RESUMO
Psoriasis is a chronic inflammatory skin condition. Repeated epicutaneous application of Aldara® (imiquimod) cream results in psoriasiform dermatitis in mice. The Aldara®-induced psoriasiform dermatitis (AIPD) mouse model has been used to examine the pathogenesis of psoriasis. Here, we used a forward genetics approach in which we compared AIPD that developed in 13 different inbred mouse strains to identify genes and pathways that modulated disease severity. Among our primary results, we found that the severity of AIPD differed substantially between different strains of inbred mice and that these variations were associated with polymorphisms in Itga11. The Itga11 gene encodes the integrin α11 subunit that heterodimerizes with the integrin ß1 subunit to form integrin α11ß1. Less information is available about the function of ITGA11 in skin inflammation; however, a role in the regulation of cutaneous wound healing, specifically the development of dermal fibrosis, has been described. Experiments performed with Itga11 gene-deleted (Itga11-/- ) mice revealed that the integrin α11 subunit contributes substantially to the clinical phenotype as well as the histopathological and molecular findings associated with skin inflammation characteristic of AIPD. Although the skin transcriptomes of Itga11-/- and WT mice do not differ from one another under physiological conditions, distinct transcriptomes emerge in these strains in response to the induction of AIPD. Most of the differentially expressed genes contributed to extracellular matrix organization, immune system, and metabolism of lipids pathways. Consistent with these findings, we detected a reduced number of fibroblasts and inflammatory cells, including macrophages, T cells, and tissue-resident memory T cells in skin samples from Itga11-/- mice in response to AIPD induction. Collectively, our results reveal that Itga11 plays a critical role in promoting skin inflammation in AIPD and thus might be targeted for the development of novel therapeutics for psoriasiform skin conditions. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Dermatite , Cadeias alfa de Integrinas , Psoríase , Animais , Camundongos , Dermatite/genética , Dermatite/patologia , Modelos Animais de Doenças , Imiquimode/efeitos adversos , Inflamação/patologia , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismo , Psoríase/induzido quimicamente , Psoríase/genética , Pele/patologiaRESUMO
PURPOSE: Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYK variants. METHODS: We phenotypically characterized Dstyk knockout mice of 3 separate inbred backgrounds and re-analyzed the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to as "SSV" below). DSTYK loss of function (LOF) and SSVs were annotated in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis vs controls. A phenome-wide association study analysis was also performed using United Kingdom Biobank (UKBB) data. RESULTS: Results demonstrate â¼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk-/- mice. Phenotypic penetrance increased to â¼40% in C3H/HeJ mutants, with mild-to-moderate severity. Re-analysis of the original family segregating the rare SSV showed low penetrance (43.8%) and no alternative genetic causes for CAKUT. LOF DSTYK variants burden showed significant excess for CAKUT and epilepsy vs controls and an exploratory phenome-wide association study supported association with neurological disorders. CONCLUSION: These data support causality for DSTYK LOF variants and highlights the need for large-scale sequencing studies (here >200,000 cases) to accurately assess causality for genes and variants to lowly penetrant traits with common population prevalence.
