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1.
BMC Med Genet ; 20(1): 157, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31510946

RESUMO

BACKGROUND: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by germline mutations in the Bruton tyrosine kinase (BTK) gene on X chromosome. These mutations disturb B-cell development, decrease immunoglobulin levels, increase susceptibility to infection or neoplasms, and increase the risk of developing colorectal cancer (CRC). For occasional cases of CRC have been reported in XLA patients, low levels of B lymphocytes and immunoglobulins induced by congenital immune disorder make them more susceptible to drug-related toxicities (DRT). Therefore, gene sequencing, therapeutic drug monitoring and any possible measurement to predict DRT should be considered before determining the course of chemotherapy for XLA patients with CRC. CASE PRESENTATION: In this study, we reported a 21-year-old male who developed metastatic CRC in the context of XLA. Since the whole exome sequencing and therapeutic drug monitoring did not reveal any predictive markers of DRT, we applied standard first-line chemotherapy to the patient. However, progressive disease occurred after the fifth treatment cycle. Therefore, the administration of oxaliplatin was changed to irinotecan as second-line therapy. After that, the patient firstly suffered from severe hypocalcemia and eventually died due to metastatic CRC after the eighth treatment cycle. The overall survival time was 7.5 months. CONCLUSIONS: This study reported the first written record of a Chinese XLA patient with metastatic CRC and severe hypocalcemia. Whole exome sequencing and bioinformatic analysis indicated the somatic mutations in ABCA6, C6 and PAX3 genes might contribute to the early-onset and metastasis CRC. Besides, a number of germline mutations in genes related to calcium metabolism (CACNA2D4, CD36, etc.) and the administration of irinotecan were speculated to be the causes of severe hypocalcemia. We therefore suggested that in order to avoid severe DRT, clinicians should take genetic background and therapeutic drug monitoring into consideration while planning chemotherapy treatment for XLA patients with CRC.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Neoplasias Colorretais/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença/genética , Hipocalcemia/complicações , Irinotecano/administração & dosagem , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Agamaglobulinemia/diagnóstico por imagem , Grupo com Ancestrais do Continente Asiático , Linfócitos B , Canais de Cálcio Tipo L/genética , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Complemento C6/genética , Monitoramento de Medicamentos , Tratamento Farmacológico , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Humanos , Hipocalcemia/induzido quimicamente , Imunoglobulinas , Irinotecano/uso terapêutico , Masculino , Mutação , Oxaliplatina/uso terapêutico , Fator de Transcrição PAX3/genética , Sequenciamento Completo do Exoma , Adulto Jovem
3.
Infez Med ; 27(1): 73-76, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30882382

RESUMO

Agammaglobulinemia is a congenital deficit of humoral immunity characterized by a decreased level or complete absence of immunoglobulins and profound reduction of B-lymphocytes associated with an increased risk of life-threatening bacterial infection. We report a case of invasive Pseudomonas aeruginosa severe skin and soft tissue infection treated with vacuum-assisted closure and antibiotics in a toddler with a previously unreported mutation of the Bruton tyrosin kinase gene.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa , Dermatopatias Bacterianas/microbiologia , Humanos , Lactente , Úlcera da Perna/terapia , Masculino , Mutação , Tratamento de Ferimentos com Pressão Negativa , Infecções por Pseudomonas/terapia , Dermatopatias Bacterianas/terapia
4.
Nat Immunol ; 20(3): 350-361, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718914

RESUMO

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.


Assuntos
Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Proteínas de Transporte de Cátions/imunologia , Zinco/imunologia , Agamaglobulinemia/genética , Agamaglobulinemia/metabolismo , Animais , Linfócitos B/metabolismo , Proteínas de Transporte de Cátions/deficiência , Proteínas de Transporte de Cátions/genética , Pré-Escolar , Citosol/imunologia , Citosol/metabolismo , Modelos Animais de Doenças , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Linhagem , Zinco/metabolismo
5.
Allergol. immunopatol ; 47(1): 24-31, ene.-feb. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-180767

RESUMO

Background: X-linked agammaglobulinemia (XLA) is characterized by absent or severely reduced B cells, low or undetectable immunoglobulin levels, and clinically by extracellular bacterial infections which mainly compromise the respiratory tract. We aimed to analyze the clinical, immunological and genetic characteristics of 22 male children with XLA. Methods: Twenty-two children with XLA from 12 unrelated families were enrolled in this study. Clinical and demographic features of patients, serum immunoglobulin levels, percentage of B cells and BTK gene mutations were reviewed retrospectively. Results: We identified 12 different mutations in 22 patients from 12 unrelated families. The most frequent type of mutation was premature stop codon (33.3%). Ten mutations had been reported previously including three missense mutations (c.1774T>C, c.1684C>T, c.83G>T), three premature stop codons (c.1558C>T, c.1573C>T, c.753G>A), two splice-site (c.683-1G>A, c.1567-12_1567-9delTTTG) and two small nucleotide deletions (c.902-904_delAAG, c.179_181delAGA). Two novel mutations of the BTK gene were also presented and included one splice-site mutation (c.391+1G>C) and one premature stop codon mutation (c.1243_1243delG). Six out of 12 mutations of the BTK gene were located in the SH1 domain, two in the PH domain, two in the SH3 domain and two in the SH2 domain. Three patients had a history of severe infection before diagnosis. We did not identify any correlation between severity of clinical symptoms and the genotype. Conclusions: Our results show that mutations in southeast Turkey could be different from those in the rest of the world and molecular genetic tests are an important tool for early confirmed diagnosis of XLA


No disponible


Assuntos
Humanos , Masculino , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Agamaglobulinemia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Genótipo , Mutação/genética , Agamaglobulinemia/fisiopatologia , Progressão da Doença , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Predisposição Genética para Doença
7.
Immunogenetics ; 71(4): 299-305, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30610243

RESUMO

Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by autosomal recessive mutations in Cat Eye Syndrome Chromosome Region 1 (CECR1) gene. In this report, we aimed to describe the clinical manifestations, immunological features, genotype, and treatments of one Chinese patient with novel CECR1 gene mutations. This patient initially presented with recurrent fever and rashes from the age of 3 months, but no pathogen was found. She then developed dry gangrene of the fingers at 5 months of age. Laboratory examinations revealed elevated levels of C-reactive protein and thrombocytes. The expression of interleukin-6 (IL-6) and IL-8 were both elevated. Sequencing results revealed that she had compound heterozygous mutations in CECR1 gene (c.1211T>C, p.Phe404Ser and c.1114 G>A, p.Val372Met). Subsequently, treatment with anti-IL-6 (tocilizumab) was started. However, she developed blurred vision in the right eye with occlusion of the central retinal artery, accompanied by unsteady gait. Magnetic resonance imaging (MRI) showed infarction of the right thalamus. Finally, she underwent hematopoietic stem cell transplantation (HSCT) and is currently in remission. Our findings suggest that HSCT could cure this disease.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Doenças Hereditárias Autoinflamatórias/terapia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Imunodeficiência Combinada Severa/terapia , Adenosina Desaminase/genética , Agamaglobulinemia/diagnóstico por imagem , Agamaglobulinemia/genética , Grupo com Ancestrais do Continente Asiático , Sequência de Bases , China , Feminino , Doenças Hereditárias Autoinflamatórias/diagnóstico por imagem , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Lactente , Imagem por Ressonância Magnética , Indução de Remissão , Análise de Sequência de DNA , Imunodeficiência Combinada Severa/diagnóstico por imagem , Imunodeficiência Combinada Severa/genética
8.
BMC Med Genet ; 20(1): 11, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30634948

RESUMO

BACKGROUND: Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder resulting in early-onset hearing impairment, gradual dystonia and optic atrophy. MTS is caused by variations in the nuclear TIMM8A gene, which is involved in mitochondrial transport of metabolites. This study aimed to identify the pathogenic gene variations in three Chinese families associated with predicted MTS with or without X-linked agammaglobulinaemia. METHODS: Otologic examinations, vestibular, neurological, optical and other clinical evaluations were conducted on the family members. Targeted genes capture combining next generation sequencing (NGS) was performed, and then Sanger sequencing was used to confirm the causative variation. RESULTS: A novel variation, c.232_233insCAAT, in TIMM8A was identified as the pathogenic variation in one Chinese family. This variation co-segregated with the most frequent phenotypic deafness and was absent in the 1000 Genomes Project, ExAC and 1751 ethnicity-matched controls. Clinically, otological examinations illustrated the typical postsynaptic auditory neuropathy for the proband without the symptoms of dystonia or optic atrophy. MRI demonstrated abnormal small cochlear symmetric nerves, while the vestibular function appeared to be less influenced. Furthermore, we found another two TIMM8A variations, the deletion c.133_135delGAG and a copy number variation (CNV) including the TIMM8A gene, in two independent case, when we performed NGS on an auditory neuropathy population. CONCLUSION: We identified two novel variations in the TIMM8A gene (c.232_233insCAAT and c.133_135delGAG) and a CNV including the TIMM8A gene in three independent Chinese families with predicted MTS. To our knowledge, this is the first report of TIMM8A variations being identified in a Chinese population. Our results enrich the variation spectrum of TIMM8A and clinical heterogeneity of MTS. Genetic detection and diagnosis is a powerful tool for better understanding and managing syndromic hearing impairments, such as MTS, before they become full-blown.


Assuntos
Transtornos da Surdocegueira/diagnóstico , Transtornos da Surdocegueira/genética , Distonia/diagnóstico , Distonia/genética , Testes Genéticos/métodos , Perda Auditiva Central/diagnóstico , Perda Auditiva Central/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Proteínas de Membrana Transportadoras/genética , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Fenótipo , Agamaglobulinemia/genética , Grupo com Ancestrais do Continente Asiático/genética , Variações do Número de Cópias de DNA , Surdez/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Variação Genética , Humanos , Masculino , Mutação , Linhagem
9.
Clin Immunol ; 198: 100-101, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30063982

RESUMO

Autosomal Recessive Agammaglobulinemia (ARA) is an uncommon type of primary immunodeficiency characterized by mutations in genes responsible for early B cell differentiation and function. One such gene is the TCF3 gene, which encodes a transcription factor important for immunoglobulin gene expression. We present the case of a 9 year old girl with history of diarrhea and recurrent pneumonias. Laboratory investigation showed significantly reduced levels of immunoglobulins along with a significant fall in the number of CD19+ cells. Genetic analysis identified a TCF3 gene base deletion covering exons 5-11.


Assuntos
Agamaglobulinemia/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Mutação , Criança , Feminino , Humanos
10.
Allergol Immunopathol (Madr) ; 47(1): 24-31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30072168

RESUMO

BACKGROUND: X-linked agammaglobulinemia (XLA) is characterized by absent or severely reduced B cells, low or undetectable immunoglobulin levels, and clinically by extracellular bacterial infections which mainly compromise the respiratory tract. We aimed to analyze the clinical, immunological and genetic characteristics of 22 male children with XLA. METHODS: Twenty-two children with XLA from 12 unrelated families were enrolled in this study. Clinical and demographic features of patients, serum immunoglobulin levels, percentage of B cells and BTK gene mutations were reviewed retrospectively. RESULTS: We identified 12 different mutations in 22 patients from 12 unrelated families. The most frequent type of mutation was premature stop codon (33.3%). Ten mutations had been reported previously including three missense mutations (c.1774T>C, c.1684C>T, c.83G>T), three premature stop codons (c.1558C>T, c.1573C>T, c.753G>A), two splice-site (c.683-1G>A, c.1567-12_1567-9delTTTG) and two small nucleotide deletions (c.902-904_delAAG, c.179_181delAGA). Two novel mutations of the BTK gene were also presented and included one splice-site mutation (c.391+1G>C) and one premature stop codon mutation (c.1243_1243delG). Six out of 12 mutations of the BTK gene were located in the SH1 domain, two in the PH domain, two in the SH3 domain and two in the SH2 domain. Three patients had a history of severe infection before diagnosis. We did not identify any correlation between severity of clinical symptoms and the genotype. CONCLUSIONS: Our results show that mutations in southeast Turkey could be different from those in the rest of the world and molecular genetic tests are an important tool for early confirmed diagnosis of XLA.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Genótipo , Mutação/genética , Adolescente , Agamaglobulinemia/fisiopatologia , Criança , Pré-Escolar , Progressão da Doença , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Predisposição Genética para Doença , Perfil Genético , Humanos , Lactente , Masculino , Linhagem , Polimorfismo Genético , Turquia , Adulto Jovem
11.
Artigo em Inglês | MEDLINE | ID: mdl-30559311

