RESUMO
Background and Objectives: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. Materials and Methods: 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0-77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with "secondary" hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6-14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to CTLA4-mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. Results: We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Conclusion: Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.
Assuntos
Antígeno CTLA-4 , Diagnóstico Tardio , Humanos , Grécia/epidemiologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Criança , Idoso , Diagnóstico Tardio/estatística & dados numéricos , Adolescente , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/epidemiologia , Adulto Jovem , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/imunologia , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/epidemiologia , Agamaglobulinemia/imunologia , Agamaglobulinemia/complicaçõesRESUMO
BACKGROUND AIMS: The high genetic diversity of HLA across populations significantly confines the effectiveness of a donor or umbilical cord blood search for allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to probe the HLA immunogenetic profile of the population of Crete, a Greek region with specific geographic and historical characteristics, and to investigate potential patterns in HLA distribution following comparison with the Deutsche Knochenmarkspenderdatei (DKMS) donor registry. It also aims to highlight the importance of regional public cord blood banks (PCBBs) in fulfilling HSCT needs, especially in countries with significant genetic diversity. METHODS: A cohort of 1835 samples representative of the Cretan population was typed for HLA class I (HLA-A, HLA-B, HLA-C) and class II (HLA-DRB1, HLA-DQB1, HLA-DPB1) loci by high-resolution second field next-generation sequencing. Data were compared with the respective HLA profiles of 12 DKMS populations (n = 20â032). Advanced statistical and bioinformatics methods were employed to assess specific intra- and inter-population genetic indexes associated with the regional and geographic distribution of HLA alleles and haplotypes. RESULTS: A considerable HLA allelic and haplotypic diversity was identified among the Cretan samples and between the latter and the pooled DKMS cohort. Even though the HLA allele and haplotype frequency distribution was similar to regions of close geographic proximity to Crete, a clinal distribution pattern from the northern to southern regions was identified. Significant differences were also observed between Crete and the Greek population of DKMS. CONCLUSIONS: This study provides an in-depth characterization of the HLA immunogenetic profile in Crete and reveals the importance of demographic history in HLA heterogeneity and donor selection. The novel HLA allele and haplotype frequency comparative data between the Cretan and other European populations signify the importance of regional PCBBs in prioritizing HLA diversity to efficiently promote the HSCT program at the national level and beyond.
Assuntos
Medula Óssea , Sangue Fetal , Antígenos HLA , Bancos de Sangue , Frequência do Gene , Variação Genética , Grécia , Antígenos HLA/genética , Haplótipos/genética , Humanos , Imunogenética , Sistema de Registros , Doadores de TecidosRESUMO
BACKGROUND: In about 5% of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected. METHODS: C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002%), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants. RESULTS: In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic. CONCLUSIONS: For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration.
Assuntos
Angioedemas Hereditários/genética , Proteína Inibidora do Complemento C1/genética , Predisposição Genética para Doença , Íntrons , Mutação , Alelos , Angioedemas Hereditários/diagnóstico , Biologia Computacional/métodos , Frequência do Gene , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
Evidence accumulated over the last two decades indicates that recurrent angioedema without wheals constitutes a diverse family of disorders with a much higher complexity than was previously regarded. Indicatively, during the last two years, novel variants of three genes other than SERPING1 and F12 have been identified in association with hereditary angioedema. Most interestingly, functional studies of at least one of these variants (the variant c.807Gâ¯>â¯T of ANGPT1 gene) imply the existence of a new disease endotype in which the altered bradykinin metabolism and function does not play a central role. Therefore, using conventional approaches, it seems that the complexity of this disease cannot be sufficiently elucidated and any attempt to interrelate its many diverse aspects seems unrealistic. Similar to other rare and chronic diseases, a Precision Medicine approach, discovering the right target and giving "the right drug, for the right patient, at the right time, every time" seems the optimal future practice. Herein, we review recent data challenging and dictating the need for a switch of angioedema research into high-throughput approaches and we present the expected advantages for better understanding of the disease and patients management.