Assuntos
Epilepsia , Sistema Urinário , Anormalidades Urogenitais , Animais , Camundongos , Humanos , Penetrância , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Anormalidades Urogenitais/genética , Rim/anormalidades , Fatores de Risco , Epilepsia/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genéticaRESUMO
BACKGROUND: To gain insight into the pathogenesis of collapsing glomerulopathy, a rare form of FSGS that often arises in the setting of viral infections, we performed a genome-wide association study (GWAS) among inbred mouse strains using a murine model of HIV-1 associated nephropathy (HIVAN). METHODS: We first generated F1 hybrids between HIV-1 transgenic mice on the FVB/NJ background and 20 inbred laboratory strains. Analysis of histology, BUN, and urinary NGAL demonstrated marked phenotypic variation among the transgenic F1 hybrids, providing strong evidence for host genetic factors in the predisposition to nephropathy. A GWAS in 365 transgenic F1 hybrids generated from these 20 inbred strains was performed. RESULTS: We identified a genome-wide significant locus on chromosome 13-C3 and multiple additional suggestive loci. Crossannotation of the Chr. 13 locus, including single-cell transcriptomic analysis of wildtype and HIV-1 transgenic mouse kidneys, nominated Ssbp2 as the most likely candidate gene. Ssbp2 is highly expressed in podocytes, encodes a transcriptional cofactor that interacts with LDB1 and LMX1B, which are both previously implicated in FSGS. Consistent with these data, older Ssbp2 null mice spontaneously develop glomerulosclerosis, tubular casts, interstitial fibrosis, and inflammation, similar to the HIVAN mouse model. CONCLUSIONS: These findings demonstrate the utility of GWAS in mice to uncover host genetic factors for rare kidney traits and suggest Ssbp2 as susceptibility gene for HIVAN, potentially acting via the LDB1-LMX1B transcriptional network.
Assuntos
Nefropatia Associada a AIDS/genética , Proteínas de Ligação a DNA/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Glomerulosclerose Segmentar e Focal/genética , Animais , Modelos Animais de Doenças , Feminino , Estudo de Associação Genômica Ampla , Masculino , Camundongos , Camundongos TransgênicosRESUMO
The G protein-coupled receptor 15 (GPR15) regulates homing of different T-cell populations into the gut, thus, preserving tissue homeostasis. Its potential role in the preservation of homeostasis on other body interfaces, including the skin, is less well understood. We addressed the impact of GPR15 on cutaneous T-cell populations and the skin microbiome under steady-state conditions. Genetic deficiency in GPR15 substantially altered the composition of skin-resident T-cell populations. Precisely, dendritic epidermal T cells were almost absent in the epidermis of Gpr15-/- mice. The niche of dendritic epidermal T cells in the epidermis was, instead, populated by αß TCR+ T cells. These changes were associated with shifts in the skin microbiota in Gpr15-/- mice. Collectively, our results uncover a role of GPR15 in the regulation of the cutaneous immune system and, thus, highlight the receptor as important general regulator of tissue homeostasis of exterior body interfaces.
Assuntos
Microbiota/fisiologia , RNA Ribossômico 16S/genética , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Benzofuranos , Células Cultivadas , Homeostase , Camundongos , Camundongos Knockout , Quinolinas , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores Acoplados a Proteínas G , Pele/microbiologiaRESUMO
The impact of environmental factors, such as diet, and the genetic basis of autoimmune pancreatitis (AIP) are largely unknown. Here, we used an experimental murine AIP model to identify the contribution of diet to AIP development, as well as to fine-map AIP-associated genes in outbred mice prone to develop the disease. For this purpose, we fed mice of an autoimmune-prone intercross line (AIL) three different diets (control, calorie-reduced and western diet) for 6 months, at which point the mice were genotyped and phenotyped for AIP. Overall, 269 out of 734 mice (36.6%) developed AIP with signs of parenchymal destruction, equally affecting mice of both sexes. AIP prevalence and severity were reduced by approximately 50% in mice held under caloric restriction compared to those fed control or western diet. We identified a quantitative trait locus (QTL) on chromosome 4 to be associated with AIP, which is located within a previously reported QTL. This association does not change when considering diet or sex as an additional variable for the mapping. Using whole-genome sequences of the AIL founder strains, we resolved this QTL to a single candidate gene, namely Map3k7. Expression of Map3k7 was largely restricted to islet cells as well as lymphocytes found in the exocrine pancreas of mice with AIP. Our studies suggest a major impact of diet on AIP. Furthermore, we identify Map3k7 as a novel susceptibility gene for experimental AIP. Both findings warrant clinical translation.
Assuntos
Pancreatite Autoimune/etiologia , Dieta/efeitos adversos , Suscetibilidade a Doenças , Predisposição Genética para Doença , Alelos , Animais , Pancreatite Autoimune/diagnóstico , Pancreatite Autoimune/metabolismo , Biomarcadores , Mapeamento Cromossômico , Modelos Animais de Doenças , Feminino , Expressão Gênica , Interação Gene-Ambiente , Genótipo , Imuno-Histoquímica , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos , Locos de Características Quantitativas , Índice de Gravidade de DoençaRESUMO
Animal models have enhanced our understanding of the pathogenesis of autoimmune diseases. For these models, genetically identical, inbred mice have commonly been used. Different inbred mouse strains, however, show a high variability in disease manifestation. Identifying the factors that influence this disease variability could provide unrecognized insights into pathogenesis. We established a novel Ab transfer-induced model of epidermolysis bullosa acquisita (EBA), an autoimmune disease characterized by (muco)-cutaneous blistering caused by anti-type VII collagen (COL7) autoantibodies. Blistering after anti-COL7 IgG (directed against the von Willebrand factor A-like domain 2) transfer showed clear variability among inbred mouse strains, that is, severe cutaneous blistering and inflammation in C57BL/6J and absence of skin lesions in MRL/MpJ mice. The transfer of anti-COL7 IgG into irradiated, EBA-resistant MRL/MpJ mice, rescued by transplantation with bone marrow from EBA-susceptible B6.AK-H2k mice, induced blistering. To the contrary, irradiated EBA-susceptible B6.AK-H2k mice that were rescued using MRL/MpJ bone marrow were devoid of blistering. In vitro, immune complex activation of neutrophils from C57BL/6J or MRL/MpJ mice showed an impaired reactive oxygen species release from the latter, whereas no differences were observed after PMA activation. This finding was paralleled by divergent expression profiles of immune complex-activated neutrophils from either C57BL/6J or MRL/MpJ mice. Collectively, we demonstrate that radiosensitive cells determine the varying extent of skin inflammation and blistering in the end-stage effector phase of EBA.
Assuntos
Células da Medula Óssea/imunologia , Transplante de Medula Óssea/métodos , Dermatite/imunologia , Epidermólise Bolhosa Adquirida/imunologia , Animais , Autoanticorpos/imunologia , Vesícula/imunologia , Células da Medula Óssea/efeitos da radiação , Colágeno Tipo VII/imunologia , Modelos Animais de Doenças , Redes Reguladoras de Genes/imunologia , Humanos , Imunoglobulina G/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Neutrófilos/imunologia , Neutrófilos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Coelhos , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Especificidade da Espécie , Transcriptoma/imunologiaRESUMO
BACKGROUND: MicroRNAs (miRNAs) are small endogenous non-coding RNAs that control genes at post-transcriptional level. They are essential for development and tissue differentiation, and such altered miRNA expression patterns are linked to the pathogenesis of inflammation and cancer. There is evidence that miRNA expression is genetically controlled similar to the transcription of protein-coding genes and previous studies identified quantitative trait loci (QTL) for miRNA expression in the liver. So far, little attention has been paid to miRNA expression in the skin. Moreover, epistatic control of miRNA expression remains unknown. In this study, we characterize genetic regulation of cutaneous miRNA and their correlation with skin inflammation using a previously established murine autoimmune-prone advanced intercross line. RESULTS: We identified in silico 42 eQTL controlling the expression of 38 cutaneous miRNAs and furthermore found two chromosomal hot-spots on chromosomes 2 and 8 that control the expression of multiple miRNAs. Moreover, for 8 miRNAs an interacting effect from pairs of SNPs was observed. Combining the constraints on genes from the statistical interaction of their loci and further using curated protein interaction networks, the number of candidate genes for association of miRNAs was reduced to a set of several genes. A cluster analysis identified miR-379 and miR-223 to be associated with EBA severity/onset, where miR-379 was observed to be associated to loci on chromosome 6. CONCLUSION: The murine advanced intercross line allowed us to identify the genetic loci regulating multiple miRNA in skin. The recurrence of trans-eQTL and epistasis suggest that cutaneous miRNAs are regulated by yet an unexplored complex gene networks. Further, using co-expression analysis of miRNA expression levels we showed that multiple miRNA contribute to multiple pathways that might be involved in pathogenesis of autoimmune skin blistering disease. Specifically, we provide evidence that miRNA such as miR-223 and miR-379 may play critical role in disease progression and severity.
Assuntos
Doenças Autoimunes/genética , Vesícula/genética , Estudos de Associação Genética , Predisposição Genética para Doença , MicroRNAs/genética , Pele/metabolismo , Animais , Doenças Autoimunes/imunologia , Vesícula/imunologia , Modelos Animais de Doenças , Epistasia Genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Camundongos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Pele/patologia , TranscriptomaRESUMO
Genetic studies have added to the understanding of complex diseases. Here, we used a combined genetic approach for risk-loci identification in a prototypic, organ-specific, autoimmune disease, namely experimental epidermolysis bullosa acquisita (EBA), in which autoantibodies to type VII collagen (COL7) and neutrophil activation cause mucocutaneous blisters. Anti-COL7 IgG induced moderate blistering in most inbred mouse strains, while some showed severe disease or were completely protected. Using publicly available genotyping data, we identified haplotype blocks that control blistering and confirmed two haplotype blocks in outbred mice. To identify the blistering-associated genes, haplotype blocks encoding genes that are differentially expressed in EBA-affected skin were considered. This procedure identified nine genes, including retinoid-related orphan receptor alpha (RORα), known to be involved in neurological development and function. After anti-COL7 IgG injection, RORα+/- mice showed reduced blistering and homozygous mice were completely resistant to EBA induction. Furthermore, pharmacological RORα inhibition dose-dependently blocked reactive oxygen species (ROS) release from activated neutrophils but did not affect migration or phagocytosis. Thus, forward genomics combined with multiple validation steps identifies RORα to be essential to drive inflammation in experimental EBA.
Assuntos
Epidermólise Bolhosa Adquirida/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Pele/metabolismo , Animais , Autoanticorpos/imunologia , Colágeno Tipo VII/imunologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Agonismo Parcial de Drogas , Epidermólise Bolhosa Adquirida/genética , Epidermólise Bolhosa Adquirida/imunologia , Epidermólise Bolhosa Adquirida/patologia , Predisposição Genética para Doença , Genômica/métodos , Haplótipos , Heterozigoto , Homozigoto , Imunoglobulina G/imunologia , Camundongos Knockout , Ativação de Neutrófilo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/deficiência , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Especificidade da Espécie , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Fatores de TempoRESUMO
UNLABELLED: Non-coding RNAs (ncRNAs) are known to play important functional roles in the cell. However, their identification and recognition in genomic sequences remains challenging. In silico methods, such as classification tools, offer a fast and reliable way for such screening and multiple classifiers have already been developed to predict well-defined subfamilies of RNA. So far, however, out of all the ncRNAs, only tRNA, miRNA and snoRNA can be predicted with a satisfying sensitivity and specificity. We here present ptRNApred, a tool to detect and classify subclasses of non-coding RNA that are involved in the regulation of post-transcriptional modifications or DNA replication, which we here call post-transcriptional RNA (ptRNA). It (i) detects RNA sequences coding for post-transcriptional RNA from the genomic sequence with an overall sensitivity of 91% and a specificity of 94% and (ii) predicts ptRNA-subclasses that exist in eukaryotes: snRNA, snoRNA, RNase P, RNase MRP, Y RNA or telomerase RNA. AVAILABILITY: The ptRNApred software is open for public use on http://www.ptrnapred.org/.
Assuntos
RNA não Traduzido/classificação , Análise de Sequência de RNA/métodos , Software , Biologia Computacional/métodos , Regulação da Expressão Gênica , RNA não Traduzido/química , Máquina de Vetores de SuporteRESUMO
Babesia spp. are tick-borne, intraerythrocytic hemoparasites that use antigenic variation to resist host immunity, through sequential modification of the parasite-derived variant erythrocyte surface antigen (VESA) expressed on the infected red blood cell surface. We identified the genomic processes driving antigenic diversity in genes encoding VESA (ves1) through comparative analysis within and between three Babesia species, (B. bigemina, B. divergens and B. bovis). Ves1 structure diverges rapidly after speciation, notably through the evolution of shortened forms (ves2) from 5' ends of canonical ves1 genes. Phylogenetic analyses show that ves1 genes are transposed between loci routinely, whereas ves2 genes are not. Similarly, analysis of sequence mosaicism shows that recombination drives variation in ves1 sequences, but less so for ves2, indicating the adoption of different mechanisms for variation of the two families. Proteomic analysis of the B. bigemina PR isolate shows that two dominant VESA1 proteins are expressed in the population, whereas numerous VESA2 proteins are co-expressed, consistent with differential transcriptional regulation of each family. Hence, VESA2 proteins are abundant and previously unrecognized elements of Babesia biology, with evolutionary dynamics consistently different to those of VESA1, suggesting that their functions are distinct.
Assuntos
Variação Antigênica , Babesia/genética , Evolução Molecular , Genes de Protozoários , Interações Hospedeiro-Parasita/genética , Pontos de Quebra do Cromossomo , Genoma de Protozoário , Proteínas de Protozoários/genética , Recombinação GenéticaRESUMO
The experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the central nervous system commonly used to study multiple sclerosis (MS). We combined clinical EAE phenotypes with genome-wide expression profiling in spleens from 150 backcross rats between susceptible DA and resistant PVG rat strains during the chronic EAE phase. This enabled correlation of transcripts with genotypes, other transcripts and clinical EAE phenotypes and implicated potential genetic causes and pathways in EAE. We detected 2285 expression quantitative trait loci (eQTLs). Sixty out of 599 cis-eQTLs overlapped well-known EAE QTLs and constitute positional candidate genes, including Ifit1 (Eae7), Atg7 (Eae20-22), Klrc3 (eEae22) and Mfsd4 (Eae17). A trans-eQTL that overlaps Eae23a regulated a large number of small RNAs and implicates a master regulator of transcription. We defined several disease-correlated networks enriched for pathways involved in cell-mediated immunity. They include C-type lectins, G protein coupled receptors, mitogen-activated protein kinases, transmembrane proteins, suppressors of transcription (Jundp2 and Nr1d1) and STAT transcription factors (Stat4) involved in interferon signaling. The most significant network was enriched for T cell functions, similar to genetic findings in MS, and revealed both established and novel gene interactions. Transcripts in the network have been associated with T cell proliferation and differentiation, the TCR signaling and regulation of regulatory T cells. A number of network genes and their family members have been associated with MS and/or other autoimmune diseases. Combining disease and genome-wide expression phenotypes provides a link between disease risk genes and distinct molecular pathways that are dysregulated during chronic autoimmune inflammation.
Assuntos
Autoimunidade/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Mapeamento Cromossômico , Análise por Conglomerados , Encefalomielite Autoimune Experimental/metabolismo , Epistasia Genética , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Interferons/metabolismo , Masculino , Fenótipo , Locos de Características Quantitativas , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Transdução de SinaisRESUMO
Cytokines are key regulators of physiological inflammatory responses, while aberrant cytokine expression contributes to pathogenesis of autoimmune diseases. We noted increased IL-6 levels in human and murine epidermolysis bullosa acquisita (EBA), a prototypic organ-specific autoimmune bullous dermatoses (AIBD) induced by autoantibodies to type VII collagen (COL7). In contrast to rheumatoid arthritis, blockade of IL-6 led to strikingly enhanced experimental EBA, while treatment with recombinant IL-6 was protective. This was due to classical IL-6 signalling and independent of IL-6 trans-signalling, as treatment of mice with sgp130Fc had no impact on EBA manifestation. Induction of EBA in mice led to increased IL-1ra levels in skin and serum, while blockade of IL-6 completely inhibited IL-1ra expression induced by autoantibodies to COL7. In line, treatment of mice with EBA with recombinant IL-6 induced IL-1ra concentrations exceeding those of untreated animals with EBA, and IL-1ra (anakinra) administration significantly impaired experimental EBA induction. We here identified a novel anti-inflammatory pathway in an organ-specific autoimmune disease. Modulation of this IL-1ra pathway by classical IL-6 signalling demonstrates anti-inflammatory and protective activities of IL-6 in vivo.