RESUMO

X-linked agammaglobulinemia (XLA, OMIM#300300) is a rare monogenic primary immunodeficiency caused by mutations in the Bruton tyrosine kinase (BTK) gene. XLA is characterized by insufficient immunoglobulin levels and susceptibility to life-threatening bacterial infections. We report on a patient that presented with ecthyma gangrenosum and septicemia. Rapid trio whole-genome sequencing (rWGS) revealed an apparently de novo hemizygous pathogenic variant (c.726dupT; p.Ile243TyrfsTer15) in the BTK gene. Metagenomic analysis of rWGS sequences that did not align to the human genome revealed 770 aligned to the Pseudomonas aeruginosa PAO1 genome. The patient was diagnosed with XLA and pseudomonal sepsis.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Ectima/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Tirosina Quinase da Agamaglobulinemia/metabolismo , Agamaglobulinemia/diagnóstico , Bacteriemia , Ectima/diagnóstico , Gangrena/microbiologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Síndromes de Imunodeficiência , Lactente , Masculino , Infecções por Pseudomonas/genética , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/patogenicidade , Sepse/genética , Sepse/metabolismo , Pele/microbiologia , Sequenciamento Completo do Genoma/métodos
12.
Am J Nurs ; 118(12): 72, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30461504
13.
Colomb Med (Cali) ; 49(3): 236-243, 2018 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-30410199

RESUMO

Bi-allelic mutations in LRBA (from Lipopolysaccharide-responsive and beige-like anchor protein) result in a primary immunodeficiency with clinical features ranging from hypogammaglobulinemia and lymphoproliferative syndrome to inflammatory bowel disease and heterogeneous autoimmune manifestations. LRBA deficiency has been shown to affect vesicular trafficking, autophagy and apoptosis, which may lead to alterations of several molecules and processes that play key roles for immunity. In this review, we will discuss the relationship of LRBA with the endovesicular system in the context of receptor trafficking, autophagy and apoptosis. Since these mechanisms of homeostasis are inherent to all living cells and not only limited to the immune system and also, because they are involved in physiological as well as pathological processes such as embryogenesis or tumoral transformation, we envisage advancing in the identification of potential pharmacological agents to manipulate these processes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Membrana Celular/metabolismo , Síndromes de Imunodeficiência/genética , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Animais , Apoptose/fisiologia , Autofagia/fisiologia , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/fisiopatologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Mutação
16.
Curr Opin Allergy Clin Immunol ; 18(6): 453-458, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30299399

RESUMO

PURPOSE OF REVIEW: Conventional gene therapy has been a successful, curative treatment modality for many primary immune deficiencies with significant improvements in the last decade. However, the risk of leukemic transformation with viral-mediated gene addition still remains, and unregulated gene addition is not an option for certain diseases in which the target gene is closely controlled. The recent bloom in genome modification platforms has created the opportunity to site-specifically correct mutated DNA base pairs or insert a corrective cDNA minigene while maintaining gene expression under control of endogenous regulatory elements. RECENT FINDINGS: There is an abundance of ongoing research utilizing programmable nucleases to facilitate site-specific gene correction of many primary immune deficiencies including X-linked severe combined immune deficiency, X-linked chronic granulomatous disease, Wiskott-Aldrich syndrome, X-linked hyper-IgM syndrome, X-linked agammaglobulinemia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked. In all, these studies have demonstrated the ability to integrate corrective DNA sequences at a precise location in the genome at rates likely to either cure or ameliorate disease. SUMMARY: Gene editing for primary immune deficiency (PID) has advanced to the point to that translation to clinical trials is likely to occur in the next several years. At the current pace of research in DNA repair mechanisms, stem cell biology, and genome-editing technology, targeted genome modification represents the next chapter of gene therapy for PID.


Assuntos
Agamaglobulinemia , Edição de Genes/métodos , Doenças Genéticas Ligadas ao Cromossomo X , Terapia Genética/métodos , Síndrome de Wiskott-Aldrich , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Animais , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/imunologia , Síndrome de Wiskott-Aldrich/terapia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia
17.
J Pediatr Endocrinol Metab ; 31(10): 1155-1159, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30243016

RESUMO

Background Infantile free sialic acid storage disease (ISSD) is a severe multisystemic disorder characterized by the accumulation of free sialic acid in lysosomes. Case presentation The patient presented prenatally with fetal ascites and large scrotal hernias, without pleural or pericardial effusion. During the infantile period, he was diagnosed with permanent isolated immunoglobulin G (IgG) hypogammaglobulinemia, which thus far has rarely been associated with ISSD. The analysis of the SLC17A5 gene revealed a novel homozygous 94 bp gene deletion. We further provide a detailed description of pre- and postnatal clinical and radiographic findings. Conclusions Fetal ascites could be the first sign of several lysosomal storage diseases (LSDs), including ISSD. The analysis of LSD gene panels is an effective approach to diagnosis in the case of non-specific symptoms and when specific biochemical tests are not easily available.


Assuntos
Agamaglobulinemia/complicações , Mutação , Transportadores de Ânions Orgânicos/genética , Doença do Armazenamento de Ácido Siálico/complicações , Simportadores/genética , Agamaglobulinemia/sangue , Agamaglobulinemia/diagnóstico por imagem , Agamaglobulinemia/genética , Encéfalo/diagnóstico por imagem , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Doença do Armazenamento de Ácido Siálico/sangue , Doença do Armazenamento de Ácido Siálico/diagnóstico por imagem , Doença do Armazenamento de Ácido Siálico/genética , Ultrassonografia
18.
Nat Commun ; 9(1): 3888, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250168

RESUMO

Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. Here we show that in small pre-B cells, the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 regulates over 7000 genes to repress proliferative and induce differentiation programs. However, BRWD1 does not regulate the expression of TFs required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations have B-cell transcriptional profiles and enhancer landscapes similar to those observed in Brwd1-/- mice. These data indicate that, in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B-cell development.


Assuntos
Agamaglobulinemia/genética , Proteínas de Transporte/metabolismo , Epigênese Genética/fisiologia , Linfopoese/genética , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Agamaglobulinemia/sangue , Animais , Proteínas de Transporte/genética , Diferenciação Celular/genética , Criança , Elementos Facilitadores Genéticos/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/fisiologia , Humanos , Leucócitos Mononucleares , Masculino , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Células Precursoras de Linfócitos B , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Interferente Pequeno/metabolismo , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
20.
Am J Physiol Heart Circ Physiol ; 315(5): H1358-H1367, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30095974

RESUMO

Heart-specific antibodies have been widely associated with myocardial infarction (MI). However, it remains unclear whether autoantibodies mediate disease progression or are a byproduct of cardiac injury. To disambiguate the role of immunoglobulins in MI, we characterized the development of ischemic heart failure in agammaglobulinemic mice (AID-/-µS-/-). Although these animals can produce functional B cells, they cannot synthesize secretory IgM (µS-/-) or perform Ig class switching (AID-/-), leading to complete antibody deficiency. Agammaglobulinemia did not affect overall post-MI survival but resulted in a significant reduction in infarct size. Echocardiographic analyses showed that, compared with wild-type infarcted control mice, AID-/-µS-/- mice exhibited improved cardiac function and reduced remodeling on day 56 post-MI. These differences remained significant even after animals with matched infarct sizes were compared. Infarcted AID-/-µS-/- mice also showed reduced myocardial expression levels of transcripts known to promote adverse remodeling, such as matrix metalloproteinase-9, collagen type I a1, collagen type III a1, and IL-6. An unbiased screening of the heart reactivity potential in the plasma of wild-type MI animals revealed the presence of antibodies that target the myocardial scar and collagenase-sensitive epitopes. Moreover, we found that IgG accumulated within the scar tissues of infarcted mice and remained in close proximity with cells expressing Fcγ receptors (CD16/32), suggesting the existence of an in situ IgG-Fcγ receptor axis. Collectively, our study results confirm that antibodies contribute to ischemic heart failure progression and provide novel insights into the mechanisms underlying this phenomenon. NEW & NOTEWORTHY Our study sheds some light on the long-standing debate over the relevance of autoantibodies in heart failure and might stimulate future research in the field. The observation of extracellular matrix-specific antibodies and the detection of Fcγ receptor-expressing cells within the scar provide novel insights into the mechanisms by which antibodies may contribute to adverse remodeling.


Assuntos
Agamaglobulinemia/imunologia , Autoanticorpos/imunologia , Insuficiência Cardíaca/prevenção & controle , Switching de Imunoglobulina , Imunoglobulina M/imunologia , Infarto do Miocárdio/imunologia , Miocardite/prevenção & controle , Miocárdio/imunologia , Agamaglobulinemia/complicações , Agamaglobulinemia/genética , Agamaglobulinemia/metabolismo , Animais , Autoanticorpos/metabolismo , Modelos Animais de Doenças , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrose , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Switching de Imunoglobulina/genética , Imunoglobulina M/genética , Imunoglobulina M/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocardite/imunologia , Miocardite/metabolismo , Miocardite/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular
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