Exploring Impact of Rare Variation in Systemic Lupus Erythematosus by a Genome Wide Imputation Approach

The importance of low frequency and rare variation in complex disease genetics is difficult to estimate in patient populations. Genome-wide association studies are therefore, underpowered to detect rare variation. We have used a combined approach of genome-wide-based imputation with a highly stringent sequence kernel association (SKAT) test and a case-control burden test. We identified 98 candidate genes containing rare variation that in aggregate show association with SLE many of which have recognized immunological function, but also function and expression related to relevant tissues such as the joints, skin, blood or central nervous system. In addition we also find that there is a significant enrichment of genes annotated for disease-causingmutations in the OMIM database, suggesting that in complex diseases such as SLE, such mutations may be involved in subtle or combined phenotypes or could accelerate specific organ abnormalities found in the disease. We here provide an important resource of candidate genes for SLE

Genetic associations in type I interferon related pathways with autoimmunity

Type I interferons play an outstanding role in innate and adaptive immunity by enhancing functions of dendritic cells, inducing differentiation of monocytes, promoting immunoglobulin class switching in B cells and stimulating effector functions of T cells. The increased production of IFNα/β by plasmacytoid dendritic cells could be responsible for not only efficient antiviral defence, but it also may be a pathological factor in the development of various autoimmune disorders. The first evidence of a genetic link between type I interferons and autoimmune diseases was the observation that elevated IFNα activity is frequently detected in the sera of patients with systemic lupus erythematosus, and that this trait shows high heritability and familial aggregation in their first-degree healthy relatives. To date, a number of genes involved in interferon signalling have been associated with various autoimmune diseases. Patients with systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, psoriasis, and a fraction of patients with rheumatoid arthritis display a specific expression pattern of interferon-dependent genes in their leukocytes, termed the interferon signature. Here, in an attempt to understand the role of type I interferons in the pathogenesis of autoimmunity, we review the recent advances in the genetics of autoimmune diseases focusing on the association of genes involved in type I interferon pathways

El peso de la historia en la inmigración peruana en Chile

En el presente artículo, se sostiene que el actual escenario internacional se ha caracterizado por una profunda interrelación, y la integración emerge como una estrategia de inserción global de relevancia, especialmente para países como Chile. Esta integración no es sólo económica sino que también incluye el movimiento de personas. No obstante, la integración y la movilidad de personas se ven afectadas por los prejuicios y las desconfianzas, lo que se ha reflejado en el fenómeno migratorio peruano en Chile. Desde esta perspectiva, la construcción de un marco institucional para alcanzar mayores grados de integración de los inmigrantes peruanos en Chile, no sólo requiere avances en el ámbito económico-laboral, sino que también en el área educacional-cultural, promoviendo una educación basada en la interculturalidad, capaz de marcar el camino hacia una mayor tolerancia e integración entre ambas sociedades, y así superar quiebres históricos, como lo fue la Guerra del Pacifico.Cet article affirme que l’actuelle situation internationale s’est caractérisée par une profonde interrelation, et l’intégration surgit comme une stratégie d’insertion globale d’importance, particulièrement dans les pays comme le Chili. Cette intégration n’est pas seulement économique, elle comprend également des déplacements de personnes. Cependant, l’intégration et la mobilité des personnes est affectée par des préjugés et de la méfiance, se qui s’est reflété dans le phénomène migratoire péruvien au Chili. Dans cette perspective, la construction d’un cadre institutionnel pour atteindre de plus hauts degrés d’intégration des immigrants péruviens au Chili, requiert non seulement des progrès dans le domaine économico-professionnel, mais aussi dans le domaine éducationnel-culturel, promouvant une éducation fondée sur l’interculturalité, capable de générer une plus importante tolérance et intégration entre les deux sociétés, et ainsi surmonter les ruptures historiques, comme la Guerre du Pacifique.In this paper, we suggest that the current international scenery shows a deep connection, and that integration arises as an important strategy of global insertion, especially for countries like Chile. This integration is not only economic but includes the movement of people as well. Nevertheless, the integration and the people’s movement feel the negative effects of prejudice and distrust, and Peruvian immigrants in Chile feel it too. From this point of view, to build an institutional framework to reach the integration of the Peruvian immigrants in Chile, it’s required to improve immigrants working conditions and improve the educational system, especially an education  based on interculturality, which could to set an example for tolerance and integration between both societies and thus overcome historical fractures as was the War of The Pacific