Assuntos
Doenças Autoimunes/prevenção & controle , Epidermólise Bolhosa Adquirida/prevenção & controle , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-6/farmacologia , Animais , Apoptose , Autoanticorpos/imunologia , Doenças Autoimunes/sangue , Colágeno Tipo VII/imunologia , Citocinas/sangue , Modelos Animais de Doenças , Epidermólise Bolhosa Adquirida/sangue , Epidermólise Bolhosa Adquirida/imunologia , Humanos , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/biossíntese , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes/farmacologia , Transdução de Sinais/imunologia , Pele/metabolismo , Inibidor Tecidual de Metaloproteinase-1/imunologiaRESUMO
Psoriasis is a common chronic inflammatory skin disease, associated with significant comorbidity, for example, metabolic syndrome (MetS) and coronary heart disease (CHD). This association implies that the risk to develop these diseases is commonly controlled or that the presence of one disease favours manifestation of the other. Therefore, we assessed the catalogue of genome-wide association studies (GWAS) to analyse whether psoriasis, MetS and CHD share susceptibility loci. Interestingly, genetic control of psoriasis is almost completely independent from both MetS and CHD. In contrast, MetS and CHD share 10 common loci. Like by GWAS analysis, psoriasis susceptibility genes showed close clustering in Ingenuity Pathway Analysis, while genes conferring susceptibility to MetS and CHD were interlinked separately. These findings lead to the hypothesis that the clinically observed co-occurrence of psoriasis with MetS and CHD may be due to a common environmental factor, for example, diet, which is known as a risk factor for all of these diseases.
Assuntos
Doença da Artéria Coronariana/genética , Síndrome Metabólica/genética , Psoríase/genética , Doença da Artéria Coronariana/etiologia , Dieta , Exposição Ambiental , Estudo de Associação Genômica Ampla , Antígenos HLA/genética , Humanos , Inflamação , Estilo de Vida , Síndrome Metabólica/etiologia , Psoríase/etiologia , Fatores de RiscoRESUMO
Autoantibody-mediated diseases are clinically heterogeneous and often fail conventional therapeutic strategies. Gene expression profiling has helped to identify new molecular pathways in these diseases, although their potential as treatment targets largely remains to be functionally validated. Based on weighted gene co-expression network analysis, we determined the transcriptional network in experimental epidermolysis bullosa acquisita (EBA), a paradigm of an antibody-mediated organ-specific autoimmune disease characterized by autoantibodies directed against type VII collagen. We identified 33 distinct and differentially expressed modules, including Fcγ receptor (FcγR) IV and components of the neutrophil-associated enzyme system in autoantibody transfer-induced EBA. Validation experiments, including functional analysis, demonstrated that FcγRIV expression on neutrophils crucially contributes to autoantibody-induced tissue injury in the transfer model of EBA. Mice lacking the common γ-chain of activating FcγRs, deficient in FcγRIV or treated with FcγRIV function blocking antibody, but not mice deficient in FcγRI, FcγRIIB, FcγRIII or both FcγRI and FcγRIII, were effectively protected from EBA. Skin disease was restored in γ-chain-deficient mice locally reconstituted with neutrophils from wild-type, but not from γ-chain-deficient, mice. Our findings both genetically and functionally identify a novel disease-related molecule, FcγRIV, in an autoantibody-mediated disorder, which may be of importance for the development of novel targeted therapies.
Assuntos
Doenças Autoimunes/genética , Epidermólise Bolhosa Adquirida/genética , Predisposição Genética para Doença , Receptores de IgG/genética , Animais , Anticorpos Bloqueadores/farmacologia , Autoanticorpos/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Colágeno Tipo VII/imunologia , Modelos Animais de Doenças , Epidermólise Bolhosa Adquirida/tratamento farmacológico , Epidermólise Bolhosa Adquirida/imunologia , Epidermólise Bolhosa Adquirida/patologia , Perfilação da Expressão Gênica , Imunoglobulina G/imunologia , Isotipos de Imunoglobulinas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Especificidade de Órgãos , Receptores de IgG/metabolismoRESUMO
The mammalian gut is home to a diverse microbial ecosystem, whose composition affects various physiological traits of the host. Next-generation sequencing-based metagenomic approaches demonstrated how the interplay of host genetics, bacteria, and environmental factors shape complex traits and clinical outcomes. However, the role of fungi in these complex interactions remains understudied. Here, using 228 males and 363 females from an advanced-intercross mouse line, we provide evidence that fungi are regulated by host genetics. In addition, we map quantitative trait loci associated with various fungal species to single genes in mice using whole genome sequencing and genotyping. Moreover, we show that diet and its' interaction with host genetics alter the composition of fungi in outbred mice, and identify fungal indicator species associated with different dietary regimes. Collectively, in this work, we uncover an association of the intestinal fungal community with host genetics and a regulatory role of diet in this ecological niche.
Assuntos
Micobioma , Masculino , Feminino , Animais , Camundongos , Micobioma/genética , Ecossistema , Dieta , Locos de Características Quantitativas , Bactérias/genética , Fungos/genética , Mamíferos/genéticaRESUMO
African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.
Assuntos
Glomerulosclerose Segmentar e Focal , Humanos , Glomerulosclerose Segmentar e Focal/genética , Apolipoproteína L1/genética , Predisposição Genética para Doença , Fatores de Risco , Genótipo , Apolipoproteínas/genéticaRESUMO
Black Americans have a significantly higher risk of developing chronic kidney disease (CKD), especially focal segmental glomerulosclerosis (FSGS), than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of Black Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1 -associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.
RESUMO
Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
Assuntos
Estudo de Associação Genômica Ampla , Síndrome Nefrótica , Humanos , Criança , Síndrome Nefrótica/genética , Predisposição Genética para Doença , Haplótipos , Fatores de Risco , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Background: Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease leading to irreversible airflow limitation and is characterized by chronic pulmonary inflammation, obstructive bronchiolitis and emphysema. Etiologically, COPD is mediated by toxic gases and particles, eg, cigarette smoke, while the pathogenesis of the disease is largely unknown. Several lines of evidence indicate a link between COPD and autoimmunity but comprehensive studies are lacking. Methods: By using a protein microarray assaying more than 19,000 human proteins we determined in this study the autoantibody profiles of COPD and non-COPD smokers. The discovery cohort included 5 COPD patients under acute exacerbation (AECOPD) and 5 age- and gender-matched non-COPD smokers. One putative candidate autoantibody, anti-lactoferrin IgG, was further investigated by using immunoblotting with a large validation cohort containing 124 healthy controls, 92 patients with AECOPD and 52 patients with stable COPD. Results: We show that i) autoantigens targeted by autoantibodies with higher titers in COPD patients were enriched in extracellular regions, while those with lower titers in COPD patients were enriched in intracellular compartments. ii) levels of IgG autoantibodies against many neutrophil granule proteins were significantly higher in COPD patients than in non-COPD smokers. Furthermore, increased levels of anti-lactoferrin antibodies in COPD patients were confirmed in a cohort with a large number of samples. Conclusion: The comprehensive autoantibody profiles from COPD patients established in this study demonstrated for the first time a shift in the cellular localization of antigens targeted by autoantibodies in COPD.