Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.186
Filtrar
1.
Science ; 369(6500): 202-207, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32647003

RESUMO

Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in NCKAP1L, which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.


Assuntos
Actinas/metabolismo , Citocinas/biossíntese , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteínas de Membrana/fisiologia , Fator 1 de Ribosilação do ADP/metabolismo , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Humanos , Síndromes de Imunodeficiência/imunologia , Transtornos Linfoproliferativos/imunologia , Proteínas de Membrana/genética , Linhagem , Fosforilação , Família de Proteínas da Síndrome de Wiskott-Aldrich/química , Família de Proteínas da Síndrome de Wiskott-Aldrich/metabolismo
3.
F1000Res ; 92020.
Artigo em Inglês | MEDLINE | ID: mdl-32308976

RESUMO

The immune system is central to our interactions with the world in which we live and importantly dictates our response to potential allergens, toxins, and pathogens to which we are constantly exposed. Understanding the mechanisms that underlie protective host immune responses against microbial pathogens is vital for the development of improved treatment and vaccination strategies against infections. To that end, inherited immunodeficiencies that manifest with susceptibility to bacterial, viral, and/or fungal infections have provided fundamental insights into the indispensable contribution of key immune pathways in host defense against various pathogens. In this mini-review, we summarize the findings from a series of recent publications in which inherited immunodeficiencies have helped illuminate the interplay of human immunity and resistance to infection.


Assuntos
Imunidade , Síndromes de Imunodeficiência/genética , Infecções/genética , Infecções/imunologia , Resistência à Doença , Humanos , Sistema Imunitário
4.
Mol Immunol ; 121: 28-37, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32151906

RESUMO

INTRODUCTION: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). AIM: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. PATIENT AND METHODS: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide. RESULTS: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1ß and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient. CONCLUSION: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.


Assuntos
Autoimunidade/genética , Contratura/genética , Perda Auditiva Neurossensorial/genética , Histiocitose/genética , Síndromes de Imunodeficiência/genética , Proteínas de Transporte de Nucleosídeos/genética , Adolescente , Contratura/tratamento farmacológico , Contratura/imunologia , Contratura/patologia , Glucocorticoides/uso terapêutico , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/imunologia , Perda Auditiva Neurossensorial/patologia , Histiocitose/tratamento farmacológico , Histiocitose/imunologia , Histiocitose/patologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Inflamassomos/imunologia , Lisossomos/imunologia , Lisossomos/patologia , Masculino , Mitocôndrias/imunologia , Mitocôndrias/patologia , Resultado do Tratamento
5.
Transplant Proc ; 52(2): 647-652, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32035679

RESUMO

BACKGROUND: X-linked EDA-ID1 (ectodermal dysplasia, anhidrotic, with immunodeficiency 1, Online Mendelian Inheritance in Man [OMIM] 300291), or NEMO (nuclear factor kappa B essential modulator) deficiency syndrome, is caused by mutations in the IKBKG/NEMO gene. We report the case of a boy with EDA-ID1 who underwent allogeneic stem cell transplantation. METHODS: In early infancy, the patient developed an atypical, severe, initial manifestation resembling Omenn syndrome with infections, and he underwent allogeneic stem cell transplantation from an unrelated 9 of 10 HLA matched donor with a mismatch in the DQB1 allele after conditioning with treosulfan, fludarabine, thiotepa, and antithymocyte globulin (Grafalon). The post-transplant period was complicated by cytomegalovirus replication and mild, grade 2 graft vs host disease. Because of NEMO deficiency syndrome-associated enteropathy and continuous weight loss, parenteral nutrition was started and the patient was fed an elemental formula and a gluten-free diet. Over a period of 3 years, the patient had 7 incidents of blood stream infections caused by Staphylococci or gut-derived Gram-negative flora, with 1 incident of septic shock caused by Escherichia coli. The blood stream infection stopped after gastrointestinal tract decontamination was done once per month for 7-day courses alternately with rifaximin, vancomycin, and gentamicin sulfate. CONCLUSIONS: Patients with NEMO deficiency syndrome require very complex, multidisciplinary care, and immunodeficiency correction can only be observed as one of the critical points in patient care. Developmental problems, enteropathy with the need for intravenous hyperalimentation, and specific interventions for other clinical manifestations of multifaceted syndrome are needed for proper care.


