The V_H gene repertoire of splenic B cells and somatic hypermutation in systemic lupus erythematosus

In systemic lupus erythematosus (SLE) it has been hypothesized that self-reactive B cells arise from virgin B cells that express low-affinity, nonpathogenic germline V genes that are cross-reactive for self and microbial antigens, which convert to high-affinity autoantibodies via somatic hypermutation. The aim of the present study was to determine whether the V<sub>H</sub> family repertoire and pattern of somatic hypermutation in germinal centre (GC) B cells deviates from normal in SLE. Rearranged immunoglobulin V<sub>H</sub> genes were cloned and sequenced from GCs of a SLE patient's spleen. From these data the GC V gene repertoire and the pattern of somatic mutation during the proliferation of B-cell clones were determined. The results highlighted a bias in V<sub>H</sub>5 gene family usage, previously unreported in SLE, and under-representation of the V<sub>H</sub>1 family, which is expressed in 20–30% of IgM+ B cells of healthy adults and confirmed a defect in negative selection. This is the first study of the splenic GC response in human SLE

The role of interleukin 12 and nitric oxide in the development of spontaneous autoimmune disease in MRL/MP-lpr/lpr mice

MRL/MP-lpr/lpr (MRL/lpr) mice develop a spontaneous autoimmune disease. Serum from these mice contained significantly higher concentrations of nitrite/nitrate than serum from age-matched control MRL/MP-+/+ (MRL/+), BALB/c or CBA/6J mice. Spleen and peritoneal cells from MRL/lpr mice also produced significantly more nitric oxide (NO) than those from the control mice when cultured with interferon (IFN) gamma and lipopolysaccharide (LPS) in vitro. It is interesting to note that peritoneal cells from MRL/lpr mice also produced markedly higher concentrations of interleukin (IL) 12 than those from MRL/+ or BALB/c mice when cultured with same stimuli. It is striking that cells from MRL/lpr mice produced high concentrations of NO when cultured cells from MRL/+ or BALB/c mice. The enhanced NO synthesis induced by IFN- gamma/LPS was substantially inhibited by anti-IL-12 antibody. In addition, IL-12-induced NO production can also be markedly inhibited by anti-IFN-gamma antibody, but only weakly inhibited by anti-tumor necrosis factor alpha antibody. The effect of IL-12 on NO production was dependent on the presence of natural killer and possibly T cells. Serum from MRL/lpr mice contained significantly higher concentrations of IL-12 compared with those of MRL/+ or BALB/c control mice. Daily injection of recombinant IL-12 led to increased serum levels of IFN- gamma and NO metabolites, and accelerated glomerulonephritis in the young MRL/lpr mice (but not in the MRL/+ mice) compared with controls injected with phosphate-buffered saline alone. These data, together with previous finding that NO synthase inhibitors can ameliorate autoimmune disease in MRL/lpr mice, suggest that high capacity of such mice to produce IL-12 and their greater responsiveness to IL-12, leading to the production of high concentrations of NO, are important factors in this spontaneous model of autoimmune disease

Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease: the salivary glands of patients with Sjögren's syndrome

Structures resembling germinal centers are seen in the salivary glands of patients with Sjögren's syndrome, but it is not known whether the microenvironment of these cell clusters is sufficient for the induction of a germinal center response. Therefore, we cloned and sequenced rearranged Ig V genes expressed by B cells isolated from sections of labial salivary gland biopsies from two Sjögren's syndrome patients. Rearranged V genes from B cells within one cell cluster were polyclonal and most had few somatic mutations. Two adjacent clusters from another patient each contained one dominant B cell clone expressing hypermutated V genes. None of the rearranged V genes was found in both clusters, suggesting that cells are unable to migrate out into the surrounding tissue and seed new clusters. The ratios of replacement to silent mutations in the framework and complementarity determining regions suggest antigen selection of high-affinity mutants. These results show that an antigen-driven, germinal center-type B cell response is taking place within the salivary glands of Sjögren's syndrome patients. In view of the recent demonstration of a germinal center response within the rheumatoid synovial membrane and the existence of similar structures in the target tissues of other autoimmune. diseases, we propose that germinal center- type responses can be induced in the nonlymphoid target tissues of a variety of autoimmune diseases

Automatic Metro Map Layout Using Multicriteria Optimization

This paper describes an automatic mechanism for drawing metro maps. We apply multicriteria optimization to find effective placement of stations with a good line layout and to label the map unambiguously. A number of metrics are defined, which are used in a weighted sum to find a fitness value for a layout of the map. A hill climbing optimizer is used to reduce the fitness value, and find improved map layouts. To avoid local minima, we apply clustering techniques to the map the hill climber moves both stations and clusters when finding improved layouts. We show the method applied to a number of metro maps, and describe an empirical study that provides some quantitative evidence that automatically-drawn metro maps can help users to find routes more efficiently than either published maps or undistorted maps. Moreover, we found that, in these cases, study subjects indicate a preference for automatically-drawn maps over the alternatives