Assuntos
Angioedemas Hereditários , Medicina de Precisão , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/genética , Angioedemas Hereditários/imunologia , Angiopoietina-1/genética , Angiopoietina-1/imunologia , Proteína Inibidora do Complemento C1/genética , Proteína Inibidora do Complemento C1/imunologia , Fator XII/genética , Fator XII/imunologiaRESUMO
BACKGROUND AND AIMS: Chronic viral hepatitis is a prevalent disease with major health implications. Its underlying pathophysiological mechanisms are not fully understood. IL-1ß and the NLRP3 inflammasome involvement has been suggested in recent years, from in vitro data and data from peripheral blood samples. Therefore, we investigated IL-1ß and the NLRP3 inflammasome in liver tissues in an effort to clarify their role in the pathophysiology of chronic viral hepatitis. METHODS: We studied liver biopsies from patients with a new diagnosis of either chronic hepatitis B (CHB) and chronic hepatitis C (CHC) or patients with chronic hepatitis B in remission (CHB-rem). The biopsies were separated in two parts. The first part was sent to histology to determine the grade of inflammation and fibrosis. From the second part, RNA was extracted and converted to cDNA used in semi-quantitative Real-Time PCR to measure the levels of IL1B, CASP1, NLRP3, ASC and IL1RA. The cell lines used in the in vitro experiments were Huh7.5, LX2 and THP-1 in variety of combinations of monocultures, co-cultures and triple cultures with one of the cell lines infected with the JFH-1 HCV clone. From the cell cultures RNA was extracted and converted to cDNA. For cell lines, we focused in the expression of IL1B and NLRP3. RESULTS: The expression of IL1B, CASP1 and NLRP3 were found significantly different between our groups (pâ¯=â¯0.001, pâ¯=â¯0.001 and pâ¯=â¯0.038, respectively). CHB patients displayed significantly higher IL1B and CASP1 mRNA levels compared to both CHB-rem and CHC patients. IL1B expression significantly correlates with liver biochemical data in CHB patients (AST: pâ¯=â¯0.006, râ¯=â¯0.457; ALT pâ¯=â¯0.002, râ¯=â¯0.497). Finally, mRNA levels of IL1B in CHB patients significantly correlate with the degree of inflammation (pâ¯=â¯0.016) but not the stage of fibrosis (pâ¯=â¯0.362). Interestingly, the relative expression of IL1B in triple culture experiments in vitro was below of 1.5-fold, suggesting no activation of IL1B. Moreover, no activation of NLRP3 was demonstrated in all investigated in vitro conditions. CONCLUSION: IL-1ß might play an important role in the pathogenesis of chronic hepatic inflammation from HBV, but not from HCV.
Assuntos
Inflamassomos/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Fígado/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Adulto , Idoso , Caspase 1/metabolismo , Linhagem Celular , Feminino , Fibrose/metabolismo , Fibrose/virologia , Hepatite B Crônica/metabolismo , Hepatite B Crônica/virologia , Hepatite C Crônica/metabolismo , Hepatite C Crônica/virologia , Humanos , Inflamação/virologia , Fígado/virologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Transdução de Sinais/fisiologia , Adulto JovemRESUMO
BACKGROUND: In view of the large heterogeneity in the clinical presentation of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), great efforts are being made towards detecting measurable biological determinants of disease severity that can help to improve the management of the disease. Considering the central role that plasma kallikrein plays in bradykinin production, we investigated the contribution of the functional polymorphism KLKB1-428G/A to the disease phenotype. METHODS: We studied 249 C1-INH-HAE patients from 114 European families, and we explored possible associations of C1-INH-HAE clinical features with carriage of KLKB1-428G/A, combined or not with that of the functional F12-46C/T polymorphism. RESULTS: Carriers of the G allele of the KLKB1-428G/A polymorphism exhibited a significantly delayed disease onset (i.e., by 4.1 years [p < 0.001], depending on the zygocity status), while carriers of both the KLKB1-428G/A and the F12-46C/T polymorphism displayed an 8.8-year delay in disease onset (p < 0.001) and a 64% lower probability of needing long-term prophylactic treatment (p = 0.019). CONCLUSIONS: These findings support our initial hypothesis that functional alterations in genes of proteins involved in bradykinin metabolism and function affect the clinical phenotype and possibly contribute to the pathogenesis of C1-INH-HAE. Given that an earlier onset of symptoms is inversely correlated with the subsequent course of the disease and, eventually, the need for long-term prophylaxis, these polymorphisms may be helpful prognostic biomarkers of disease severity.
