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2.
Mol Genet Metab Rep ; 20: 100477, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31194046

RESUMO

Lysosomal Storage Diseases (LSDs) are rare genetic diseases, the majority of which are caused by specific lysosomal enzyme deficiencies and all are characterized by malfunctioning lysosomes. Lysosomes are key regulators of many different cellular processes and are vital for the function of the immune system. Several studies have shown the coexistence of LSDs and immune abnormalities. In this study, we investigated the presence of autoantibodies in the plasma of patients with Gaucher disease (GD; n = 6), Sanfilippo Syndrome B (SFB; n = 8) and Niemann - Pick type C disease (NPC; n = 5) before and following Miglustat treatment (n = 3). All were examined for antibodies to antigens of Hep-2 cells and antiganglioside antibodies (AGSA). No autoantibodies were detected in GD patients. 3/8 SFB patients showed only AGSA (2/3 IgM / IgG; 1/3 IgG), 3/8 only anti-Sm E/F and 2/8 showed both IgM / IgG or IgG AGSA and anti-Sm E/F. 3/5 NPC patients showed AGSA (2/3 IgM and IgG, 1/3 IgM) and one anti-Sm E/F and IgM AGSA. Following treatment one patient with no AGSA developed IgM AGSA and two with both IgG and IgM showed only IgG AGSA. In our study, investigating similar numbers of patients, autoantibodies were observed in NPC and SFB patients but not in GD patients. Our findings suggest that, independently of the development of an autoimmune disease in patients with LSDs, there seems to be an autoimmune activation that differs in different disorders. Further studies including more patients, also at different stages of disease and treatment, are needed in order to get further insight into the immune irregularities associated with different LSDs and their significance.

3.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

5.
J Allergy Clin Immunol ; 142(6): 1932-1946, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29729943

RESUMO

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.


Assuntos
Antígeno CTLA-4/genética , Síndromes de Imunodeficiência/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Síndromes de Imunodeficiência/diagnóstico por imagem , Síndromes de Imunodeficiência/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Adulto Jovem
6.
Curr Opin Hematol ; 25(1): 7-12, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29135572

RESUMO

PURPOSE OF REVIEW: Chronic granulomatous disease (CGD) is a primary immunodeficiency, with a defect of phagocytes in killing specific pathogens. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory response. Since its first description as fatal disease about 60 years ago, a significant improvement in outcome has been achieved in the last 20 years. The purpose of this review is to framework recent advances in CGD immunopathogenesis, management of disease manifestation and cure of CGD patients. RECENT FINDINGS: For years, CGD is a known cause of life-threatening infections and excessive inflammation. The cause and the management of inflammatory reactions, however, have not been clarified, and the range of clinical presentation is growing with corresponding novel therapeutic interventions. Recent work focuses on the best outcome of hematopoietic stem cell transplantation (HSCT) and gene therapy for the cure of CGD patients, more specifically, those with X-linked and p47 mutations. SUMMARY: The genetics and phenotype of CGD is well characterized; however, the underlying mechanisms, the treatment of its inflammatory manifestations and the cure of CGD is under further investigation.


Assuntos
Doença Granulomatosa Crônica , Terapia Genética , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Inflamação/imunologia , Inflamação/terapia
10.
Front Immunol ; 8: 798, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769923

RESUMO

Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.

11.
J Allergy Clin Immunol ; 139(4): 1282-1292, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27697500

RESUMO

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Síndrome de Imunodeficiência com Hiper-IgM/mortalidade , Síndrome de Imunodeficiência com Hiper-IgM/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tempo , Adulto Jovem
12.
Hum Genomics ; 10(1): 34, 2016 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-27836013

RESUMO

BACKGROUND: Celiac disease is a complex chronic immune-mediated disorder of the small intestine. Today, the pathobiology of the disease is unclear, perplexing differential diagnosis, patient stratification, and decision-making in the clinic. METHODS: Herein, we adopted a next-generation sequencing approach in a celiac disease trio of Greek descent to identify all genomic variants with the potential of celiac disease predisposition. RESULTS: Analysis revealed six genomic variants of prime interest: SLC9A4 c.1919G>A, KIAA1109 c.2933T>C and c.4268_4269delCCinsTA, HoxB6 c.668C>A, HoxD12 c.418G>A, and NCK2 c.745_746delAAinsG, from which NCK2 c.745_746delAAinsG is novel. Data validation in pediatric celiac disease patients of Greek (n = 109) and Serbian (n = 73) descent and their healthy counterparts (n = 111 and n = 32, respectively) indicated that HoxD12 c.418G>A is more prevalent in celiac disease patients in the Serbian population (P < 0.01), while NCK2 c.745_746delAAinsG is less prevalent in celiac disease patients rather than healthy individuals of Greek descent (P = 0.03). SLC9A4 c.1919G>A and KIAA1109 c.2933T>C and c.4268_4269delCCinsTA were more abundant in patients; nevertheless, they failed to show statistical significance. CONCLUSIONS: The next-generation sequencing-based family genomics approach described herein may serve as a paradigm towards the identification of novel functional variants with the aim of understanding complex disease pathobiology.


Assuntos
Doença Celíaca/genética , Sítios de Ligação , Criança , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Moleculares , Mutação , Polimorfismo de Nucleotídeo Único , Fatores de Risco
13.
J Cyst Fibros ; 15(5): 587-96, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26922860

RESUMO

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) and Aspergillus fumigatus sensitization (AFS) are quite often observed in cystic fibrosis (CF) patients. The aim of this study was to evaluate the use of basophil activation test (BAT) in these manifestations of hypersensitivity reactions. METHODS: BAT (CD63 and CD203c) was performed for 56 CF patients (17 ABPA, 24 AFS and 15 non-AFS). A receiver operating characteristic (ROC) curve analysis and a survival analysis were performed. RESULTS: Both markers significantly contributed in ABPA diagnosis (P value<0.001 for both). Twelve AFS patients fulfilled the criteria for ABPA diagnosis during the follow-up period. The median time to ABPA diagnosis was 9months for patients whose values were over the best cutoffs (P value<0.001 for both). CONCLUSIONS: BAT could be considered as an additional criterion for ABPA diagnosis in CF as well as a potential marker for the monitoring of patients with AFS.


Assuntos
Aspergilose Broncopulmonar Alérgica , Aspergillus fumigatus , Basófilos/imunologia , Fibrose Cística , Testes Imunológicos/métodos , Tetraspanina 30/análise , Adolescente , Alérgenos/análise , Antígenos de Fungos/análise , Aspergilose Broncopulmonar Alérgica/complicações , Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergilose Broncopulmonar Alérgica/imunologia , Aspergillus fumigatus/imunologia , Aspergillus fumigatus/isolamento & purificação , Biomarcadores/análise , Criança , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Fibrose Cística/imunologia , Técnicas Citológicas/métodos , Feminino , Humanos , Masculino , Curva ROC , Reprodutibilidade dos Testes , Escarro/imunologia
14.
J Allergy Clin Immunol ; 137(1): 223-230, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26768763

RESUMO

BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by biallelic mutations in LRBA that abolish LRBA protein expression. OBJECTIVE: We sought to report the extended phenotype of LRBA deficiency in a cohort of 22 LRBA-deficient patients. METHODS: Clinical criteria, protein detection, and genetic sequencing were applied to diagnose LRBA deficiency. RESULTS: Ninety-three patients met the inclusion criteria and were considered to have possible LRBA deficiency. Twenty-four patients did not express LRBA protein and were labeled as having probable LRBA deficiency, whereas 22 were genetically confirmed as having definitive LRBA deficiency, with biallelic mutations in LRBA. Seventeen of these were novel and included homozygous or compound heterozygous mutations. Immune dysregulation (95%), organomegaly (86%), recurrent infections (71%), and hypogammaglobulinemia (57%) were the main clinical complications observed in LRBA-deficient patients. Although 81% of LRBA-deficient patients had normal T-cell counts, 73% had reduced regulatory T (Treg) cell numbers. Most LRBA-deficient patients had low B-cell subset counts, mainly in switched memory B cells (80%) and plasmablasts (92%), with a defective specific antibody response in 67%. Of the 22 patients, 3 are deceased, 2 were treated successfully with hematopoietic stem cell transplantation, 7 are receiving immunoglobulin replacement, and 15 are receiving immunosuppressive treatment with systemic corticosteroids alone or in combination with steroid-sparing agents. CONCLUSION: This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Síndromes de Imunodeficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Linfócitos B/imunologia , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/terapia , Imunossupressores/uso terapêutico , Lactente , Masculino , Mutação , Fenótipo , Linfócitos T/imunologia
15.
Biomed Res Int ; 2015: 806042, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26550577