Protocol for large scale whole blood immune monitoring by mass cytometry and Cyto Quality Pipeline

Support has been received (PI: M.E.A.) from the IMI2-JU project GA No 831434 (3TR) and IMI-JU project GA No 115565 (PRECISESADS). P.R. has received support from EMBO (7966) and from Consejería de Salud de Junta de Andalucía (EF-0091-2018). C.M. acknowledges funding from Programa Nicolas Monardes (C2-0002-2019). J.M.M. is funded by European Union-NextGenerationEU, Ministry of Universities (Spain’s Government) and the Recovery, Transformation and Resilience Plan. These results form a part of the P.R. PhD thesis in Biomedicine at the University of Granada. We are grateful to Olivia Santiago and Jose Diaz Cuéllar for technical support as a Core facility in Genyo research center. Also, we would like to express our gratitude to the donors. The figures in this paper were created with BioRender.comMass cytometry (MC) is a powerful large-scale immune monitoring technology. To maximize MC data quality, we present a protocol for whole blood analysis together with an R package, Cyto Quality Pipeline (CytoQP), which minimizes the experimental artifacts and batch effects to ensure data reproducibility. We describe the steps to stimulate, fix, and freeze blood samples before acquisition to make them suitable for retrospective studies. We then detail the use of bar-coding and reference samples to facilitate multicenter and multi-batch experiments.For complete details on the use and execution of this protocol, please refer to Rybakowska et al. (2021a) and (2021b).IMI2-JU project GA 831434IMI-JUproject GA 115565European Molecular Biology Organization (EMBO) 7966Junta de Andalucía EF-0091-2018Programa Nicolás Monardes C2-0002-2019European Union-NextGenerationEUMinistry of Universities (Spain's Government) and the Recovery, Transformation and Resilience Pla

The TREX1 Dinosaur Bites the Brain through the LINE

In this issue of Cell Stem Cell, Thomas et al. (2017) define the nature of accumulated ssDNA present in the neuron and astrocyte cytoplasm of TREX1 mutated stem cell-derived organoids. Accumulated ssDNAs are derived from LINE-1 endogenous retroelements, providing new clues as to the development of Aicardi-Goutières syndrome in the neural system

Whole blood DNA methylation analysis reveals respiratory environmental traits involved in COVID-19 severity following SARS-CoV-2 infection

SARS-CoV-2 infection can cause an inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea, and in ~5% of these, death. DNAmethylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth. In this study, we aim to evaluate the implication of DNA methylation in COVID-19 progression by means of a genome-wide DNA methylation analysis combined with DNA genotyping. The results reveal the existence of epigenomic regulation of functional pathways associated with COVID-19 progression andmediated by genetic loci.We find an environmental trait-related signature that discriminatesmild from severe cases and regulates, among other cytokines, IL-6 expression via the transcription factor CEBP. The analyses suggest that an interaction between environmental contribution, genetics, and epigenetics might be playing a role in triggering the cytokine storm described in the most severe cases.Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades of the regional government of AndaluciaEuropean Union through European Regional Development Fund CV20-10150Consejo Superior de Investigaciones cientificas CSIC-COV19-016/202020E155Junta de Castilla y Leon COVID 07.04.467B04.74011.0Consejeria de Salud y Familias of the regional government of Andalucia PECOVID-0072-2020Instituto de Salud Carlos III (ISCIII, Spanish Health Ministry) through the Sara Borrell subprogram CD18/00153Programa Estrategico Instituto de Biologia y Genetica Molecular, IBGM excellence programme CLU-2029-02 CCVC848

Propiedades psicométricas del Cuestionario de conductas compensatorias para la conducción

The purpose of this study was to construct and validate an instrument that meets the necessary requirements in order to know which strategies are drivers when driving must be adapted due to the decline or psycho-physical limitations or circumstances. In the validation study was involved 312 drivers (80,4% men and 19,6% women), aged from 20 to 80 years. The analysis of internal consistency obtained a Cronbach alpha value of 0,90 for the questionnaire. The values of item-total correlations ranged from 0,44 to 0,66. The concurrent validity relative to benchmark ‘Questionnaire 55 or+’ was 0,53. Factor analysis has a structure of 3 factors: Displacement, driving skills, and environmental conditions that explain 57,11% of the variance. In conclusion, the ‘Compensatory behaviors for driving questionnaire’ is a short instrument to assess adaptation to driving which shows adequate psychometric values.El propósito del presente estudio fue construir y validar un instrumento que reuniera las propiedades psicométricas adecuadas con objeto de conocer qué estrategias siguen los conductores cuando deben adaptarse a la conducción debido al declive o a las limitaciones psicofísicas, o a las circunstancias. En el estudio de validación participaron 312 conductores (80,4% varones y 19,6% mujeres), con edades de 20 a 80 años. El análisis de la consistencia interna obtuvo un valor alfa de Cronbach para el cuestionario de 0,90. Los valores de correlación ítem-total oscilaron entre 0,44 y 0,66. La validez de criterio concurrente respecto al criterio de referencia «Cuestionario 55 o+» fue 0,53. El análisis factorial presenta una estructura de 3 factores: desplazamiento, habilidad para la conducción y condiciones ambientales, que explican el 57,11% de la varianza. En conclusión, el «Cuestionario de conductas compensatorias» es un instrumento breve para evaluar la adaptación a la conducción, que muestra valores psicométricos adecuados

Single-cell immune profiling of Meniere Disease patients

This work was supported by B-CTS-68-UGR20 Grant by FEDER Funds, PI17/1644 and PI20-1126 grants from ISCIII by FEDER Funds from the EU, CLINMON-2 from the Meniere's Society UK, and Impact Data Science (IMP0001) . MF is funded by F18/00228 grant from ISCIII by FEDER Funds from the EU. AEB is funded by the EU's Horizon 2020 Research and Innovation Programme, Grant Agreement Number 848261. LF is funded by CD20/0153 grant from ISCIII by FEDER Funds from the EU. Funding for open access charge: Universidad de Granada/CBUA.Background: Meniere Disease (MD) is an inner ear syndrome, characterized by episodes of vertigo, tinnitus and fluctuating sensorineural hearing loss. The pathological mechanism leading to sporadic MD is still poorly understood, however an allergic inflammatory response seems to be involved in some patients with MD. Objective: Decipher an immune signature associated with the syndrome. Methods: We performed mass cytometry immune profiling on peripheral blood from MD patients and controls. We analyzed differences in state and differences in abundance of the different cellular subsets. IgE levels were quantified through ELISA on supernatant of cultured whole blood. Results: We have identified two clusters of individuals according to the single cell cytokine profile. These clusters presented differences in IgE levels, immune cell population abundance, including a reduction of CD56dim NKcells, and changes in cytokine expression with a different response to bacterial and fungal antigens. Conclusion: Our results support a systemic inflammatory response in some MD patients that show a type 2 response with allergic phenotype, which could benefit from personalized IL-4 blockers.FEDER Funds B-CTS-68-UGR20, B-CTS-68-UGR20Instituto de Salud Carlos III Spanish Government PI17/1644, PI20-1126, CD20/0153, 848261EUMeniere's Society UKImpact Data Science F18/00228Horizon 2020 IMP0001Universidad de Granada/CBU

Gut epithelial barrier dysfunction in lupus triggers a differential humoral response against gut commensals

Introduction: Systemic lupus erythematosus is an autoimmune disease with multisystemic involvement including intestinal inflammation. Lupus-associated intestinal inflammation may alter the mucosal barrier where millions of commensals have a dynamic and selective interaction with the host immune system. Here, we investigated the consequences of the intestinal inflammation in a TLR7-mediated lupus model. Methods: IgA humoral and cellular response in the gut was measured. The barrier function of the gut epithelial layer was characterised. Also, microbiota composition in the fecal matter was analysed as well as the systemic humoral response to differential commensals. Results: The lupus-associated intestinal inflammation modifies the IgA+ B cell response in the gut-associated lymphoid tissue in association with dysbiosis. Intestinal inflammation alters the tight junction protein distribution in the epithelial barrier, which correlated with increased permeability of the intestinal barrier and changes in the microbiota composition. This permeability resulted in a differential humoral response against intestinal commensals. Discussion: Lupus development can cause alterations in microbiota composition, allowing specific species to colonize only the lupus gut. Eventually, these alterations and the changes in gut permeability induced by intestinal inflammation could lead to bacterial translocationGAP 838548, the Consejerı́a de Salud y Familias, Junta de Andalucı́a grant PE-0297-2019Ministerio de Economı́a y Competitividad grant SAF2016-78631-P (MA-R),Ministerio de Ciencia e Innovación grant PID2020-113776GB-100Swedish Research Council, grant No 2022-0100