Assuntos
Angioedema/genética , Angioedemas Hereditários/genética , Biomarcadores/sangue , Genótipo , Calicreínas/sangue , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Angioedema/diagnóstico , Angioedema/epidemiologia , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/epidemiologia , Bradicinina/metabolismo , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Adulto JovemAssuntos
Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/genética , Proteína Inibidora do Complemento C1/genética , Íntrons , Mutação , Adulto , Alelos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , LinhagemRESUMO
OBJECTIVES: Although animal studies demonstrated that Smad7 induction ameliorates TGF-ß/SMAD-mediated fibrogenesis, its role in human hepatic diseases is rather obscure. Our study explored the activation status of TGF-ß/activin pathway in patients with chronic liver diseases, and how it is affected by successful antiviral treatment in chronic HBV hepatitis (CHB). METHODS: Thirty-seven CHB patients (19 with active disease, 14 completely remitted on long-term antiviral treatment and 4 with relapse after treatment withdrawal), 18 patients with chronic HCV hepatitis, 12 with non-alcoholic fatty liver disease (NAFLD), and 3 controls were enrolled in the study. Liver mRNA levels of CTGF, all TGF-ß/activin isoforms, their receptors and intracellular mediators (SMADs) were evaluated using qRT-PCR and were correlated with the grade of liver inflammation and fibrosis staging. The expression and localization of pSMAD2 and pSMAD3 were assessed by immunohistochemistry. RESULTS: TGF-ß signalling is activated in CHB patients with active disease, while SMAD7 is up-regulated during the resolution of inflammation after successful treatment. SMAD7 overexpression was also observed in NAFLD patients exhibiting no or minimal fibrosis, despite the activation of TGF-ß/activin signaling. CONCLUSIONS: SMAD7 overexpression might represent a mechanism limiting TGF-ß-mediated fibrogenesis in human hepatic diseases; therefore, SMAD7 induction likely represents a candidate for novel therapeutic approaches.
Assuntos
Hepatite B/metabolismo , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adulto , Idoso , Antivirais/uso terapêutico , Doença Crônica , Feminino , Fibrose , Hepatite B/tratamento farmacológico , Hepatite B/genética , Hepatite B/patologia , Hepatite C/genética , Hepatite C/metabolismo , Hepatite C/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Mensageiro/metabolismo , Transdução de Sinais , Proteína Smad7/genética , Fator de Crescimento Transformador beta/genética , Adulto JovemRESUMO
Aberrant removal of necrotic debris is considered a feature with inflammatory consequences in SLE. Herein, primary Sjögren's syndrome (SS) patients were investigated for the first time for the capacity of their sera to degrade secondary necrotic cell remnants (SNEC) and DNA (endonuclease DNase1 activity), as well as for uptake of SNEC by blood-borne phagocytes. For comparison, specimens from unselected SLE and RA patients and from healthy blood donors (HBD) were also studied. Compared to HBD, the sera from SS and SLE patients studied (but not RA) were found to exhibit significantly impaired capacity for degradation of SNEC (both for p = 0.007) and deficient DNase1 activity (both for p < 0.0001). The deficient DNase1 activity in SS and SLE sera did not owe to decreased DNase1 protein levels. It correlated inversely with increased serum levels of circulating nucleosomes and cell-free DNA (p < 0.0001), as well as with the disease activity indices of SS (r = -0.445, p = 0.0001) and SLE (r = -0.500, p = 0.013). In ex-vivo whole blood analyses, SS and SLE patients (but not RA) also manifested significantly increased SNEC-phagocytosis by monocytes and granulocytes (all for p < 0.0001) that also correlated with disease severity indices of SS (p = 0.001) and SLE (p = 0.01). In various cross-admixture experiments, such aberration was found to reside in the hyperfunctional activity of phagocytes, the impaired degrading activity of serum DNase1 and the SNEC-binding capacity of serum IgG of SS and SLE patients. The sera of SS and SLE patients (but not of RA) induced significant SNEC-phagocytosis by healthy monocytes that correlated inversely with the DNase1 activity (r = -0.634, p < 0.0001) of these sera. In line with this, the inhibition of DNase1 in HBD sera by G-actin was found to lead to significantly diminished SNEC degradation and increased SNEC uptake by healthy phagocytes (p = 0.0009), supporting the important physiologic role of serum DNase1 in the prevention of SNEC-phagocytosis. Purified serum IgG preparations from SS and SLE patients manifested increased binding to SNEC and were able to enhance significantly the engulfment of SNEC by healthy phagocytes both directly (under serum-free conditions, p ≤ 0.009) and via the prevention of physiologic degradation of SNEC by serum, most likely due to their "shielding" against endonuclease digestion (p = 0.0005). These data indicate that upon cell necrosis, the immune system of SS and SLE patients may be overly exposed to the necrotic debris, a fact that probably holds a key role in the pathogenesis of inflammatory and autoimmune reactions observed in these disorders.
Assuntos
Fagocitose/imunologia , Síndrome de Sjogren/sangue , Síndrome de Sjogren/imunologia , Adulto , Idoso , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Desoxirribonuclease I/sangue , Ativação Enzimática , Feminino , Granulócitos/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Necrose/imunologia , Fagócitos/imunologia , Índice de Gravidade de Doença , Síndrome de Sjogren/diagnósticoRESUMO
BACKGROUND: No published data presently exist concerning hereditary angioedema (HAE) in Greece. The aim of this study was to present the results from patients recorded by the Greek Hereditary Angioedema Registry over the last 3 years (July 2010 to June 2013). METHODS: A systematic recording of HAE cases was undertaken following a physician awareness campaign and confirmation of diagnosis. A questionnaire was also used for the assessment of key parameters of the patients' disease-specific quality of life. RESULTS: One hundred and sixteen patients from 41 non-related families were recorded. There were 33 (80.5%) families with type I HAE, 7 (17%) with type II HAE and 1 (2.5%) with non-C1 inhibitor (C1-INH), non-FXII HAE. Two further non-C1-INH, non-FXII HAE sporadic cases were recorded. An investigation of non-symptomatic family members revealed another 6 asymptomatic individuals with C1-INH deficiency. The average delay in diagnosis was 16.5 years and the incidence of death in the families of patients was 1 for every 2 families. The use of newer therapeutic agents seems to fall significantly short of the existing needs. HAE was found to affect the quality of life slightly in 14%, greatly in 63% and significantly in 23% of the patients. CONCLUSION: Until recently, there has been a significant degree of underdiagnosis of HAE in Greece. Very low compliance with the provisions of the applicable international guidelines and consensus positions, with adverse consequences on the patients' quality of life, was also observed. The centralized model we used to uncover the patients could be effective in other countries presenting with comparable disease characteristics.
Assuntos
Angioedemas Hereditários/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Criança , Pré-Escolar , Danazol/uso terapêutico , Antagonistas de Estrogênios/uso terapêutico , Feminino , Seguimentos , Grécia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Sistema de Registros , Inquéritos e Questionários , Adulto JovemRESUMO
A 2-year-old female was presented with high levels of serum ferritin (890 ng/mL) in a routine blood test. Clinical and laboratory investigations excluded the presence of iron overload and secondary causes of hyperferritinemia. A detailed family history and laboratory examinations revealed the presence of early-onset cataract in her 33-year-old mother, who also displayed hyperferritinemia (633 ng/mL), similar to other family members. Genetic testing confirmed the diagnosis of hereditary hyperferritinemia cataract syndrome (HHCS), demonstrating a C39>G (c.-161C>G) mutation into FTL gene. HHCS should be considered in the differential diagnosis of childhood hyperferritinemia, especially in the presence of normal transferrin saturation.
Assuntos
Apoferritinas/genética , Catarata/congênito , Ferritinas/sangue , Distúrbios do Metabolismo do Ferro/congênito , Mutação , Adulto , Catarata/diagnóstico , Catarata/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Prognóstico , SíndromeRESUMO
BACKGROUND: Limited evidence suggests that variants in TNFRSF11A gene, encoding RANK, may contribute to systemic autoinflammatory disease (SAID). AIM/METHODS: To estimate the prevalence of TNFRSF11A variants in a cohort of patients with SAIDs screened for 26 related genes and describe the disease phenotypic expression. RESULTS: A total of 12 out of 167 patients, 7 males, aged (median) 38 years at disease onset, yielded at least one TNFRSF11A rare variant. All patients carried a coexisting variant in at least one other SAID-related gene, most frequently MEFV (6 patients), but also TNFRSF1A, NOD2, NLRP3, NLRP7, MVK, IL36RN, RBCK1, PLCG2 and PSMB8. SAID episodes lasting (median) 9 days manifested with high grade fever (91%), myalgias (75%), malaise (67%), serositis (58%), arthralgias/arthritis (58%), gastrointestinal involvement (33%), and rash (25%), and responded to corticosteroids. The most common initial clinical diagnosis was TNF-associated periodic fever syndrome (TRAPS), which was, however, confirmed, in only one patient. The emergence of MEFV variations supported the diagnosis of atypical Familial Mediterranean Fever in two cases, whereas the diagnosis of Yao syndrome was speculated in two patients with NOD2 variants. The presence of atypical disease and the inability of defining diagnosis in the remaining 7 patients, supported the possible involvement of TNFRSF11A variants in the phenotypic expression of SAIDs. CONCLUSION: TNFRSF11A variants, occurring in 7% of SAID patients always in combination with other SAID-related gene variants, contribute to the development of an autoinflammatory syndrome resembling to TRAPS. Additional studies to confirm novel pathogenic SAID pathways are clearly warranted.
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Objective: To assess the impact conferred by NOD2 variants on the clinical spectrum of patients with systemic autoinflammatory diseases (SAIDs) in Greece. Methods: Consecutive patients (n=167) with confirmed SAIDs who underwent screening by next generation sequencing (NGS) targeting 26 SAID-associated genes, and carried at least one NOD2 gene variant, were retrospectively studied. The demographic, clinical and laboratory parameters were recorded. Results: In total, 24 rare NOD2 variants in 23/167 patients (14%) were detected. Notably, 18 patients had at least one co-existing variant in 13 genes other than NOD2. Nine patients had juvenile- and 14 adult-onset disease. All patients presented with symptoms potentially induced by the NOD2 variants. In particular, the candidate clinical diagnosis was Yao syndrome (YAOS) in 12 patients (7% of the whole SAID cohort). The clinical spectrum of patients with YAOS (mean episode duration 8 days) was fever (n=12/12), articular symptoms (n=8), gastrointestinal symptoms (n=7; abdominal pain/bloating in 7; diarrhea in 4; oral ulcers in 3), serositis (n=7), and rash (n=5), while the inflammatory markers were elevated in all but one patient. Most of these patients showed a poor response to nonsteroidal anti-inflammatory drugs (n=7/9), colchicine (n=6/8) and/or anti-TNF treatment (n=3/4), while a complete response was observed in 6/10 patients receiving steroids and 3/5 on anti-IL1 treatment. Another 8 patients were diagnosed with either FMF (n=6) or PFAPA syndrome (n=2) presenting with prominent diarrhea (n=7), oral ulcers (n=2), periorbital swelling and sicca-like symptoms (n=1), or maculopapular rash (n=1). One patient had a clinically undefined SAID, albeit characterized by oral ulcers and diarrhea. Finally, one patient presented with chronic relapsing urticaria with periorbital edema and inflammatory markers, and another one had a Crohn-like syndrome with good response to anti-IL-1 but refractory to anti-TNF treatment. Conclusion: NOD2 variants were detected in 1 out of 7 SAID patients and seem to have an impact on disease phenotype and treatment response. Further studies should validate combined molecular and clinical data to better understand these distinct nosological entities.
Assuntos
Exantema , Doenças Hereditárias Autoinflamatórias , Úlceras Orais , Síndrome de Imunodeficiência Adquirida dos Símios , Adulto , Animais , Humanos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/genética , Estudos Retrospectivos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Diarreia/etiologia , Proteína Adaptadora de Sinalização NOD2/genéticaRESUMO
Background: Hereditary angioedema (HAE) is a potentially life-threatening disorder characterized by recurrent episodes of subcutaneous or submucosal swelling. HAE with normal C1 inhibitor (HAE-nC1-INH) is an underdiagnosed condition. Although the association with genetic variants has been identified for some families, the genetic causes in many patients with HAE-nC1-INH remain unknown. The role of genes associated with bradykinin catabolism is not fully understood. Objective: We sought to investigate the biological parameters and the genes related to kallikrein-kinin system in families with a clinical phenotype of HAE-nC1-INH and presenting with a carboxypeptidase N (CPN) deficiency. Methods: This study includes 4 families presenting with HAE-nC1-INH and CPN deficiency. Patients' clinical records were examined, biological parameters of kallikrein-kinin system were measured, and genetics was analyzed by next-generation sequencing and Sanger sequencing. Predictive algorithms (Human Splicing Finder, Sorting Intolerant From Tolerant, Polymorphism Phenotyping v2, MutationTaster, and ClinPred) were used to classify variants as affecting splicing, as benign to deleterious, or as disease-causing. Results: Patients presented with angioedema and urticaria, mainly on face/lips, but also with abdominal pain or laryngeal symptoms. Affected patients displayed low CPN activity-30% to 50% of median value in plasma. We identified 3 variants of the CPN1 gene encoding the catalytic 55-kDa subunit of CPN: c.533G>A, c.582A>G, and c.734C>T. CPN deficiency associated with genetic variants segregated with HAE-nC1-INH symptoms in affected family members. Conclusions: CPN1 gene variants are associated with CPN deficiency and HAE-nC1-INH symptoms in 4 unrelated families. Genetic CPN deficiency may contribute to bradykinin and anaphylatoxin accumulation, with synergistic effects in angioedema and urticarial symptoms.
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TNFRSF13B/TACI defects have been associated with CVID pathogenesis and/or phenotype, especially the development of benign lymphoproliferation and autoimmunity. Our purpose was to investigate the role of TNFRSF13B/TACI defects in the pathogenesis of two common lymphoproliferative disorders, namely, sarcoidosis and tonsillar hypertrophy (TH). 105 patients (71 with sarcoidosis and 34 with TH, including 19 without infectious causative and 15 due to Haemophilus influenzae) were analyzed for TNFRSF13B/TACI defects. Two out of 19 TH patients without infectious cause (10.5%) and 2 patients with sarcoidosis (2.8%) displayed rare TNFRSF13B/TACI defects (I87N, L69TfsX12, E36L, and R202H, resp.). Both mutations identified in TH patients have been assessed as deleterious for protein function, while the patient with the R202H mutation and sarcoidosis exhibited also sIgG4D. Our study further supports the notion that TNFRSF13B/TACI defects alone do not result in CVID but may be also found frequently in distinct clinical phenotypes, including benign lymphoproliferation and IgG subclass deficiencies.
Assuntos
Heterozigoto , Tonsila Palatina/metabolismo , Tonsila Palatina/patologia , Sarcoidose/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Feminino , Frequência do Gene , Humanos , Hipertrofia , Masculino , Pessoa de Meia-Idade , Mutação , Tonsila Palatina/imunologia , Polimorfismo de Nucleotídeo Único , Sarcoidose/imunologia , Adulto JovemRESUMO
We report here the identification by next-generation sequencing of a novel HLA allele, DRB1*11:308, in a Greek individual as a part of a research project investigating diagnostic and prognostic biomarkers in head and neck cancer (BIOKARETRA).
Assuntos
Cadeias HLA-DRB1 , Humanos , Cadeias HLA-DRB1/genética , Sequência de Bases , Alelos , GréciaRESUMO
Advances in next generation sequencing technologies, as well as their expanded accessibility and clinical use over the past 2 decades, have led to an exponential increase in the number of identified single gene disorders. Among these are primary atopic disorders-inborn errors of immunity resulting in severe allergic phenotypes as a primary presenting feature. Two cardinal aspects of type I immediate hypersensitivity allergic reactions are hives and angioedema. Mast cells (MCs) are frequent primary drivers of these symptoms, but other cells have also been implicated. Even where MC degranulation is believed to be the cause, mediator-induced symptoms may greatly vary among individuals. Angioedema-particularly in the absence of hives-may also be caused by hereditary angioedema conditions resulting from aberrant regulation of contact system activation and excessive bradykinin generation or impairment of vascular integrity. In these patients, swelling can affect unpredictable locations and fail to respond to MC-directed therapies. Genetic variants have helped delineate key pathways in the etiology of urticaria and nonatopic angioedema and led to the development of targeted therapies. Herein, we describe the currently known inherited and acquired genetic causes for these conditions, highlight specific features in their clinical presentations, and discuss the benefits and limitations of biomarkers that can help distinguish them.
Assuntos
Angioedema , Angioedemas Hereditários , Hipersensibilidade Imediata , Urticária , Humanos , Angioedema/diagnóstico , Urticária/diagnóstico , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/genética , Angioedemas Hereditários/complicações , Hipersensibilidade Imediata/complicações , BiomarcadoresRESUMO
BACKGROUND AND OBJECTIVES: Endothelin-1 (ET-1), a potent vasoconstricting peptide, plays an important role in carcinogenesis. Previous in vitro studies have shown that colorectal cancer cells produce ET-1. METHODS: ET-1 and its receptors ET-A (ET(A) R) and ET-B (ET(B) R) were analyzed in colorectal cancer cell lines and tumors by Western blot and immunohistochemistry. Also, ET-1 levels were measured by ELISA in blood samples collected before and after tumor resection. RESULTS: ET-1 was immunohistochemically expressed by tumor cells at a variable level in 39 cases tested. The adjacent normal mucosa was negative for ET-1 expression. Strong ET(A) R expression observed in the deeper infiltrating areas at the periphery of neoplastic tissue correlated significantly with tumor stage. ET(B) R levels were very low or undetectable. Western blot analysis in paired (normal, tumor) fresh-frozen samples of colorectal cancers and in four colon carcinoma cell lines confirmed these findings. In addition, lower levels of ET-1 in the peripheral circulation after the tumor resection were found by ELISA as compared to those observed before surgery. CONCLUSIONS: ET-1 and ET(A) R, but not ET(B) R, are expressed at a higher level in primary and cultured colon carcinoma cells as compared to normal colon mucosa cells. Further functional studies are needed to explore the role of ET-1/ET(A) R axis in colon carcinogenesis.
Assuntos
Neoplasias Colorretais/química , Endotelina-1/análise , Receptor de Endotelina A/análise , Receptor de Endotelina B/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Endotelina-1/fisiologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-IdadeRESUMO
Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of the SERPING1 gene (n = 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of SERPING1 and pertaining to 5.6% de novo variants. C1-INH is the major control serpin of the kallikrein-kinin system (KKS). In addition, C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing the failed control of C1s protease or KKS provides the diagnosis of C1-INH-HAE. SERPING1 variants usually behave in an autosomal-dominant character with an incomplete penetrance and a low prevalence. A great majority of variants (809/893; 90.5%) that were introduced into online database have been considered as pathogenic/likely pathogenic. Haploinsufficiency is a common feature in C1-INH-HAE where a dominant-negative variant product impacts the wild-type allele and renders it inactive. Small (36.2%) and large (8.3%) deletions/duplications are common, with exon 4 as the most affected one. Point substitutions with missense variants (32.2%) are of interest for the serpin structure-function relationship. Canonical splice sites can be affected by variants within introns and exons also (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients' blood-derived RNAs (n = 25). Exonic variants (n = 6) can affect exon splicing. Rare deep-intron variants (n = 6), putatively acting as pseudo-exon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance (n = 74). This category includes some homozygous (n = 10) or compound heterozygous variants (n = 11). They are presenting with minor allele frequency (MAF) below 0.00002 (i.e., lower than C1-INH-HAE frequency), and may be quantitatively unable to cause haploinsufficiency. Rare benign variants could contribute as disease modifiers. Gonadal mosaicism in C1-INH-HAE is rare and must be distinguished from a de novo variant. Situations with paternal or maternal disomy have been recorded (n = 3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. Any SERPING1 variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy.