300 research outputs found
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
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
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
Metagene projection characterizes GEN2.2 and CAL-1 as relevant human plasmacytoid dendritic cell models
Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis
Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases.
We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were
analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to
SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by
sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and
serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly
contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid
variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.MCIN/AEI by "ERDF A way of making Europe" RTI2018101332-B-100Red de Investigacion en Inflamacion y Enfermedades Reumaticas (RIER) from Instituto de Salud Carlos III RD16/0012/0013Innovative Medicines Initiative 1 & 2 Joint Undertaking (JU) 115565
831434European Union's FP7 and Horizon 2020 research and innovation programsEFPIAJuan de la Cierva Incorporacion program - MCIN/AEI IJC2018-035131-
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