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1.
Nat Commun ; 11(1): 4402, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879318

RESUMO

Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T cells over 24 h, to identify functional enhancers regulating gene expression. We characterise changes in DNA interaction and activity dynamics that correlate with changes in gene expression, and find that the strongest correlations are observed within 200 kb of promoters. Using rheumatoid arthritis as an example of T cell mediated disease, we demonstrate interactions of expression quantitative trait loci with target genes, and confirm assigned genes or show complex interactions for 20% of disease associated loci, including FOXO1, which we confirm using CRISPR/Cas9.


Assuntos
Artrite Reumatoide/genética , Linfócitos T CD4-Positivos/metabolismo , Cromatina , Proteína Forkhead Box O1/genética , Doenças Autoimunes/genética , Linfócitos T CD4-Positivos/citologia , Cromatina/química , Cromatina/genética , Elementos Facilitadores Genéticos , Proteína Forkhead Box O1/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Cultura Primária de Células , Regiões Promotoras Genéticas , Locos de Características Quantitativas
2.
Nat Commun ; 11(1): 3761, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724101

RESUMO

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4+ T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis-eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2, HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases.


Assuntos
Doenças Autoimunes/genética , Desenvolvimento Infantil/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Hipersensibilidade/genética , Locos de Características Quantitativas/imunologia , Doenças Autoimunes/imunologia , Butirofilinas/genética , Butirofilinas/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Catepsina H/genética , Catepsina H/metabolismo , Criança , Pré-Escolar , Conjuntos de Dados como Assunto , Sangue Fetal/citologia , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA-C/genética , Antígenos HLA-C/metabolismo , Humanos , Hipersensibilidade/imunologia , Lactente , Recém-Nascido , Análise da Randomização Mendeliana , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
3.
Ann Rheum Dis ; 79(9): 1234-1242, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32546599

RESUMO

OBJECTIVES: Myositis is a heterogeneous family of diseases that includes dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM), inclusion body myositis (IBM), polymyositis and overlap myositis. Additional subtypes of myositis can be defined by the presence of myositis-specific autoantibodies (MSAs). The purpose of this study was to define unique gene expression profiles in muscle biopsies from patients with MSA-positive DM, AS and IMNM as well as IBM. METHODS: RNA-seq was performed on muscle biopsies from 119 myositis patients with IBM or defined MSAs and 20 controls. Machine learning algorithms were trained on transcriptomic data and recursive feature elimination was used to determine which genes were most useful for classifying muscle biopsies into each type and MSA-defined subtype of myositis. RESULTS: The support vector machine learning algorithm classified the muscle biopsies with >90% accuracy. Recursive feature elimination identified genes that are most useful to the machine learning algorithm and that are only overexpressed in one type of myositis. For example, CAMK1G (calcium/calmodulin-dependent protein kinase IG), EGR4 (early growth response protein 4) and CXCL8 (interleukin 8) are highly expressed in AS but not in DM or other types of myositis. Using the same computational approach, we also identified genes that are uniquely overexpressed in different MSA-defined subtypes. These included apolipoprotein A4 (APOA4), which is only expressed in anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) myopathy, and MADCAM1 (mucosal vascular addressin cell adhesion molecule 1), which is only expressed in anti-Mi2-positive DM. CONCLUSIONS: Unique gene expression profiles in muscle biopsies from patients with MSA-defined subtypes of myositis and IBM suggest that different pathological mechanisms underly muscle damage in each of these diseases.


Assuntos
Doenças Autoimunes/genética , Doenças Musculares/genética , Miosite de Corpos de Inclusão/genética , Miosite/genética , Adulto , Animais , Apolipoproteínas A/metabolismo , Biópsia , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/metabolismo , Moléculas de Adesão Celular/metabolismo , Técnicas de Cultura de Células , Dermatomiosite/genética , Fatores de Transcrição de Resposta de Crescimento Precoce/metabolismo , Feminino , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Interleucina-8/metabolismo , Aprendizado de Máquina , Masculino , Camundongos , Mucoproteínas/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miosite/patologia , Polimiosite/genética , Transcriptoma
4.
Adv Exp Med Biol ; 1253: 95-104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32445092

RESUMO

Genomic predisposition fails to fully explain the onset of complex diseases, which is well illustrated by the largely incomplete concordance among monozygotic twins. Epigenetic mechanisms, including DNA methylation, chromatin remodeling, and non-coding RNA, are the link between environmental stimuli and disease onset on a permissive genetic background in autoimmune and chronic inflammatory diseases. Autoimmune diseases now include almost 100 conditions and are estimated to cumulatively affect up to 5% of the world population with a healthcare expenditure superior to cancer worldwide. Many advances in medicine have been made to treat these conditions but there are still gaps, and an innovative and efficient therapy is needed. Systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren syndrome, polymyositis, and dermatomyositis. Monozygotic twins discordant for any disease offer an ideal study design as they are matched for many factors, including genetic variation and this is a real advantage for epigenetics study. We will herein discuss the available data in the epigenetic differences leading to disease discordance in MZ twins for systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis.


Assuntos
Epigênese Genética , Epigenômica/métodos , Estudos em Gêmeos como Assunto , Gêmeos Monozigóticos/genética , Doenças Autoimunes/genética , Metilação de DNA , Humanos , Inflamação/genética
5.
PLoS Genet ; 16(4): e1008734, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32310941

RESUMO

Genome-wide association studies (GWASs) have identified many SNPs associated with various common diseases. Understanding the biological functions of these identified SNP associations requires identifying disease/trait relevant tissues or cell types. Here, we develop a network method, CoCoNet, to facilitate the identification of trait-relevant tissues or cell types. Different from existing approaches, CoCoNet incorporates tissue-specific gene co-expression networks constructed from either bulk or single cell RNA sequencing (RNAseq) studies with GWAS data for trait-tissue inference. In particular, CoCoNet relies on a covariance regression network model to express gene-level effect measurements for the given GWAS trait as a function of the tissue-specific co-expression adjacency matrix. With a composite likelihood-based inference algorithm, CoCoNet is scalable to tens of thousands of genes. We validate the performance of CoCoNet through extensive simulations. We apply CoCoNet for an in-depth analysis of four neurological disorders and four autoimmune diseases, where we integrate the corresponding GWASs with bulk RNAseq data from 38 tissues and single cell RNAseq data from 10 cell types. In the real data applications, we show how CoCoNet can help identify specific glial cell types relevant for neurological disorders and identify disease-targeted colon tissues as relevant for autoimmune diseases.


Assuntos
Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla/métodos , Software , Transcriptoma , Doenças Autoimunes/genética , Humanos , Doenças do Sistema Nervoso/genética , Especificidade de Órgãos , Característica Quantitativa Herdável , RNA-Seq/métodos
6.
Autoimmun Rev ; 19(6): 102532, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32234402

RESUMO

The human leukocytes antigen (HLA)-DRB1*16:02 allele has been suggested to be associated with many autoimmune diseases. However, a validation of the results of the different studies by a comprehensive analysis of the corresponding meta data is lacking. In this study, we performed a meta-analysis of the association between HLA-DRB1*16:02 allele with various autoimmune disorders. Our analysis shows that HLA-DRB1*16:02 allele was associated with systemic lupus erythematosus, anti-N-Methyl-d-Aspartate receptor (NMDAR) encephalitis, Graves' disease, myasthenia gravis, neuromyelitis optica and antibody-associated systemic vasculitis with microscopic polyangiitis (AASV-MPA). However, no such association was found for multiple sclerosis, autoimmune hepatitis type 1, rheumatoid arthritis, type 1 diabetes and Vogt-Koyanagi-Harada syndrome. Re-analysis of the studies after their categorization into autoantibody-dependent and T cell-dependent autoimmune diseases revealed that the HLA-DRB1*16:02 allele was strongly associated with disorder predominantly mediated by autoantibodies (OR = 1.93; 95% CI = 1.63-2.28, P = 1.95 × 10-14) but not with those predominantly mediated by T cells (OR = 1.08; 95% CI = 0.87-1.34, P = .474). In addition, amino acid sequence alignment of common HLA-DRB1 subtypes demonstrated that HLA-DRB1*16:02 carries a unique motif of amino acid residues at position 67-74 which encodes the third hypervariable region. Taken together, the distinct pattern of disease association and the unique amino acid sequence of the third hypervariable region of the HLA-DRB1 provide some hints on how HLA-DRB1*16:02 is involved in the pathogenesis of autoimmune diseases.


Assuntos
Alelos , Autoanticorpos/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Humanos
8.
Best Pract Res Clin Endocrinol Metab ; 34(1): 101412, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32265102

RESUMO

An adjuvant is an immunological or pharmacological substance or group of substances that can be added to a given agent to enhance its effect in terms of efficacy, effectiveness and potency. Different mechanisms have been hypothesized underlying the action of the adjuvant, including boosting immune (innate and adaptive) response: this generally results in sparing the necessary amount of the agent and can potentially reduce the frequency of the needed number of therapeutic interventions. Adjuvants can be commonly found in vaccines, immunization products, mineral oils, cosmetics, silicone breast implants and other therapeutic/medical devices, being usually safe and effective. However, in a fraction of genetically susceptible and predisposed subjects, the administration of adjuvants may lead to the insurgence of serious side-effects, called "autoimmune/inflammatory syndrome by adjuvants" (ASIA) or Shoenfeld's syndrome. The present review is aimed at focusing on the "endocrine pebbles" of the mosaic of autoimmunity and of the ASIA syndrome, collecting together 54 cases of sub-acute thyroiditis, 2 cases of Hashimoto's thyroiditis, 11 cases of primary ovarian failure/primary ovarian insufficiency, 13 cases of autoimmune diabetes type 1, and 1 case of autoimmune adrenal gland insufficiency occurred after exposure to adjuvants.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Autoimunidade/efeitos dos fármacos , Doenças do Sistema Endócrino/induzido quimicamente , Doenças Autoimunes/genética , Autoimunidade/genética , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Doenças do Sistema Endócrino/genética , Doenças do Sistema Endócrino/imunologia , Predisposição Genética para Doença , Humanos , Fatores de Risco , Síndrome
9.
Allergol. immunopatol ; 48(2): 182-186, mar.-abr. 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-191823

RESUMO

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is an autoimmune rheumatic disease, which affects primarily the joints in children under 16 years old. The etiology of JIA is yet unknown but research has shown that JIA is a multifactorial disease implicating several genes and environmental factors. Environmental factors affect immune cells via epigenetic mechanisms. One of the most important epigenetic mechanisms is DNA methylation catalyzed by DNA methyltransferases (DNMTs) and usually associated with gene silencing. In this study, we analyzed the expression of three DNA methyltransferases namely DNMT1, DNMT3a and DNMT3b in peripheral blood mononuclear cells (PBMCs) of patients with JIA and compared it with the expression of these genes in healthy young individuals. MATERIALS AND METHODS: Peripheral blood mononuclear cells of 28 JIA patients and 28 healthy controls were isolated. Total RNA was extracted, cDNA was synthesized and the transcript levels of DNMTs were analyzed by quantitative PCR. RESULTS: Analysis of DNMT1, DNMT3a and DNMT3b relative gene expression in PBMCs of JIA patients and control individuals shows that the expression of DNMT1 and DNMT3a is reduced significantly by 7 folds and 5.5 folds, respectively, in JIA patients compared to healthy controls. Furthermore, the expression of all three DNMTs were significantly and drastically reduced in young affected males compared to healthy males. CONCLUSION: This study shows that the expression of DNMTs is reduced in JIA patients and this reduction is severe in male JIA patients


No disponible


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Regulação da Expressão Gênica/imunologia , Artrite Juvenil/diagnóstico , Doenças Autoimunes/imunologia , Metilação de DNA , Leucócitos Mononucleares/metabolismo , Artrite Juvenil/imunologia , Epigenômica , Doenças Autoimunes/genética , Metilases de Modificação do DNA/imunologia , Leucócitos Mononucleares/imunologia
11.
Mol Immunol ; 121: 7-19, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32135401

RESUMO

Autoimmunity and cancer affect millions worldwide and both, in principal, result from dysregulated immune responses. There are many well-known molecules involved in immunological process playing as a double-edged sword, by which associating autoimmune diseases and cancer. In this regard, Endoplasmic reticulum aminopeptidases (ERAP) 1, which belongs to the M1 family of aminopeptidases, plays a central role as a "molecular ruler", proteolyzing of N-terminal of the antigenic peptides before their loading onto HLA-I molecules for antigen presentation in the Endoplasmic Reticulum (ER). Several genome-wide association studies (GWAS) highlighted the significance of ERAP1 and ERAP2 in autoimmune diseases, including Ankylosing spondylitis, Psoriasis, Bechet's disease, and Birdshot chorioretinopathy, as well as in cancers. The expression of ERAP1/2 is mostly altered in different cancers compared to normal cells, but how this affects anti-cancer immune responses and cancer growth has been little explored. Recent studies on the immunological outcomes and the catalytic functions of ERAP1 and ERAP2 have provided a better understanding of their potential pathogenetic role in autoimmunity and cancer. In this review, we summarize the role of ERAP1 and ERAP2 in the autoimmune diseases and cancer immunity based on the recent advances in GWAS studies.


Assuntos
Aminopeptidases/genética , Apresentação do Antígeno/genética , Doenças Autoimunes/genética , Antígenos de Histocompatibilidade Menor/genética , Neoplasias/imunologia , Aminopeptidases/antagonistas & inibidores , Aminopeptidases/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Modelos Animais de Doenças , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Antígenos de Histocompatibilidade Menor/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Polimorfismo de Nucleotídeo Único/imunologia
12.
Clin Immunol ; 214: 108376, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32135276

RESUMO

Primary immunodeficiencies (PIDs) are a heterogeneous group of monogenic inborn errors of immunity. The genetic causes of these diseases can be identified using whole exome sequencing (WES). Here, DNA samples from 106 patients with a clinical suspicion of PID were subjected to WES in order to test the diagnostic yield of this test in a highly consanguineous community. A likely genetic diagnosis was achieved in 70% of patients. Several factors were considered to possibly influence the diagnostic rate of WES among our cohort including early age, presence of consanguinity, family history suggestive of PID, the number of family members who underwent WES and the clinical phenotype of the patient. The highest diagnostic rate was in patients with combined immunodeficiency or with a syndrome. Notably, WES findings altered the clinical management in 39% (41/106) of patients in our cohort. Our findings support the use of WES as an important diagnostic tool in patients with suspected PID, especially in highly consanguineous communities.


Assuntos
Mutação , Doenças da Imunodeficiência Primária/diagnóstico , Sequenciamento Completo do Exoma , Adolescente , Adulto , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Criança , Pré-Escolar , Tomada de Decisão Clínica , Consanguinidade , Gerenciamento Clínico , Feminino , Genótipo , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Recém-Nascido , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/genética , Israel/epidemiologia , Masculino , Doenças da Imunodeficiência Primária/epidemiologia , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/terapia , Adulto Jovem
13.
Nat Commun ; 11(1): 1237, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144282

RESUMO

Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we use seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in five disease-relevant immune cell lines, based on a set of features related to regulatory potential. Trait/disease-associated variants are enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 have at least one variant meeting one or both of these criteria, 5 of which are further supported by genetic fine-mapping. Our work provides a comprehensive strategy to characterize genetic variation at important disease-associated loci, and aids in the effort to identify trait causal genetic variants.


Assuntos
Doenças Autoimunes/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Linhagem Celular Tumoral , Predisposição Genética para Doença , Variação Genética/imunologia , Haplótipos/genética , Haplótipos/imunologia , Humanos , Desequilíbrio de Ligação , Herança Multifatorial/imunologia , Estudo de Prova de Conceito
14.
Autoimmun Rev ; 19(5): 102508, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173518

RESUMO

The past decade has witnessed a significant paradigm shift in the clinical approach to autoimmune diseases, lead primarily by initiatives in precision medicine, precision health and precision public health initiatives. An understanding and pragmatic implementation of these approaches require an understanding of the drivers, gaps and limitations of precision medicine. Gaining the trust of the public and patients is paramount but understanding that technologies such as artificial intelligences and machine learning still require context that can only be provided by human input or what is called augmented machine learning. The role of genomics, the microbiome and proteomics, such as autoantibody testing, requires continuing refinement through research and pragmatic approaches to their use in applied precision medicine.


Assuntos
Doenças Autoimunes , Medicina de Precisão , Autoanticorpos/análise , Autoanticorpos/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Genômica , Humanos , Aprendizado de Máquina , Proteômica
16.
Zhonghua Er Ke Za Zhi ; 58(3): 218-222, 2020 Mar 02.
Artigo em Chinês | MEDLINE | ID: mdl-32135594

RESUMO

Objective: To explore the clinical phenotype, immunological features, pathogenesis and gene variation of a case with A20 haploinsufficiency (HA20). Methods: A patient diagnosed with tumor necrosis factor α-induced protein 3 (TNFAIP3) mutated HA20 was admitted into Shenzhen Children's Hospital in May,2019.The clinical data was analyzed. Flow cytometry was used to detect the patient's peripheral blood lymphocyte subsets, and also, the percentage of follicular helper T cell (TFH) cells in the patient and thirteen healthy controls. After the construction of empty vector, wild-type and mutant plasmid vectors, a wild-type or mutant overexpression system of the TNFAIP3 gene was established in 293T cells and Hela cells. Then, the expression level of A20 in 293T cells and the expression of inhibitor K binding α (IKBα) in green fluorescent protein (GFP)+Hela cells before and after tumor necrosis factor α (TNF-α) stimulation were measured, to verify the pathogenicity of this variation. Results: A 5 years and 11 months old boy, presented with recurrent oral ulcer, abdominal pain, joint swelling and arthralgia. Oral ulcer, chronic skin rashes, knee joint swelling were observed. The levels of inflammatory markers were increased. Colonoscopy showed congestion of mucosa and multiple ulcers in terminal ileum and ileocecus. The absolute number of naive B cells was 124×10(6) cells/L (reference range 147×10(6)-431×10(6) cells/L), accounting for 0.430 of the total B cells (reference range 0.484-0.758). Compared to healthy controls (0.016-0.071), the percentage of TFH cells in CD4(+)T cells was much lower (0.008).A heterozygous mutation of TNFAIP3 gene (c.909_913 del, p.L303fs) was identified by genetic analysis. In vitro study showed that truncated A20 protein was expressed in TNFAIP3 mutant overexpressed 293T cells, which verified the pathogenicity of this variation. Besides, after TNF-α stimulation, the degradation rate of IkBα protein in mutant overexpressed Hela cells (35%) was between the other two groups (15% in the wild-type group and 57% in the non-loaded group). Conclusions: This case with HA20 due to a de novo TNFAIP3 gene mutation presents with early onset Behcet-like autoinflammatory syndrome. This variation leads to expression of truncated A20 protein, enhanced degradation of IkBα, and further activation of nuclear factor κB signaling pathway.


Assuntos
Doenças Autoimunes , Haploinsuficiência , NF-kappa B , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Pré-Escolar , Haploinsuficiência/genética , Células HeLa , Heterozigoto , Humanos , Masculino , Fenótipo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
17.
PLoS One ; 15(3): e0230052, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214327

RESUMO

Biallelic mutations in ACP5, encoding tartrate-resistant acid phosphatase (TRACP), have recently been identified to cause the inherited immuno-osseous disorder, spondyloenchondrodysplasia (SPENCD). This study was undertaken to characterize the eight reported missense mutations in ACP5 associated with SPENCD on TRACP expression. ACP5 mutant genes were synthesized, transfected into human embryonic kidney (HEK-293) cells and stably expressing cell lines were established. TRACP expression was assessed by cytochemical and immuno-cytochemical staining with a panel of monoclonal antibodies. Analysis of wild (WT) type and eight mutant stable cell lines indicated that all mutants lacked stainable enzyme activity. All ACP5 mutant constructs were translated into intact proteins by HEK-293 cells. The mutant TRACP proteins displayed variable immune reactivity patterns, and all drastically reduced enzymatic activity, revealing that there is no gross inhibition of TRACP biosynthesis by the mutations. But they likely interfere with folding thereby impairing enzyme function. TRACP exists as two isoforms. TRACP 5a is a less active monomeric enzyme (35kD), with the intact loop peptide and TRACP 5b is proteolytically cleaved highly active enzyme encompassing two subunits (23 kD and 16 kD) held together by disulfide bonds. None of the mutant proteins were proteolytically processed into isoform 5b intracellularly, and only three mutants were secreted in significant amounts into the culture medium as intact isoform 5a-like proteins. Analysis of antibody reactivity patterns revealed that T89I and M264K mutant proteins retained some native conformation, whereas all others were in "denatured" or "unfolded" forms. Western blot analysis with intracellular and secreted TRACP proteins also revealed similar observations indicating that mutant T89I is amply secreted as inactive protein. All mutant proteins were attacked by Endo-H sensitive glycans and none could be activated by proteolytic cleavage in vitro. In conclusion, determining the structure-function relationship of the SPENCD mutations in TRACP will expand our understanding of basic mechanisms underlying immune responsiveness and its involvement in dysregulated bone metabolism.


Assuntos
Doenças Autoimunes/patologia , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Osteocondrodisplasias/patologia , Fosfatase Ácida Resistente a Tartarato/metabolismo , Substituição de Aminoácidos , Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Glicosilação , Humanos , Proteínas Mutantes/química , Proteínas Mutantes/genética , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/genética , Proteólise , Fosfatase Ácida Resistente a Tartarato/química , Fosfatase Ácida Resistente a Tartarato/genética
18.
Clin Immunol ; 213: 108366, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32092471

RESUMO

The nuclease Artemis is a enzyme for V(D)J recombination allowing for the creation of T and B lymphocytes as well as for the repair of radiation-induced DNA double strand breaks encoded by the DCLRE1C gene. Artemis-null mutations are a known cause of severe combined immunodeficiencies (SCIDs) with radiosensitivity. Hypomorphic mutations in Artemis have been reported to cause a "leaky SCID"" phenotype, typically with hypogammaglobulinemia. We present four patients, all harboring the same unique hypomorphic mutation in the DCLRE1C gene, an 8-base pair insertion (c.1299_1306dup, p.Cys436*) presenting with a relatively mild phenotype including pulmonary infectious EBV-related lymphoproliferative diseases, an autoimmune phenomenon. Non-typical findings of IgG hypergammaglobulinemia accompanied by IgA and IgE deficiency were recorded in all patients. The typical viral, fungal, and opportunistic infections were absent, and patients reached a relatively old age.


Assuntos
Proteínas de Ligação a DNA/genética , Endonucleases/genética , Hipergamaglobulinemia/genética , Imunoglobulina G , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Adolescente , Doenças Autoimunes/genética , Feminino , Humanos , Deficiência de IgA/genética , Imunoglobulina E/deficiência , Transtornos Linfoproliferativos/genética , Masculino , Mutação , Fenótipo , Imunodeficiência Combinada Severa/complicações
19.
Cytogenet Genome Res ; 160(2): 80-84, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32018271

RESUMO

Unbalanced X;autosome translocations are a rare occurrence with a wide variability in clinical presentation in which the X chromosome unbalance is usually mitigated by a favorable X inactivation pattern. In most cases, this compensation mechanism is incomplete, and the patients show a syndromic clinical presentation. We report the case of a family with 4 women, of 3 different generations, carrying an unbalanced X;7 translocation with a derivative X;7 chromosome and showing a skewed X inactivation pattern with a preferential activation of the normal X. None of the carriers show intellectual disability, and all of them have a very mild clinical presentation mainly characterized by gynecological/hormonal issues and autoimmune disorders. We underline the necessity of family testing for a correct genetic consultation, especially in the field of prenatal diagnosis. We indeed discuss the fact that X;autosome translocations may lead to self-immunization, as skewed X chromosome inactivation has already been proved to be related to autoimmune disorders.


Assuntos
Doenças Autoimunes/genética , Transtornos Cromossômicos/genética , Cromossomos Humanos X/genética , Translocação Genética , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Linhagem , Fenótipo , Gravidez , Inativação do Cromossomo X
20.
PLoS Biol ; 18(2): e3000590, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32069316

RESUMO

DO (HLA-DO, in human; murine H2-O) is a highly conserved nonclassical major histocompatibility complex class II (MHC II) accessory molecule mainly expressed in the thymic medulla and B cells. Previous reports have suggested possible links between DO and autoimmunity, Hepatitis C (HCV) infection, and cancer, but the mechanism of how DO contributes to these diseases remains unclear. Here, using a combination of various in vivo approaches, including peptide elution, mixed lymphocyte reaction, T-cell receptor (TCR) deep sequencing, tetramer-guided naïve CD4 T-cell precursor enumeration, and whole-body imaging, we report that DO affects the repertoire of presented self-peptides by B cells and thymic epithelium. DO induces differential effects on epitope presentation and thymic selection, thereby altering CD4 T-cell precursor frequencies. Our findings were validated in two autoimmune disease models by demonstrating that lack of DO increases autoreactivity and susceptibility to autoimmune disease development.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença/genética , Antígenos de Histocompatibilidade Classe II/genética , Animais , Células Apresentadoras de Antígenos/imunologia , Doenças Autoimunes/imunologia , Autoimunidade/genética , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Colágeno/administração & dosagem , Colágeno/imunologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/imunologia , Peptídeos/imunologia , Células Precursoras de Linfócitos T/imunologia , Timo/imunologia
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