Assuntos
Bussulfano/análogos & derivados , Displasia Ectodérmica/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Soro Antilinfocitário/uso terapêutico , Bussulfano/uso terapêutico , Humanos , Quinase I-kappa B/deficiência , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Lactente , Masculino , Tiotepa/uso terapêutico , Transplante Homólogo , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
6.
Eur J Endocrinol ; 182(3): C9-C12, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31972544

RESUMO

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients.


Assuntos
Doença de Addison/genética , Hiperplasia Suprarrenal Congênita/genética , Doença de Addison/complicações , Doença de Addison/diagnóstico , Doença de Addison/fisiopatologia , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/fisiopatologia , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/fisiopatologia , Encefalopatias/etiologia , Encefalopatias/genética , Encefalopatias/fisiopatologia , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Transtornos do Desenvolvimento Sexual/etiologia , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/fisiopatologia , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/fisiopatologia , Humanos , Hipoadrenocorticismo Familiar/complicações , Hipoadrenocorticismo Familiar/diagnóstico , Hipoadrenocorticismo Familiar/genética , Hipoadrenocorticismo Familiar/fisiopatologia , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/fisiopatologia , Técnicas de Diagnóstico Molecular , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/genética , Síndrome Nefrótica/fisiopatologia , Dermatopatias/etiologia , Dermatopatias/genética , Dermatopatias/fisiopatologia
7.
Int J Hematol ; 111(6): 897-902, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31993940

RESUMO

Regulatory T-cells (Tregs) are major mediators of mammalian self-tolerance via cytotoxic T-lymphocyte antigen 4 (CTLA4) signaling pathways. An immune dysregulation syndrome associated with heterozygous germline mutations in CTLA4 was recently reported. Clinical features include recurrent infections, systemic lymphadenopathy, various autoimmune conditions, hypogammaglobulinemia, and autosomal dominant inheritance, characteristic of primary immunodeficient disease (PID). PID symptoms are variable and few patients with sporadic de novo CTLA4 germline mutations have been described. Here, we report the case of a 26-year-old man with an immune dysregulation syndrome and a de novo CTLA4 germline mutation. The patient exhibited several clinical features associated with PID. Next-generation sequencing revealed a CTLA4 germline mutation, c.436G>A; p.G146R, in exon 2 of CTLA4. Sanger sequencing confirmed the patient was the only member of his family with this germline mutation. The patient was diagnosed with an immune dysregulation syndrome associated with de novo germline CTLA4 mutation, complicated by steroid-refractory rheumatoid arthritis. Treatment with abatacept, a CTLA4-immunoglobulin fusion molecule, was initiated, resulting in dramatic resolution of the patient's clinical symptoms. As PID with CTLA4 germline mutation is rare and patients may be under-diagnosed, physicians should be aware of the features of PID.


Assuntos
Abatacepte/uso terapêutico , Antígeno CTLA-4/genética , Mutação em Linhagem Germinativa , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/genética , Adulto , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/etiologia , Autoimunidade , Heterozigoto , Humanos , Tolerância Imunológica , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/imunologia , Masculino , Linfócitos T Reguladores/imunologia , Resultado do Tratamento
8.
Curr Opin Pediatr ; 31(6): 835-842, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31693595

RESUMO

PURPOSE OF REVIEW: Even with the evident improvement in knowledge about clinical and molecular aspects and the technology used to diagnose primary immunodeficiency diseases (PIDs), there is still a significant delay in recognition of these diseases in the developing world, specifically in Latin America. In this review, the goal is to outline the challenges that need to overcome for the diagnosis of PIDs and the optimization of resources available based on our experience. RECENT FINDINGS: We describe the advances achieved in the past decade in Latin America in terms of recognition of PIDs, as well as the need for improvement. We outline the need for continued medical education, the lack of resources for laboratory testing, and how genetic testing through next-generation sequencing (that is becoming a day-to-day tool) can be achieved in the developing world. SUMMARY: We aim to gather information about the limitations and challenges for the diagnosis of PIDs in a low-resource environment and the opportunities to benefit from the available advanced tools for diagnosis.