RESUMO

OBJECTIVE: We assessed the lipopolysaccharide (LPS) or heat shock (HS) induction of heat shock protein-72 (HSP72) in peripheral blood mononuclear cells (PBMCs) of patients with severe sepsis (SS) or trauma-related systemic inflammatory response syndrome (SIRS), compared to healthy individuals (H); we also investigated any pre- or posttreatment modulating glutamine (Gln) effect. METHODS: SS (11), SIRS (10), and H (19) PBMCs were incubated with 1 µg/mL LPS or 43°HS. Gln 10 mM was either added 1 h before or 1 h after induction or was not added at all. We measured monocyte (m), lymphocyte (l), mRNA HSP72, HSP72 polymorphisms, interleukins (ILs), monocyte chemoattractant protein-1 (MCP-1), and cortisol levels. RESULTS: Baseline lHSP72 was higher in SS (p < 0.03), and mHSP72 in SIRS (p < 0.02), compared to H. Only HS induced l/mHSP72/mRNA HSP72; LPS induced IL-6, IL-8, IL-10, and MCP-1. Induced mRNA was related to l/mHSP72, and was related negatively to cytokines. Intracellular l/mHSP72/HSP72 mRNA was related to serum ILs, not being influenced by cortisol, illness severity, and HSP72 polymorphisms. Gln did not induce mRNA in any group but modified l/mHSP72 after LPS/HS induction unpredictably. CONCLUSIONS: HSP72 mRNA and l/mHSP72 are higher among critically ill patients, further induced by HS, not by LPS. HSP72 proteins and HSP72 mRNA are related to serum ILs and are negatively related to supernatant cytokines, not being influenced by HSP72 polymorphisms, cortisol, or illness severity. Gln may depress l/mHSP72 after LPS exposure and enhance them after HS induction, but it may not affect early induced HSP72 mRNA.


Assuntos
Glutamina/administração & dosagem , Proteínas de Choque Térmico HSP72/imunologia , Linfócitos/imunologia , Monócitos/imunologia , Sepse/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Células Cultivadas , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico HSP72/genética , Resposta ao Choque Térmico , Humanos , Lipopolissacarídeos/administração & dosagem , Linfócitos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , RNA Mensageiro/metabolismo , Sepse/patologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Ferimentos e Lesões/imunologia , Ferimentos e Lesões/patologia
17.
Pediatrics ; 134(5): e1468-73, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25349319

RESUMO

Neonatal onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous and articular (CINCA) syndrome is a rare, early-onset autoinflammatory disorder and the most severe form of cryopyrin-associated periodic syndrome, which is associated with overproduction of interleukin (IL)-1ß. This is a case report of a 70-day-old boy, who was diagnosed with NOMID/CINCA syndrome and who has been treated with anti-IL-1ß monoclonal antibody (canakinumab) since then, despite his early infancy. The patient presented with fever, aseptic meningitis, and rash. The clinical manifestations combined with the elevated acute-phase reactants strengthened the suspicion of the diagnosis of NOMID/CINCA syndrome. Specific immunologic workup revealed high levels of serum amyloid A and IL-6. The clinical diagnosis was confirmed by the detection of a de novo mutation of the CIAS1/NLR3 gene (p.Thr348Met), and canakinumab was started at a dose of 4 mg/kg, higher than the recommended dose for older age. White blood cell, serum amyloid A, C-reactive protein, and IL-6 levels quickly decreased and became normal within a month, and the clinical condition of the patient improved significantly. The infant remains without recurrence of disease or further complications and with satisfactory mental development with anti-IL-1ß monoclonal antibody treatment for >2 years. This report indicates the importance of early diagnosis of NOMID/CINCA syndrome and medication with IL-1 blockers as soon as possible for the improvement of the prognosis of cryopyrin-associated periodic syndrome and of a better patient outcome.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Anticorpos Monoclonais Humanizados , Gerenciamento Clínico , Seguimentos , Humanos , Lactente , Masculino , Resultado do Tratamento
18.
Nat Med ; 20(12): 1410-1416, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25329329

RESUMO

The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.


Assuntos
Agamaglobulinemia/genética , Doenças Autoimunes/genética , Antígeno CTLA-4/genética , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Agamaglobulinemia/imunologia , Anemia Hemolítica Autoimune/genética , Anemia Hemolítica Autoimune/imunologia , Animais , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Antígeno B7-1/metabolismo , Antígeno CTLA-4/imunologia , Criança , Códon sem Sentido , Endocitose/genética , Endocitose/imunologia , Éxons , Feminino , Granuloma/genética , Granuloma/imunologia , Heterozigoto , Humanos , Doenças do Sistema Imunitário/genética , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/imunologia , Recidiva , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Síndrome , Adulto Jovem
19.
Front Immunol ; 5: 340, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25101082

RESUMO

The Wiskott-Aldrich syndrome (WAS) is due to mutations of the WAS gene encoding for the cytoskeletal WAS protein, leading to abnormal downstream signaling from the T cell and B cell antigen receptors (TCR and BCR). We hypothesized that the impaired signaling through the TCR and BCR in WAS would subsequently lead to aberrations in the immune repertoire of WAS patients. Using next generation sequencing (NGS), the T cell receptor ß and B cell immunoglobulin heavy chain (IGH) repertoires of eight patients with WAS and six controls were sequenced. Clonal expansions were identified within memory CD4(+) cells as well as in total, naïve and memory CD8(+) cells from WAS patients. In the B cell compartment, WAS patient IGH repertoires were also clonally expanded and showed skewed usage of IGHV and IGHJ genes, and increased usage of IGHG constant genes, compared with controls. To our knowledge, this is the first study that demonstrates significant abnormalities of the immune repertoire in WAS patients using NGS.

20.
Arthritis Care Res (Hoboken) ; 66(5): 773-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-25100215

RESUMO

OBJECTIVE: To determine IgG4 levels in a cohort of consecutive patients with primary Sjögren's syndrome (SS) and other autoimmune diseases and explore whether they associate with distinct clinical, serologic, and histopathologic features. METHODS: Serum IgG4 levels were measured in 133 primary SS patients and 49 healthy donors (HDs). Seventy-four lupus and 54 rheumatoid arthritis (RA) patients served as disease controls. Immunohistochemical IgG4 analysis was performed in paraffin-embedded minor salivary gland (MSG) tissues. RESULTS: Raised IgG4 serum levels (>135 mg/dl) were detected in 10 (7.5%) of 133 primary SS patients (high-IgG4 group), in 8 (10.8%) of 74 lupus patients, in 7 (12.9%) of 54 RA patients, and in 1 (2%) of 49 HDs. Compared to the normal-IgG4 (<135 mg/dl) primary SS group, high-IgG4 patients exhibited increased prevalence of IgG4-related features (autoimmune cholangitis, autoimmune pancreatitis, and interstitial nephritis), lower rates of antinuclear antibody positivity, and higher IgG2 and IgE levels. Positive staining for IgG4+ plasma cells with an IgG4:IgG ratio ≥40% was detected in 3 of 6 available MSG tissues in the high-IgG4 group. Criteria of possible or definite IgG4-related disease (IgG4-RD) were fulfilled by 10 (7.5%) of 133 of our primary SS cohort. CONCLUSION: Raised IgG4 serum levels were detected in 7.5% of primary SS patients in association with IgG4RD-reminiscent clinical, serologic, and histopathologic features. Whether this high-IgG4 primary SS group represents a misclassified IgG4-RD group or a distinct primary SS subtype remains to be further explored in future studies.


Assuntos
Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Imunoglobulina G/biossíntese , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia , Regulação para Cima/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Doenças Autoimunes/patologia , Biomarcadores/sangue , Colangite/imunologia , Colangite/patologia , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Imunoglobulina G/sangue , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/imunologia , Nefrite Intersticial/patologia , Pancreatite/imunologia , Pancreatite/patologia , Glândulas Salivares Menores/imunologia , Glândulas Salivares Menores/patologia , Síndrome de Sjogren/patologia , Adulto Jovem
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