Neither Genius nor fudge : Edgar Allan Poe and Eureka

Eureka (1848) has been taken at face value as an expanded version of a lecture on cosmology that Poe gave earlier the same year. However, its seriousness as a work of science should be questioned. Its treatment of themes found in other works by Poe shows the author's unconcern for consistency, and the text unlikely to have resulted from a serious engagement with scientific argument. Instead it should be approached as a hoax: an attempt to reveal the gullibility of its readers. Poe's hoaxes relied for their effect on the trust created in readers by their recognition of generic conventions, and Eureka exploited and ridiculed public trust in cosmological lecturers such as John Bovee Dods.Eureka (1848) ha sido considerado superficialmente como una versión expandida de una conferencia sobre cosmología que Poe había dado ese mismo año. Sin embargo, la seriedad de este trabajo como un trabajo científico debería ser cuestionada. El tratamiento de algunos temas, que se encuentran en otros escritos de Poe, muestra que el autor no busca ser consistente. Entonces, el texto no parece el resultado de un interés serio por la argumentación científica. Por el contrario, debería ser considerado un engaño: un intento de revelar la credulidad de los lectores. Los engaños de Poe contaban con el hecho de que el reconocimiento de convenciones de género llevan a la confianza, y Eureka aprovecha y ridiculiza la confianza pública en conferenciantes cosmológicos como John Bovee Dods.Eureka (1848) ha estat considerat superficialment com una versió expandida d'una conferència sobre cosmologia que Poe va donar aquell mateix any. Tot i així, la serietat d'aquest text com a treball científic hauria d'ésser qüestionada. El tratament d'alguns temes, que es poden trobar a d'altres escrits de Poe, mostra que l'autor no cerca d'ésser consistent. Aleshores, el text no sembla el resultat d'un interés seriós per l'argumentació científica sinó que hauria de ser considerat un engany: un intent de revelar la credulitat dels lectors. Els enganys de Poe es basen en el fet que el reconeixement de les convencions genèriques impliquen confiança, i Eureka aprofita i ridiculitza aquesta confiança publica en conferenciants cosmològics com John Bovee Dods.Eureka 1848ko otsailean Poek kosmologiari buruz eman zuen ikastaro baten bertsio luzatutzat onartua izan da. Hala ere, obra testu zientifikoa ote den ez dago hain garbi. Poeren beste obra batzuetan ikusi da gaiak lantzerakoan ez zuela koherentziarekiko arretarik jartzen; ondorioz Eureka ezin da hartu pentsamendu zientifikoaren emaitza gisa. Iruzurra bat dela pentsatu behar da: irakurleen sinesgarritasuna salatzeko saiakera bat. Irakurleei konbentzio orokorrak aurkitzeak eragiten dien sinesgarritasunean datza, hain zuzen, Poeren txantxa. Eurekak John Bovee Dods bezalako irakurleen konfiantza erabili eta irrigarri utzi zuen ikuskera kosmologikoa ematen zela uste izan zutelako

Antibodies to acetylcholine receptor in parous women with myasthenia: evidence for immunization by fetal antigen

The weakness in myasthenia gravis (MG) is mediated by autoantibodies against adult muscle acetylcholine receptors (AChR) at the neuromuscular junction; most of these antibodies also bind to fetal AChR, which is present in the thymus. In rare cases, babies of mothers with MG, or even of asymptomatic mothers, develop a severe developmental condition, arthrogryposis multiplex congenita, caused by antibodies that inhibit the ion channel function of the fetal AChR while not affecting the adult AChR. Here we show that these fetal AChR inhibitory antibodies are significantly more common in females sampled after pregnancy than in those who present before pregnancy, suggesting that they may be induced by the fetus. Moreover, we were able to clone high-affinity combinatorial Fab antibodies from thymic cells of two mothers with MG who had babies with arthrogryposis multiplex congenita. These Fabs were highly specific for fetal AChR and did not bind the main immunogenic region that is common to fetal and adult AChR. The Fabs show strong biases to VH3 heavy chains and to a single Vk1 light chain in one mother. Nevertheless, they each show extensive intraclonal diversification from a highly mutated consensus sequence, consistent with antigen-driven selection in successive steps. Collectively, our results suggest that, in some cases of MG, initial immunization against fetal AChR is followed by diversification and expansion of B cells in the thymus; maternal autoimmunity will result if the immune response spreads to the main immunogenic region and other epitopes common to fetal and adult AChR

Measures of readiness for cognitive behavioural therapy in people with intellectual disability: A systematic review

BACKGROUND AND AIMS: Cognitive behavioural therapy (CBT) is a promising treatment for mental health problems in people with intellectual disabilities but some may not be suited or ready. This review critically evaluates the quality and utility of measures of CBT readiness in people with intellectual disabilities. METHODS AND PROCEDURES: Twelve studies of six measures based on three aspects of CBT readiness were identified through systematic review. OUTCOMES AND RESULTS: Across measures, measurement quality was largely poor or un-assessed. Only one study evaluated measurement change over the course of CBT. Not all participants with intellectual disabilities could ‘pass’ readiness measures and performance may be affected by levels of language and cognitive functioning. There was some evidence that CBT readiness is trainable with brief interventions. CONCLUSIONS AND IMPLICATIONS: Before using readiness measures in a clinical context, further work is needed to extend initial evidence on recognising cognitive mediation as a CBT readiness ability. Given the lack of consensus as to the definition of CBT readiness and the heterogeneity of CBT interventions, future research could also focus on developing readiness measures using a bottom up approach, developing measures within the context of CBT interventions themselves, before further refining and establishing their psychometric properties. WHAT THIS PAPER ADDS: This paper is the first to systematically review measures of skills thought necessary to be ready for cognitive behavioural therapy in intellectual disabilities. The findings suggest that while readiness skills may be trainable with brief interventions, the available measures of these skills have not been fully evaluated for quality. Levels of functioning on these measures have yet to be established relative to those without intellectual disabilities and critically, there is very little evidence as to whether these skills are important in cognitive behavioural therapy process and outcome. We suggest that future research could focus on those constructs where there is preliminary evidence for utility such as recognising cognitive mediation and also on developing the concept of readiness perhaps by developing measures within the context of specific CBT interventions. Until this is done, clinicians should exercise caution in using these measures to assess readiness for cognitive behavioural therapy in people with intellectual disabilities