Assuntos
Doenças da Imunodeficiência Primária/diagnóstico , Análise de Sequência de DNA , Predisposição Genética para Doença , Testes Genéticos , Conhecimentos, Atitudes e Prática em Saúde , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndromes de Imunodeficiência/genética , América Latina
9.
BMC Med Genet ; 20(1): 182, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727123

RESUMO

BACKGROUND: Majeed syndrome is a rare, autosomal recessive autoinflammatory disorder first described in 1989. The syndrome starts during infancy with recurrent relapses of osteomyelitis typically associated with fever, congenital dyserythropoietic anemia (CDA), and often neutrophilic dermatosis. Mutations in the LPIN2 gene located on the short arm of chromosome 18 have been identified as being responsible for Majeed syndrome. CASE PRESENTATION: We report an 8-month-old boy, who presented with recurrent fever, mild to moderate anemia, and severe neutropenia. Erythrocyte sedimentation rate and C-reactive protein were elevated. Molecular testing identified a paternal splicing donor site variant c.2327 + 1G > C and a maternal frameshift variant c.1691_1694delGAGA (Arg564Lysfs*3) in LPIN2. CONCLUSIONS: Only a few cases with LPIN2 mutation have been reported, mainly in the Middle East with homozygous variants. Our patient exhibited a mild clinical phenotype and severe neutropenia, different from previous reports.


Assuntos
Anemia Diseritropoética Congênita/genética , Febre/complicações , Síndromes de Imunodeficiência/genética , Mutação , Neutropenia/complicações , Proteínas Nucleares/genética , Osteomielite/genética , Anemia Diseritropoética Congênita/complicações , Feminino , Humanos , Síndromes de Imunodeficiência/complicações , Lactente , Masculino , Osteomielite/complicações , Linhagem , Recidiva , Índice de Gravidade de Doença
11.
Allergol. immunopatol ; 47(5): 491-498, sept.-oct. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-186524

RESUMO

Background: Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by increased susceptibility to weakly virulent mycobacteria (Bacillus Calmette-Guérin [BCG] vaccines and environmental mycobacteria), Mycobacterium tuberculosis, Candida spp. and Salmonella spp. The aim of this study is to evaluate clinical features and immunological findings of MSMD patients with interleukin 12 receptor beta 1 (IL12Rβ1) deficiency. Methods: Among 117 screened patients with BCG infection following vaccination, 23 suspected MSMD subjects were recruited to this study by the exclusion of severe combined immunodeficiencies and chronic granulomatous diseases. Flow cytometric assessment for surface expression of IL12Rβ1 was performed. Moreover, the clinical and immunological data from the patients was evaluated. Results: A significant decrease (less than 1%) in the surface expression of IL12Rβ1 was reported in six cases which showed a significant increase in the count of lymphocytes (p = 0.009) and CD8+ T cells (p = 0.008) as compared to MSMD subjects with normal expression of surface IL12Rβ1. The frequency of disseminated BCGosis (50% vs. 20%, p = 0.29), recurrent infection (83.3% vs. 40%, p = 0.14) and salmonellosis (33.3% vs. 0.0%, p = 0.07) was higher in IL12Rβ1 deficient subjects than IL12Rβ1 sufficient individuals. Conclusion: MSMD patients with childhood onset of mycobacteriosis (mostly after BCG vaccination) and recurrent salmonellosis could be evaluated for IL12Rβ1 expression with flow cytometry for punctual diagnosis


No disponible


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Herpes Simples/imunologia , Síndromes de Imunodeficiência/imunologia , Mutação/genética , Mycobacterium bovis/imunologia , Infecções por Mycobacterium não Tuberculosas/imunologia , Simplexvirus/fisiologia , Receptores de Interleucina-12/genética , Predisposição Genética para Doença , Herpes Simples/genética , Síndromes de Imunodeficiência/genética , Infecções por Mycobacterium não Tuberculosas/genética , Estudos Prospectivos , Receptores de Interleucina-12/metabolismo
12.
Blood ; 134(18): 1510-1516, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31501153

RESUMO

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.


