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1.
Clin Exp Med ; 24(1): 65, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38564026

RESUMO

Observational studies showed possible associations between systemic lupus erythematosus and multiple myeloma. However, whether there is a casual relationship between different types of autoimmune diseases (type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, primary sclerosing cholangitis, primary biliary cirrhosis, and juvenile idiopathic arthritis) and multiple myeloma (MM) is not well known. We performed a two-sample Mendelian randomization (MR) study to estimate the casual relationship. Summary-level data of autoimmune diseases were gained from published genome-wide association studies while data of MM was obtained from UKBiobank. The Inverse-Variance Weighted (IVW) method was used as the primary analysis method to interpret the study results, with MR-Egger and weighted median as complementary methods of analysis. There is causal relationship between primary sclerosing cholangitis [OR = 1.00015, 95% CI 1.000048-1.000254, P = 0.004] and MM. Nevertheless, no similar causal relationship was found between the remaining seven autoimmune diseases and MM. Considering the important role of age at recruitment and body mass index (BMI) in MM, we excluded these relevant instrument variables, and similar results were obtained. The accuracy and robustness of these findings were confirmed by sensitivity tests. Overall, MR analysis suggests that genetic liability to primary sclerosing cholangitis could be causally related to the increasing risk of MM. This finding may serve as a guide for clinical attention to patients with autoimmune diseases and their early screening for MM.


Assuntos
Doenças Autoimunes , Colangite Esclerosante , Lúpus Eritematoso Sistêmico , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Doenças Autoimunes/genética
2.
Front Immunol ; 15: 1325868, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38585265

RESUMO

Background: Many observational studies have been reported that patients with autoimmune or allergic diseases seem to have a higher risk of developing senile cataract, but the views are not consistent. In order to minimize the influence of reverse causality and potential confounding factors, we performed Mendelian Randomization (MR) analysis to investigate the genetic causal associations between autoimmune, allergic diseases and senile cataract. Methods: Single nucleotide polymorphisms associated with ten common autoimmune and allergic diseases were obtained from the IEU Open genome-wide association studies (GWAS) database. Summary-level GWAS statistics for clinically diagnosed senile cataract were obtained from the FinnGen research project GWAS, which consisted of 59,522 individuals with senile cataracts and 312,864 control individuals. MR analysis was conducted using mainly inverse variance weighted (IVW) method and further sensitivity analysis was performed to test robustness. Results: As for ten diseases, IVW results confirmed that type 1 diabetes (OR = 1.06; 95% CI = 1.05-1.08; p = 2.24×10-12), rheumatoid arthritis (OR = 1.05; 95% CI = 1.02-1.08; p = 1.83×10-4), hypothyroidism (OR = 2.4; 95% CI = 1.42-4.06; p = 1.12×10-3), systemic lupus erythematosus (OR = 1.02; 95% CI = 1.01-1.03; p = 2.27×10-3), asthma (OR = 1.02; 95% CI = 1.01-1.03; p = 1.2×10-3) and allergic rhinitis (OR = 1.07; 95% CI = 1.02-1.11; p = 2.15×10-3) were correlated with the risk of senile cataract. Celiac disease (OR = 1.04; 95% CI = 1.01-1.08; P = 0.0437) and atopic dermatitis (OR = 1.05; 95% CI = 1.01-1.10; P = 0.0426) exhibited a suggestive connection with senile cataract after Bonferroni correction. These associations are consistent across weighted median and MR Egger methods, with similar causal estimates in direction and magnitude. Sensitivity analysis further proved that these associations were reliable. Conclusions: The results of the MR analysis showed that there were causal relationships between type 1 diabetes, rheumatoid arthritis, hypothyroidism, systemic lupus erythematosus, asthma, allergic rhinitis and senile cataract. To clarify the possible role of autoimmune and allergy in the pathophysiology of senile cataract, further studies are needed.


Assuntos
Artrite Reumatoide , Asma , Doenças Autoimunes , Catarata , Diabetes Mellitus Tipo 1 , Hipotireoidismo , Lúpus Eritematoso Sistêmico , Rinite Alérgica , Humanos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Asma/epidemiologia , Asma/genética , Catarata/genética
3.
Transl Psychiatry ; 14(1): 172, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561342

RESUMO

Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.


Assuntos
Doenças Autoimunes , Doença de Hashimoto , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/genética , Fenótipo , Proteína C-Reativa , Doenças Autoimunes/genética , Biomarcadores , Estudo de Associação Genômica Ampla
4.
Nat Commun ; 15(1): 2936, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580644

RESUMO

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.


Assuntos
Doenças Autoimunes , Colangite , Cirrose Hepática Biliar , Camundongos , Animais , Cirrose Hepática Biliar/terapia , Imunoterapia Adotiva , Receptor de Morte Celular Programada 1 , Linfócitos T CD8-Positivos , Colangite/terapia , Doenças Autoimunes/genética
5.
BMC Med ; 22(1): 161, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38616254

RESUMO

BACKGROUND: To study the shared genetic structure between autoimmune diseases and B-cell acute lymphoblastic leukemia (B-ALL) and identify the shared risk loci and genes and genetic mechanisms involved. METHODS: Based on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic overlaps between autoimmune diseases and B-ALL, and cross-trait pleiotropic analysis was performed to detect shared pleiotropic loci and genes. A series of functional annotation and tissue-specific analysis were performed to determine the influence of pleiotropic genes. The heritability enrichment analysis was used to detect crucial immune cells and tissues. Finally, bidirectional Mendelian randomization (MR) methods were utilized to investigate the casual associations. RESULTS: Our research highlighted shared genetic mechanisms between seven autoimmune disorders and B-ALL. A total of 73 pleiotropic loci were identified at the genome-wide significance level (P < 5 × 10-8), 16 of which had strong evidence of colocalization. We demonstrated that several loci have been previously reported (e.g., 17q21) and discovered some novel loci (e.g., 10p12, 5p13). Further gene-level identified 194 unique pleiotropic genes, for example IKZF1, GATA3, IKZF3, GSDMB, and ORMDL3. Pathway analysis determined the key role of cellular response to cytokine stimulus, B cell activation, and JAK-STAT signaling pathways. SNP-level and gene-level tissue enrichment suggested that crucial role pleiotropic mechanisms involved in the spleen, whole blood, and EBV-transformed lymphocytes. Also, hyprcoloc and stratified LD score regression analyses revealed that B cells at different developmental stages may be involved in mechanisms shared between two different diseases. Finally, two-sample MR analysis determined causal effects of asthma and rheumatoid arthritis on B-ALL. CONCLUSIONS: Our research proved shared genetic architecture between autoimmune disorders and B-ALL and shed light on the potential mechanism that might involve in.


Assuntos
Artrite Reumatoide , Asma , Doenças Autoimunes , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Estudo de Associação Genômica Ampla , Doenças Autoimunes/genética
6.
Front Public Health ; 12: 1333811, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38605869

RESUMO

Background: In recent years, an increasing number of observational studies have reported the impact of air pollution on autoimmune diseases (ADs). However, no Mendelian randomization (MR) studies have been conducted to investigate the causal relationships. To enhance our understanding of causality, we examined the causal relationships between particulate matter (PM) and nitrogen oxides (NOx) and ADs. Methods: We utilized genome-wide association study (GWAS) data on PM and NOx from the UK Biobank in European and East Asian populations. We also extracted integrated GWAS data from the Finnish consortium and the Japanese Biobank for two-sample MR analysis. We employed inverse variance weighted (IVW) analysis to assess the causal relationship between PM and NOx exposure and ADs. Additionally, we conducted supplementary analyses using four methods, including IVW (fixed effects), weighted median, weighted mode, and simple mode, to further investigate this relationship. Results: In the European population, the results of MR analysis suggested a statistically significant association between PM2.5 and psoriasis only (OR = 3.86; 95% CI: 1.89-7.88; PIVW < 0.00625), while a potential association exists between PM2.5-10 and vitiligo (OR = 7.42; 95% CI: 1.02-53.94; PIVW < 0.05), as well as between PM2.5 and systemic lupus erythematosus (OR = 68.17; 95% CI: 2.17-2.1e+03; PIVW < 0.05). In East Asian populations, no causal relationship was found between air pollutants and the risk of systemic lupus erythematosus and rheumatoid arthritis (PIVW > 0.025). There was no pleiotropy in the results. Conclusion: Our results suggest a causal association between PM2.5 and psoriasis in European populations. With the help of air pollution prevention and control, the harmful progression of psoriasis may be slowed.


Assuntos
Poluição do Ar , Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Psoríase , Humanos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Doenças Autoimunes/etiologia , Doenças Autoimunes/genética , Poluição do Ar/efeitos adversos , Material Particulado/efeitos adversos , Psoríase/etiologia , Psoríase/genética
7.
Front Immunol ; 15: 1343480, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38660310

RESUMO

Background: Previous studies have demonstrated that autoimmune diseases are closely associated with bronchiectasis (BE). However, the causal effects between autoimmune diseases and BE remain elusive. Methods: All summary-level data were obtained from large-scale Genome-Wide Association Studies (GWAS). The univariate Mendelian randomization (UVMR) was utilized to investigate the genetic causal correlation (rg) of 12 autoimmune diseases and bronchiectasis, The Multivariable Mendelian Randomization (MVMR) method was used to explore the effects of the confounding factors. Further investigation was conducted to identify potential intermediate factors using mediation analysis. Finally, the linkage disequilibrium score regression (LDSC) method was used to identify genetic correlations among complex traits. A series of sensitivity analyses was performed to validate the robustness of the results. Results: The LDSC analysis revealed significant genetic correlations between BE and Crohn's disease (CD) (rg = 0.220, P = 0.037), rheumatoid arthritis (RA) (rg = 0.210, P = 0.021), and ulcerative colitis (UC) (rg = 0.247, P = 0.023). However, no genetic correlation was found with other autoimmune diseases (P > 0.05). The results of the primary IVW analysis suggested that for every SD increase in RA, there was a 10.3% increase in the incidence of BE (odds ratio [OR] = 1.103, 95% confidence interval [CI] 1.055-1.154, P = 1.75×10-5, FDR = 5.25×10-5). Furthermore, for every standard deviation (SD) increase in celiac disease (CeD), the incidence of BE reduced by 5.1% (OR = 0.949, 95% CI 0.902-0.999, P = 0.044, FDR = 0.044). We also observed suggestive evidence corresponding to a 3% increase in BE incidence with T1DM (OR = 1.033, 95% CI 1.001-1.066, P = 0.042, FDR = 0.063). Furthermore, MVMR analysis showed that RA was an independent risk factor for BE, whereas mediator MR analysis did not identify any mediating factors. The sensitivity analyses corroborated the robustness of these findings. Conclusion: LDSC analysis revealed significant genetic correlations between several autoimmune diseases and BE, and further MVMR analysis showed that RA is an independent risk factor for BE.


Assuntos
Doenças Autoimunes , Bronquiectasia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Bronquiectasia/genética , Doenças Autoimunes/genética , Doenças Autoimunes/epidemiologia , Polimorfismo de Nucleotídeo Único , Desequilíbrio de Ligação , Artrite Reumatoide/genética
8.
Front Public Health ; 12: 1322140, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38550316

RESUMO

Background: In recent times, reports have emerged suggesting that a variety of autoimmune disorders may arise after the coronavirus disease 2019 (COVID-19) vaccination. However, causality and underlying mechanisms remain unclear. Methods: We collected summary statistics of COVID-19 vaccination and 31 autoimmune diseases from genome-wide association studies (GWAS) as exposure and outcome, respectively. Random-effects inverse variance weighting (IVW), MR Egger, weighted median, simple mode, and weighted mode were used as analytical methods through Mendelian randomization (MR), and heterogeneity and sensitivity analysis were performed. Results: We selected 72 instrumental variables for exposure (p < 5 × 10-6; r2 < 0.001, genetic distance = 10,000 kb), and MR analyses showed that COVID-19 vaccination was causally associated with an increased risk of multiple sclerosis (MS) (IVW, OR: 1.53, 95% CI: 1.065-2.197, p = 0.026) and ulcerative colitis (UC) (IVW, OR: 1.00, 95% CI: 1.000-1.003, p = 0.039). If exposure was refined (p < 5 × 10-8; r2 < 0.001, genetic distance = 10,000 kb), the associations became negative. No causality was found for the remaining outcomes. These results were robust to sensitivity and heterogeneity analyses. Conclusion: Our study provided potential evidence for the impact of COVID-19 vaccination on the risk of MS and UC occurrence, but it lacks sufficient robustness, which could provide a new idea for public health policy.


Assuntos
Doenças Autoimunes , COVID-19 , Colite Ulcerativa , Humanos , Vacinas contra COVID-19 , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , COVID-19/epidemiologia , COVID-19/prevenção & controle , Doenças Autoimunes/etiologia , Doenças Autoimunes/genética , Vacinação
9.
Front Immunol ; 15: 1349601, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38487540

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet ß-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 (IFIH1), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 (IFIH1A946T) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that the IFIH1A946T risk variant, (IFIH1R) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developed Ifih1R knock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis in Ifih1R compared to non-risk Ifih1 (Ifih1NR) mice and a significant acceleration of diabetes onset in Ifih1R females. Ifih1R mice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared to Ifih1NR, indicative of increased IFN I signaling. Ifih1R mice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8+ T cells. Our results indicate that IFIH1R may contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects of Ifih1R in NOD mice, which will be important to consider for the development of therapeutics for T1D.


Assuntos
Doenças Autoimunes , Diabetes Mellitus Tipo 1 , Feminino , Animais , Camundongos , Helicase IFIH1 Induzida por Interferon/genética , RNA Helicases DEAD-box/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Predisposição Genética para Doença , Camundongos Endogâmicos NOD , Doenças Autoimunes/genética , Interferons/genética
10.
Clin Immunol ; 262: 110177, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38460894

RESUMO

Calcium/calmodulin-dependent protein kinase IV (CaMK4) serves as a pivotal mediator in the regulation of gene expression, influencing the activity of transcription factors within a variety of immune cells, including T cells. Altered CaMK4 signaling is implicated in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, which are characterized by dysregulated immune responses and clinical complexity. These conditions share common disturbances in immune cell functionality, cytokine production, and autoantibody generation, all of which are associated with disrupted calcium-calmodulin signaling. This review underscores the consequences of dysregulated CaMK4 signaling across these diseases, with an emphasis on its impact on Th17 differentiation and T cell metabolism-processes central to maintaining immune homeostasis. A comprehensive understanding of roles of CaMK4 in gene regulation across various autoimmune disorders holds promise for the development of targeted therapies, particularly for diseases driven by Th17 cell dysregulation.


Assuntos
Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Humanos , Calmodulina/metabolismo , Calmodulina/uso terapêutico , Cálcio/metabolismo , Cálcio/uso terapêutico , Diferenciação Celular , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Células Th17
11.
Autoimmunity ; 57(1): 2330392, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38515381

RESUMO

BACKGROUND: Despite growing knowledge regarding the pathogenesis of autoimmune diseases (ADs) onset, the current treatment remains unsatisfactory. This study aimed to identify innovative therapeutic targets for ADs through various analytical approaches. RESEARCH DESIGN AND METHODS: Utilizing Mendelian randomization, Bayesian co-localization, phenotype scanning, and protein-protein interaction network, we explored potential therapeutic targets for 14 ADs and externally validated our preliminary findings. RESULTS: This study identified 12 circulating proteins as potential therapeutic targets for six ADs. Specifically, IL12B was judged to be a risk factor for ankylosing spondylitis (p = 1.61E - 07). TYMP (p = 6.28E - 06) was identified as a protective factor for ulcerative colitis. For Crohn's disease, ERAP2 (p = 4.47E - 14), HP (p = 2.08E - 05), and RSPO3 (p = 6.52E - 07), were identified as facilitators, whereas FLRT3 (p = 3.42E - 07) had a protective effect. In rheumatoid arthritis, SWAP70 (p = 3.26E - 10), SIGLEC6 (p = 2.47E - 05), ISG15 (p = 3.69E - 05), and FCRL3 (p = 1.10E - 10) were identified as risk factors. B4GALT1 (p = 6.59E - 05) was associated with a lower risk of Type 1 diabetes (T1D). Interestingly, CTSH was identified as a protective factor for narcolepsy (p = 1.58E - 09) but a risk factor for T1D (p = 7.36E - 11), respectively. External validation supported the associations of eight of these proteins with three ADs. CONCLUSIONS: Our integrated study identified 12 potential therapeutic targets for ADs and provided novel insights into future drug development for ADs.


Assuntos
Doenças Autoimunes , Diabetes Mellitus Tipo 1 , Humanos , Proteoma , Diabetes Mellitus Tipo 1/genética , Teorema de Bayes , Análise da Randomização Mendeliana , Doenças Autoimunes/genética , Doenças Autoimunes/terapia , Estudo de Associação Genômica Ampla , Aminopeptidases
12.
Methods Mol Biol ; 2789: 121-127, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38506997

RESUMO

Autoimmune responses are characterized by the presence of antibodies and lymphocytes specific to self or so-called autoantigens. Among such autoantigens is DNA; therefore, screening for antibodies recognizing single- and/or double-stranded DNA is commonly used to detect and classify autoimmune diseases. While autoimmunity affects both sexes, females are generally more affected than males, which is recapitulated in some animal models. A variety of factors, including genetic predisposition and the environment, contribute to the development of autoimmune disorders. Since certain drug products may also contribute to the development of autoimmunity, understanding a drug's potential to trigger an autoimmune response is of interest to immunotoxicology. However, models to study autoimmunity are limited, and it is generally agreed that no model can accurately predict autoimmunity in humans. Herein, we present an in vivo protocol utilizing the SJL/J mouse model to study nanoparticles' effects on the development of autoimmune responses. The protocol is adapted from the literature describing the use of this model to study chemically induced lupus.


Assuntos
Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Humanos , Masculino , Camundongos , Feminino , Animais , Autoimunidade , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/genética , Autoantígenos , Camundongos Endogâmicos , DNA
13.
Adv Exp Med Biol ; 1444: 19-32, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467970

RESUMO

One of the difficulties in studying the pathogenesis of autoimmune diseases is that the disease is multifactorial involving sex, age, MHC, environment, and some genetic factors. Because deficiency of Aire, a transcriptional regulator, is an autoimmune disease caused by a single gene abnormality, Aire is an ideal research target for approaching the enigma of autoimmunity, e.g., the mechanisms underlying Aire deficiency can be studied using genetically modified animals. Nevertheless, the exact mechanisms of the breakdown of self-tolerance due to Aire's dysfunction have not yet been fully clarified. This is due, at least in part, to the lack of information on the exact target genes controlled by Aire. State-of-the-art research infrastructures such as single-cell analysis are now in place to elucidate the essential function of Aire. The knowledge gained through the study of Aire-mediated tolerance should help our understanding of the pathogenesis of autoimmune disease in general.


Assuntos
Doenças Autoimunes , Poliendocrinopatias Autoimunes , Animais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Autoimunidade/genética , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/metabolismo , Aprendizagem , Timo
14.
Adv Exp Med Biol ; 1444: 3-18, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467969

RESUMO

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic inborn error of autoimmunity that is caused by damaging germline variants in the AIRE gene and clinically manifests with multiple autoimmune diseases in patients. Studies on the function of the AIRE gene, discovered in 1997, have contributed to fundamental aspects of human immunology as they have been important in understanding the basic mechanism of immune balance between self and non-self. This chapter looks back to the discovery of the AIRE gene, reviews its main properties, and discusses the key findings of its function in the thymus. However, more recent autoantibody profilings in APECED patients have highlighted a gap in our knowledge of the disease pathology and point to the need to revisit the current paradigm of AIRE function. The chapter reviews these new findings in APECED patients, which potentially trigger new thoughts on the mechanism of immune tolerance.


Assuntos
Doenças Autoimunes , Poliendocrinopatias Autoimunes , Humanos , Autoimunidade/genética , Poliendocrinopatias Autoimunes/genética , Fatores de Transcrição/genética , 60533 , Doenças Autoimunes/genética , Mutação
15.
PLoS Pathog ; 20(3): e1012095, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38512979

RESUMO

The 1858C>T allele of the tyrosine phosphatase PTPN22 is present in 5-10% of the North American population and is strongly associated with numerous autoimmune diseases. Although research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its pro-autoimmune allele has in anti-viral immunity remains poorly defined. Here, we use single cell RNA-sequencing and functional studies to interrogate the impact of this pro-autoimmune allele on anti-viral immunity during Lymphocytic Choriomeningitis Virus clone 13 (LCMV-cl13) infection. Mice homozygous for this allele (PEP-619WW) clear the LCMV-cl13 virus whereas wildtype (PEP-WT) mice cannot. This is associated with enhanced anti-viral CD4 T cell responses and a more immunostimulatory CD8α- cDC phenotype. Adoptive transfer studies demonstrated that PEP-619WW enhanced anti-viral CD4 T cell function through virus-specific CD4 T cell intrinsic and extrinsic mechanisms. Taken together, our data show that the pro-autoimmune allele of Ptpn22 drives a beneficial anti-viral immune response thereby preventing what is normally a chronic virus infection.


Assuntos
Doenças Autoimunes , Coriomeningite Linfocítica , Animais , Camundongos , Alelos , Doenças Autoimunes/genética , Autoimunidade/genética , Monoéster Fosfórico Hidrolases/genética , Tirosina
16.
Cells ; 13(5)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38474381

RESUMO

Selective IgA deficiency (SIgAD) is the most common form and common variable immunodeficiency (CVID) is the most symptomatic form of predominant antibody deficiency. Despite differences in the clinical picture, a similar genetic background is suggested. A common feature of both disorders is the occurrence of autoimmune conditions. Regulatory T cells (Tregs) are the major immune cell type that maintains autoimmune tolerance. As the different types of abnormalities of Treg cells have been associated with autoimmune disorders in primary immunodeficiency (PID) patients, in our study we aimed to analyze the gene expression profiles of Treg cells in CVID and SIgAD patients compared to age-matched healthy controls. The transcriptome-wide gene profiling was performed by microarray technology. As a result, we analyzed and visualized gene expression patterns of isolated population of Treg cells. We showed the differences at the gene level between patients with and without autoimmunizations. Our findings suggest that the gene signatures of Treg cells isolated from SIgAD and CVID patients differ from age-matched healthy controls and from each other, presenting transcriptional profiles enriched in innate immune or Th response, respectively. The occurrence of autoimmunity in both types of PID is associated with down-regulation of class I IFNs signaling pathways. In summary, our findings improve our understanding of Treg dysfunctions in patients with common PIDs and associated autoimmunity.


Assuntos
Doenças Autoimunes , Imunodeficiência de Variável Comum , Deficiência de IgA , Linfócitos T Reguladores , Transcriptoma , Criança , Humanos , Doenças Autoimunes/genética , Imunodeficiência de Variável Comum/genética , Deficiência de IgA/genética , Linfócitos T Reguladores/metabolismo
17.
JCI Insight ; 9(3)2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38329126

RESUMO

Linear ubiquitin chains, which are generated specifically by the linear ubiquitin assembly complex (LUBAC) ubiquitin ligase, play crucial roles in immune signaling, including NF-κB activation. LUBAC comprises catalytic large isoform of heme-oxidized iron regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) interacting protein (HOIP), accessory HOIL-1L, and SHANK-associated RH domain-interacting protein (SHARPIN). Deletion of the ubiquitin ligase activity of HOIL-1L, an accessory ligase of LUBAC, augments LUBAC functions by enhancing LUBAC-mediated linear ubiquitination, which is catalyzed by HOIP. Here, we show that HOIL-1L ΔRING1 mice, which exhibit augmented LUBAC functions upon loss of the HOIL-1L ligase, developed systemic lupus erythematosus (SLE) and Sjögren's syndrome in a female-dominant fashion. Augmented LUBAC activity led to hyperactivation of both lymphoid and myeloid cells. In line with the findings in mice, we sought to identify missense single nucleotide polymorphisms/variations of the RBCK1/HOIL-1L gene in humans that attenuate HOIL-1L ligase activity. We found that the R464H variant, which is encoded by rs774507518 within the RBCK1/HOIL-1L gene, attenuated HOIL-1L ligase activity and augmented LUBAC-mediated immune signaling, including that mediated by Toll-like receptors. We also found that rs774507518 was enriched significantly in patients with SLE, strongly suggesting that RBCK1/HOIL-1L is an SLE susceptibility gene and that augmented linear ubiquitin signaling generated specifically by LUBAC underlies the pathogenesis of this prototype systemic autoimmune disease.


Assuntos
Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Humanos , Feminino , Animais , Camundongos , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinas , Doenças Autoimunes/genética , Proteínas de Transporte/genética
18.
Front Immunol ; 15: 1323072, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38380333

RESUMO

Genome-wide association studies (GWAS) have identified thousands of variants in the human genome with autoimmune diseases. However, identifying functional regulatory variants associated with autoimmune diseases remains challenging, largely because of insufficient experimental validation data. We adopt the concept of semi-supervised learning by combining labeled and unlabeled data to develop a deep learning-based algorithm framework, sscNOVA, to predict functional regulatory variants in autoimmune diseases and analyze the functional characteristics of these regulatory variants. Compared to traditional supervised learning methods, our approach leverages more variants' data to explore the relationship between functional regulatory variants and autoimmune diseases. Based on the experimentally curated testing dataset and evaluation metrics, we find that sscNOVA outperforms other state-of-the-art methods. Furthermore, we illustrate that sscNOVA can help to improve the prioritization of functional regulatory variants from lead single-nucleotide polymorphisms and the proxy variants in autoimmune GWAS data.


Assuntos
Doenças Autoimunes , Estudo de Associação Genômica Ampla , Humanos , Redes Neurais de Computação , Algoritmos , Doenças Autoimunes/genética
19.
Semin Hematol ; 61(1): 3-8, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38423847

RESUMO

Clonal hematopoiesis (CH) has been associated with aging, occurring in about 10% of individuals aged >70 years, and immune dysfunction. Aged hematopoietic stem and progenitor cells exhibit pathological changes in immune function and activation of inflammatory pathways. CH clones commonly harbor a loss of function mutation in DNMT3A or TET2, which causes increased expression of inflammatory signaling genes, a proposed mechanism connected to CH and the development of age-related diseases. Additionally, inflammation may stress the hematopoietic compartment, driving the expansion of mutant clones. While the epidemiologic overlap between CH, hematologic malignancies, and atherosclerotic cardiovascular diseases has been reported, the mechanisms linking these concepts are largely unknown and merit much further investigation. Here, we review studies highlighting the interplay between CH, inflamm-aging, the immune system, and the prevalence of CH in autoimmune diseases.


Assuntos
Doenças Autoimunes , Hematopoiese Clonal , Humanos , Hematopoiese Clonal/genética , Autoimunidade , Hematopoese/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Mutação , Doenças Autoimunes/genética
20.
Cell ; 187(3): 733-749.e16, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38306984

RESUMO

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.


Assuntos
Autoanticorpos , Doenças Autoimunes , RNA Longo não Codificante , Animais , Feminino , Humanos , Masculino , Camundongos , Autoanticorpos/genética , Doenças Autoimunes/genética , Autoimunidade/genética , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Cromossomo X/genética , Cromossomo X/metabolismo , Inativação do Cromossomo X , Caracteres Sexuais
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