibited significant homology to eukaryotic thiol-specific-antioxidant (TSA) proteins. Therefore, we have designated this protein L. major TSA protein. Southern blot hybridization analyses indicate that there are multiple copies of the TSA gene in all species of Leishmania analyzed. Northern blot analyses demonstrated that the TSA gene is constitutively expressed in L. major promastigotes and amastigotes. Recombinant TSA protein containing an amino-terminal six-histidine tag was expressed in Escherichia coli with the pET17b system and was purified to homogeneity by affinity chromatography. Immunization of BALB/c mice with recombinant TSA protein resulted in the development of strong cellular immune responses and conferred protective immune responses against infection with L. major when the protein was combined with interleukin 12. In addition, recombinant TSA protein elicited in vitro proliferative responses from peripheral blood mononuclear cells of human leishmaniasis patients and significant TSA protein-specific antibody titers were detected in sera of both cutaneous-leishmaniasis and visceral-leishmaniasis patients. Together, these data suggest that the TSA protein may be useful as a component of a subunit vaccine against leishmaniasis.     

Physical characteristics of the ECAT EXACT3D positron tomograph

The 'EXACT3D' positron tomograph, which is now in routine clinical research use, was developed with the aim of achieving unprecedented sensitivity, high spatial and temporal resolution and simplicity of design using proven detector technology. It consists of six rings of standard detector blocks (CTI/Siemens EXACT HR+) with 4.39 mm x 4.05 mm x 30 mm elements, giving an axial field of view (FOV) of 23.4 cm. This extended FOV and the absence of interplane septa and retractable transmission rod sources has allowed greatly simplified gantry and detector cassette design. Operation in exclusive 3D mode requires an alternative to the conventional coincidence method for transmission scanning, and a single photon approach using a hydraulically driven 137Cs point source has been implemented. The tomograph has no other moving parts. A single time frame of data without any compression is very large (> 300 Mbyte) and two approaches are employed to overcome this difficulty: (a) adjacent sinograms can be summed automatically into different combinations and (b) listmode (event-by-event) acquisition has been instituted, which is both storage efficient (particularly for acquisition of sparse data sets) and maximizes temporal resolution. The high-speed I/O and computing hardware can maintain a sustained acquisition rate of about 4 million coincidence events per second. A disadvantage of the large axial FOV in 3D is the increased sensitivity to activity outside the coincidence FOV. However, this can be minimized by additional side shielding. The mean spatial resolution is 4.8 +/- 0.2 mm FWHM (transaxial, 1 cm off-axis) and 5.6 +/- 0.5 mm (axial, on-axis). Its absolute efficiency is 5.8% for a line source in air (just spanning the axial FOV) and 10% for a central point source (with thresholds of 350-650 keV). For a uniform 20 cm diameter cylinder, the efficiency is 69 kcps kBq(-1) ml(-1) (after subtraction of a scatter fraction of 42%). Sensitivity relative to the EXACT HR+ (with four rings of blocks) is 2.5 (3D) and 12 (2D) times respectively. The rate of random events in blood flow studies in the brain and body, using 15O-labelled water, can be controlled by limiting the administered dose and inserting additional side shielding.     

Mouse cytomegalovirus infection induces antibodies which cross-react with virus and cardiac myosin: a model for the study of molecular mimicry in the pathogenesis of viral myocarditis.

Mouse cytomegalovirus (MCMV) infection induces persisting myocarditis in the susceptible BALB/c strain. Autoantibodies to cardiac myosin are produced in both susceptible BALB/c and resistant C57BL/6 mice following MCMV infection. These affinity-purified anti-cardiac myosin antibodies cross-react with MCMV protein(s). The polypeptides of CMV which share immunological cross-reactivity with the 200,000 MW polypeptide, the heavy chain of myosin, were viral polypeptides of 83,000, 94,000 and 116,000 MW recognized by BALB/c post-infection sera and polypeptides of 66,000 and 94,000 MW recognized by C57BL/6 post-infection sera. Passive transfer of anti-cardiac myosin antibodies from Day 56 post-infection sera of the BALB/c strain induced inflammation and necrosis of the myocardium of uninfected BALB/c recipients. This late immune sera contains autoantibodies specific for the cardiac isoform of myosin. Furthermore, immunization with cardiac myosin induced myocarditis and high titres of cardiac myosin antibodies in uninfected mice of the susceptible BALB/c strain only. However, antibodies to myosin elicited in cardiac myosin-immunized BALB/c mice did not cross-react with MCMV by ELISA. We suggest that virus infection may modulate the immune recognition of the common-epitope(s) shared between MCMV protein(s) and the heavy chain of myosin. Of particular interest is the possibility that molecular mimicry of CMV with cardiac myosin may contribute to the pathogenesis of autoimmune myocarditis following virus infection.     

Depletion of peripheral blood T lymphocytes and NK cells during the course of ebola hemorrhagic Fever in cynomolgus macaques

During the course of an experimentally induced Ebola virus (EBOVA) infection of cynomolgus macaques, peripheral blood mononuclear cells were isolated and characterized by multi-color flow cytometry. Both CD4+ and CD8+ lymphocyte counts decreased 60-70% during the first 4 days after infection. Among CD8+ lymphocytes, this decline was greatest among the CD8(lo) population, which was composed mostly of CD3- CD16+ NK cells. In contrast, the number of CD20+ B lymphocytes in the blood did not significantly change during the course of the infection. Phenotypic analysis of T lymphocyte subsets by flow cytometry failed to show evidence of a robust immune response to the infection. Apoptosis could be detected as early as day 2 postinfection among the CD8+ and CD16+ subsets of lymphocytes. Increased expression of CD95 (Fas) suggests that apoptosis may be induced via signaling through the Fas/Fas-L cascade. In contrast, the number of HLA-DR+ cells increased tenfold in the blood during the course of infection. These data suggest that EBOV may block dendritic cell maturation after infection, thereby inhibiting activation of lymphocytes and eliminating those subsets that are most likely to be capable of mounting an effective response to the virus.