Assuntos
Doenças Autoimunes/genética , Síndromes de Imunodeficiência/genética , Linfoma/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Doenças Autoimunes/imunologia , Feminino , Predisposição Genética para Doença , Humanos , Síndromes de Imunodeficiência/imunologia , Linfoma/imunologia , Masculino , Linhagem , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/deficiência
13.
Nat Commun ; 10(1): 4364, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554793

RESUMO

Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/ß-dependent manner upon TLR stimulation. Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.


Assuntos
Imunidade Adaptativa/imunologia , Classe Ib de Fosfatidilinositol 3-Quinase/imunologia , Síndromes de Imunodeficiência/imunologia , Inflamação/imunologia , Microbiota/imunologia , Imunidade Adaptativa/genética , Animais , Células Cultivadas , Classe Ib de Fosfatidilinositol 3-Quinase/deficiência , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Modelos Animais de Doenças , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/metabolismo , Inflamação/genética , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
14.
Nat Immunol ; 20(10): 1322-1334, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31427773

RESUMO

We report a new immunodeficiency disorder in mice caused by a viable hypomorphic mutation of Snrnp40, an essential gene encoding a subunit of the U5 small nuclear ribonucleoprotein (snRNP) complex of the spliceosome. Snrnp40 is ubiquitous but strongly expressed in lymphoid tissue. Homozygous mutant mice showed hypersusceptibility to infection by murine cytomegalovirus and multiple defects of lymphoid development, stability and function. Cell-intrinsic defects of hematopoietic stem cell differentiation also affected homozygous mutants. SNRNP40 deficiency in primary hematopoietic stem cells or T cells or the EL4 cell line increased the frequency of splicing errors, mostly intron retention, in several hundred messenger RNAs. Altered expression of proteins associated with immune cell function was also observed in Snrnp40-mutant cells. The immunological consequences of SNRNP40 deficiency presumably result from cumulative, moderate effects on processing of many different mRNA molecules and secondary reductions in the expression of critical immune proteins, yielding a syndromic immune disorder.


Assuntos
Células-Tronco Hematopoéticas/fisiologia , Infecções por Herpesviridae/imunologia , Síndromes de Imunodeficiência/imunologia , Muromegalovirus/fisiologia , Ribonucleoproteína Nuclear Pequena U5/metabolismo , Spliceossomos/metabolismo , Linfócitos T/fisiologia , Alelos , Animais , Linhagem Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Suscetibilidade a Doenças , Infecções por Herpesviridae/genética , Síndromes de Imunodeficiência/genética , Linfopoese/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Processamento de RNA , Ribonucleoproteína Nuclear Pequena U5/genética
16.
Cells ; 8(8)2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349725

RESUMO

Aging is a risk factor for adipose tissue dysfunction, which is associated with inflammatory innate immune mechanisms. Since the adipose tissue/liver axis contributes to hepatosteatosis, we sought to determine age-related adipose tissue dysfunction in the context of the activation of the innate immune system fostering fatty liver phenotypes. Using wildtype and immune-deficient mice, we compared visceral adipose tissue and liver mass as well as hepatic lipid storage in young (ca. 14 weeks) and adult (ca. 30 weeks) mice. Adipocyte size was determined as an indicator of adipocyte function and liver steatosis was quantified by hepatic lipid content. Further, lipid storage was investigated under normal and steatosis-inducing culture conditions in isolated hepatocytes. The physiological age-related increase in body weight was associated with a disproportionate increase in adipose tissue mass in immune-deficient mice, which coincided with higher triglyceride storage in the liver. Lipid storage was similar in isolated hepatocytes from wildtype and immune-deficient mice under normal culture conditions but was significantly higher in immune-deficient than in wildtype hepatocytes under steatosis-inducing culture conditions. Immune-deficient mice also displayed increased inflammatory, adipogenic, and lipogenic markers in serum and adipose tissue. Thus, the age-related increase in body weight coincided with an increase in adipose tissue mass and hepatic steatosis. In association with a (pro-)inflammatory milieu, aging thus promotes hepatosteatosis, especially in immune-deficient mice.


Assuntos
Tecido Adiposo/metabolismo , Proteínas de Ligação a DNA/deficiência , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Adipócitos , Tecido Adiposo/patologia , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Perfilação da Expressão Gênica , Hepatócitos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo
17.
Allergol Immunopathol (Madr) ; 47(5): 491-498, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31350062

RESUMO

BACKGROUND: Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by increased susceptibility to weakly virulent mycobacteria (Bacillus Calmette-Guérin [BCG] vaccines and environmental mycobacteria), Mycobacterium tuberculosis, Candida spp. and Salmonella spp. The aim of this study is to evaluate clinical features and immunological findings of MSMD patients with interleukin 12 receptor beta 1 (IL12Rß1) deficiency. METHODS: Among 117 screened patients with BCG infection following vaccination, 23 suspected MSMD subjects were recruited to this study by the exclusion of severe combined immunodeficiencies and chronic granulomatous diseases. Flow cytometric assessment for surface expression of IL12Rß1 was performed. Moreover, the clinical and immunological data from the patients was evaluated. RESULTS: A significant decrease (less than 1%) in the surface expression of IL12Rß1 was reported in six cases which showed a significant increase in the count of lymphocytes (p=0.009) and CD8+ T cells (p=0.008) as compared to MSMD subjects with normal expression of surface IL12Rß1. The frequency of disseminated BCGosis (50% vs. 20%, p=0.29), recurrent infection (83.3% vs. 40%, p=0.14) and salmonellosis (33.3% vs. 0.0%, p=0.07) was higher in IL12Rß1 deficient subjects than IL12Rß1 sufficient individuals. CONCLUSION: MSMD patients with childhood onset of mycobacteriosis (mostly after BCG vaccination) and recurrent salmonellosis could be evaluated for IL12Rß1 expression with flow cytometry for punctual diagnosis.


Assuntos
Herpes Simples/imunologia , Síndromes de Imunodeficiência/imunologia , Mutação/genética , Infecções por Mycobacterium não Tuberculosas/imunologia , Mycobacterium bovis/imunologia , Receptores de Interleucina-12/genética , Simplexvirus/fisiologia , Adolescente , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Herpes Simples/genética , Humanos , Síndromes de Imunodeficiência/genética , Lactente , Masculino , Infecções por Mycobacterium não Tuberculosas/genética , Estudos Prospectivos , Receptores de Interleucina-12/metabolismo
18.
Rinsho Ketsueki ; 60(6): 702-707, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281163

RESUMO

Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes associated with DNA repair and telomere maintenance. In addition, mutations in ribosome-related genes cause defective hematopoiesis. Patients with IBMFS exhibit a predisposition to developing hematological malignancy or solid tumor because of the defect in cellular and molecular hemostasis. The SAMD9 mutation causes the multisystem disorder, MIRAGE syndrome, characterized by congenital adrenal hypoplasia and loss of chromosome 7, providing a novel insight into the correlation between the germline and somatic mutations of SAMD9/SAMD9L and myelodysplastic syndrome (MDS) with monosomy 7. Primary immunodeficiency diseases (PID) are caused by inborn errors of the immune system. PID patients with inadequate tumor immunity are at an elevated risk of developing malignancies such as lymphoma, leukemia, and gastrointestinal cancer. Recently, monocytopenia and mycobacterial infection (MonoMAC) syndrome with the GATA2 gene mutation have been reported as PID related to bone marrow failure. Patients with MonoMAC syndrome often develop MDS and acute myeloid leukemia. Here, we present the pediatric-onset IBMFS and/or PID with cancer predisposition and briefly discuss the tumorigenesis in each monogenic disease.


Assuntos
Anemia Aplástica/complicações , Doenças da Medula Óssea/complicações , Predisposição Genética para Doença , Hemoglobinúria Paroxística/complicações , Síndromes de Imunodeficiência/complicações , Neoplasias/genética , Anemia Aplástica/genética , Doenças da Medula Óssea/genética , Transtornos da Insuficiência da Medula Óssea , Criança , Hemoglobinúria Paroxística/genética , Humanos , Síndromes de Imunodeficiência/genética , Síndromes Mielodisplásicas
19.
Immunol Med ; 42(1): 1-9, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31204893

RESUMO

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that develops in genetically susceptible individuals in response to environmental factors. SLE and primary immunodeficiency disease (PID) share some clinical manifestations in that certain PIDs present with autoimmune phenomena. Patients with SLE become susceptible to infection via three pathways. First, SLE and PID share some genetic factors, such as complement and mannose-binding lectin genes, which predispose patients to infection. Second, patients with SLE have an inherently high risk of infection because of their intrinsic immunological abnormalities induced by SLE. Third, patients with SLE receiving immunosuppressive treatment are at high risk of infection. Further studies delineating the abnormalities related to both autoimmunity and immunodeficiency would be warranted to identify a new potential drug target for SLE.


Assuntos
Síndromes de Imunodeficiência/imunologia , Infecções/etiologia , Lúpus Eritematoso Sistêmico/imunologia , Autoimunidade , Proteínas do Sistema Complemento/imunologia , Suscetibilidade a Doenças , Predisposição Genética para Doença , Humanos , Síndromes de Imunodeficiência/genética , Imunossupressores/efeitos adversos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Lectina de Ligação a Manose/genética , Terapia de Alvo Molecular , Risco
20.
Scand J Immunol ; 90(4): e12798, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31179555

RESUMO

CD40 ligand (CD40L) deficiency is a rare but life-threatening primary immunodeficiency caused by mutations in the CD40L gene. Here, we investigated a cohort of 40 genetically diagnosed CD40L-deficient patients from the Chinese mainland, analysed their clinical and genetic data, and examined CD40L expression, the proportion of T cell subsets, B cell subsets and T follicular helper (Tfh) cells. The aim was to provide a complete picture of CD40L deficiency. Initial presentations of the patient cohort mainly involved recurrent fever (47.5%) and sinopulmonary infection (42.5%). Life-threatening infections (42.5%), caused by various pathogens, were the most serious threats faced by CD40L-deficient patients, while neutropenia (57.5%) remained the most common complication. Opportunistic infections, including Pneumocystis carinii pneumonia and invasive fungal disease associated with Talaromyces marneffei, were also common in the cohort. In addition, seven patients (17.5%) suffered BCGitis/BCGosis, which is a major problem facing a planned immunization programme in China. It was intriguing that reduced IgM levels were observed in 12.5% of patients, while normal or elevated IgA levels were shown in 47.5% of patients. Thirty-seven unique mutations were identified in 40 patients; of these, 10 were novel. Furthermore, we observed a lower percentage of NK cells, Tfh cells, and central memory CD4+ T cells, and an extremely small class-switched memory B cell population, in CD40L-deficient patients. Patients who underwent hematopoietic stem cell transplantation experienced better disease remission. Taken together, our data establish the largest database about CD40L deficiency in China and provide genetic, immunologic and clinical information about Chinese CD40L-deficient patients.


Assuntos
Ligante de CD40/genética , Síndromes de Imunodeficiência/imunologia , Células Matadoras Naturais/imunologia , Pneumopatias Fúngicas/imunologia , Pneumocystis carinii/fisiologia , Pneumonia por Pneumocystis/imunologia , Linfócitos T/imunologia , Talaromyces/fisiologia , China , Estudos de Coortes , Febre , Humanos , Imunoglobulina M/sangue , Síndromes de Imunodeficiência/genética , Memória Imunológica , Pneumopatias Fúngicas/genética , Masculino , Mycobacterium bovis , Pneumonia por Pneumocystis/genética , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA