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3.
Pediatr Allergy Immunol ; 31(5): 528-536, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32060950

RESUMO

BACKGROUND: There are no data regarding the prevalence of malignancies in patients with primary immunodeficiency (PID) in Turkey. Along with the prevalence of malignancy, we aimed to present the types of malignancy and define the underlying immune deficiency of the patients. METHOD: Between the years 1992 and 2018, from five tertiary immunology clinics, fifty-nine patients with PID who developed malignancy were included. All patients were evaluated for demographics, clinical features, and prognosis. RESULTS: The prevalence of malignancy in our cohort was detected as 0.9% (59/6392). The male-to-female ratio was 1.8 (38/21), and the median age of patients was 14 years (range: 1.5-51). The median age at diagnosis of malignancy was 10 years (range: 1.5-51). Ataxia-telangiectasia was the most frequent PID in patients with malignancy (n = 19, 32.2%), and non-Hodgkin lymphoma was the most common malignancy (n = 32, 51.6%). The rate of malignancy in DOCK8 deficiency (n = 7/43, 16.3%) was higher than AT (n = 19/193, 9.8%), Wiskott-Aldrich syndrome (n = 2/22, 9.1%), and common variable immunodeficiency (n = 11/205, 5.4%). EBV quantitative PCR was positive in 16 out of 53 patients (30.2%). Three patients had secondary malignancies. Remission was achieved in 26 patients (44.1%). However, 31 patients (52.5%) died. Two patients (3.4%) are still on chemotherapy. CONCLUSION: This study is the largest cohort investigating the association of malignancy in patients with PID in Turkey. While lymphoid malignancies were the most common malignancy and observed more frequently in AT patients, the risk for malignancy was higher in patients with DOCK8 deficiency compared to AT.

4.
Acta Radiol ; 61(10): 1377-1387, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32000505

RESUMO

BACKGROUND: Anhidrotic ectodermal dysplasia (AED) is a rare, mostly X-linked recessive genodermatosis, characterized by congenital defects of ectodermal derivative structures as the central nervous system (CNS) is primarily ectodermal in origin. PURPOSE: To evaluate CNS variations and abnormalities in AED. MATERIAL AND METHODS: A retrospective analysis was made of the neurological and neuroimaging findings of 17 children (12 boys, 5 girls; median age = 8 years; age range = 2-14 years) diagnosed with AED in our pediatric clinics during 2008-2016. The pattern of CNS variation and abnormalities were evaluated by comparing of these findings with an age- and gender-matched healthy control group with no family history. RESULTS: Of the 17 AED cases identified on the basis of neuroimaging findings, 6 (35.3%) were seen to be normal. Associated CNS variation and abnormalities including cavum septum pellucidum (35.3%), callosal dysgenesis (11.8%), prominent Virchow-Robin spaces (64.7%), cortical sulcal dilation (41.1%), mega cisterna magna (35.3%), focal cortical dysplasia (11.8%), and delayed myelination (58.8%) were observed in 11 (64.7%) children with AED. CONCLUSION: AED suggests a spectrum of CNS variation and abnormalities, presenting with neurological and neuroimaging findings, demonstrated in the embryonic surface- and neuro-ectoderm derived structures. The results of this study suggest that CNS variation and abnormalities might be associated with AED.


Assuntos
Doenças do Sistema Nervoso Central/diagnóstico por imagem , Displasia Ectodérmica/diagnóstico por imagem , Neuroimagem/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
6.
Ocul Immunol Inflamm ; 28(1): 70-78, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30556770

RESUMO

Purpose: To present the ocular findings of the members of a family that has the diagnosis of Muckle Wells syndrome, a form of cryopyrin associated periodic syndrome (CAPS).Materials and Methods: Nine patients with MWS were included in this study. Each study participant underwent a systemic evaluation, comprehensive ophthalmic examination, and auxillary testings.Results: In this study, conjunctivitis was the most prominent ocular finding. Other relatively common ocular findings included band keratopathy, clinical signs of past uveitis, and corneal topography abnormalities. Nystagmus, corneal leukoma, and optic nerve pallor with epiretinal membrane were also detected. Rare ocular manifestations were posterior stromal corneal opacification with edema, anterior iris snychecia, and mild cataract.Conclusion: MWS is a rare systemic autoinflammatory disorder that presents with a variety of ocular findings. Exacerbation of systemic and ocular findings with cold is a hallmark of the disease.

7.
J Allergy Clin Immunol ; 145(5): 1452-1463, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31887391

RESUMO

BACKGROUND: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. OBJECTIVE: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. METHOD: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. RESULTS: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. CONCLUSION: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.

8.
Reumatol. clín. (Barc.) ; 15(6): e92-e95, nov.-dic. 2019. tab
Artigo em Inglês | IBECS | ID: ibc-189658

RESUMO

OBJECTIVES: Primary Raynaud's phenomenon (PRP) manifests as episodes of transient spasms of peripheral blood vessels. To elucidate the clinical clues and laboratory characteristics will facilitate the identification of PRP. METHODS: A retrospective data collection of clinical and laboratory characteristics of 58 children with PRP was performed between January 2007 and December 2016. RESULTS: A positive ANA test at lower titers <1:100 was detected in 24.1% of the patients. There was a significant relationship between presence of ANA positivity and migraine in female patients with PRP (p = 0.01; p = 0.020 respectively). The most common accompanying disorder was migraine which was detected in 37.9% of all patients with PRP. Hemoglobin and serum ferritin levels were significantly lower in PRP patients with migraine (p = 0.045; p < 0.05, respectively). Additionally, the mean platelet volume (MPV) measurements were significantly higher in patients with migraine compared to those without migraine (p = 0.045; p < 0.05 respectively). DISCUSSION: There is limited data concerning childhood PRP. For the first time we showed a high frequency of migraine in childhood PRP. Anemia and high MPV could be the underlying triggering factors of these two episodic diseases


OBJETIVO: El fenómeno de Raynaud primario (PRP, por sus siglas en inglés) se manifiesta como episodios de vasoespasmos transitorios de vasos sanguíneos periféricos. Elucidar las características clínicas y de laboratorio facilitará la identificación del PRP, así como las enfermedades acompañantes. MÉTODOS: Se realizó una un estudio retrospectivo de datos clínicos, de laboratorio y de tratamiento en 58 niños con PRP entre enero de 2007 y diciembre de 2016. RESULTADOS: Se detectó una prueba de ANA positiva en títulos inferiores (<1:100) en el 24,1% de nuestros pacientes. Se encontró correlación estadística entre la positividad de anticuerpos antinucleares y la presencia de migraña en las mujeres con PRP (p = 0,01; p = 0,020, respectivamente, prueba exacta de Fisher, prueba de corrección de continuidad de Yates). El trastorno más común fue la presencia de migraña en el 37,9% (n=22) asociado con PRP. Los niveles de hemoglobina fueron significativamente más bajos asociados con un bajo nivel de ferritina sérica en los casos de PRP con migraña (p = 0,045; p < 0,05). Además, las mediciones del volumen plaquetario medio (VPM) fueron significativamente mayores en los casos con migraña en comparación con aquellos sin migraña (p = 0,045; p < 0,05). DISCUSIÓN: Existen datos muy limitados sobre el PRP infantil. Hemos presentado por primera vez la asociación de PRP infantil y migraña en un estudio retrospectivo. La anemia y el VPM alto podrían formar parte de los factores predisponentes de ambas enfermedades episódicas


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto Jovem , Doença de Raynaud/diagnóstico , Doença de Raynaud/complicações , Estudos Retrospectivos
9.
Reumatol Clin ; 15(6): e92-e95, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29426682

RESUMO

OBJECTIVES: Primary Raynaud's phenomenon (PRP) manifests as episodes of transient spasms of peripheral blood vessels. To elucidate the clinical clues and laboratory characteristics will facilitate the identification of PRP. METHODS: A retrospective data collection of clinical and laboratory characteristics of 58 children with PRP was performed between January 2007 and December 2016. RESULTS: A positive ANA test at lower titers <1:100 was detected in 24.1% of the patients. There was a significant relationship between presence of ANA positivity and migraine in female patients with PRP (p=0.01; p=0.020 respectively). The most common accompanying disorder was migraine which was detected in 37.9% of all patients with PRP. Hemoglobin and serum ferritin levels were significantly lower in PRP patients with migraine (p=0.045; p<0.05, respectively). Additionally, the mean platelet volume (MPV) measurements were significantly higher in patients with migraine compared to those without migraine (p=0.045; p<0.05 respectively). DISCUSSION: There is limited data concerning childhood PRP. For the first time we showed a high frequency of migraine in childhood PRP. Anemia and high MPV could be the underlying triggering factors of these two episodic diseases.


Assuntos
Doença de Raynaud/diagnóstico , Adolescente , Criança , Feminino , Humanos , Masculino , Doença de Raynaud/complicações , Estudos Retrospectivos , Adulto Jovem
10.
Turk J Pediatr ; 61(6): 937-940, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32134589

RESUMO

Çekiç S, Özgür T, Karali Y, Özkan T, Kiliç SS. Vedolizumab treatment in a patient with X-linked agammaglobulinemia, is it safe and efficient? Turk J Pediatr 2019; 61: 937-940. The loss of inflammatory regulation resulting from the absence of B-lymphocytes leads to a risk for autoimmune and autoinflammatory complications. There is no data on the use of Vedolizumab in patients with X-linked agammaglobulinemia (XLA) as well as children with another primary immunodeficiency (PID) diseases. A 4-year-old boy was admitted to our clinic with a history of recurrent respiratory tract infections. He was diagnosed with XLA based on extremely low immunoglobulins, very low level of B cells, genetic mutation of BTK gene, and family history. At the age of 8, he suffered from intermittent fever attacks, abdominal pain, weakness, oral aft, and weight loss. His clinical and laboratory features were consistent with inflammatory bowel disease. Histopathological examination of the biopsy material obtained from terminal ileum, colon and cecum showed Crohn`s disease. Initially, he was treated with prednisolone and infliximab. Because of the lack of response, infliximab treatment was switched to adalimumab. Terminal ileum was resected to relieve obstruction complication. Although he had been treated with adalimumab, a significant improvement was not observed. Vedolizumab (Entyvio™), a humanized monoclonal antibody α4ß7 integrin-receptor antagonist, was commenced. After treatment with vedolizumab, his fever and abdominal pain attacks reduced, his total daily calorie intake increased and weight gain improved. He began to walk again and continued his school education properly. No side effects were observed in 18 months. This is the first immunocompromised child treated with vedolizumab. The symptoms of the patient receded and no side effect were seen during the treatment.


Assuntos
Agamaglobulinemia/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Tirosina Quinase da Agamaglobulinemia/genética , Tirosina Quinase da Agamaglobulinemia/metabolismo , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Pré-Escolar , DNA/genética , Análise Mutacional de DNA , Fármacos Gastrointestinais/uso terapêutico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação
11.
Clin Immunol ; 194: 60-66, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30018023

RESUMO

APECED is a rare monogenic recessive disorder caused by mutations in the AIRE gene. In this manuscript, we report a male Turkish patient with APECED syndrome who presented with chronic mucocutaneous candidiasis associated with other autoimmune manifestations developed over the years. The presence of the homozygous R257X mutation of the AIRE gene confirmed the diagnosis of APECED syndrome. We further performed literature review in 23 published Turkish APECED patients and noted that Finnish major mutation R257X is common in Turks. In particular, we assessed retrospectively how often the Ferre/Lionakis criteria would have resulted in earlier diagnosis in Finns, Sardinians and Turks in respect to the classic criteria. Since an earlier diagnosis could have been possible in 18.8% of Turkish, in 23.8% of Sardinian and 38.55% of Finnish patients we reviewed from literature, Ferre/Lionakis criteria could indeed allow in future earlier initiation of immunomodulatory treatments, if found effective in future studies.


Assuntos
Candidíase Mucocutânea Crônica/genética , Mutação/genética , Poliendocrinopatias Autoimunes/genética , Adulto , Criança , Feminino , Humanos , Masculino , Fenótipo , Estudos Retrospectivos , Turquia , Adulto Jovem
12.
J Allergy Clin Immunol ; 141(2): 704-717.e5, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28601685

RESUMO

BACKGROUND: Gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life-threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. OBJECTIVE: We sought to aggregate the worldwide experience of HSCT in patients with GOF-STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft-versus-host disease, and transplant-related complications. METHODS: Data were collected from an international cohort of 15 patients with GOF-STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. RESULTS: Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event-free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. CONCLUSION: Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.


Assuntos
Mutação com Ganho de Função , Predisposição Genética para Doença , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas , Fator de Transcrição STAT1/genética , Aloenxertos , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco , Fator de Transcrição STAT1/imunologia , Taxa de Sobrevida
13.
Pediatr Int ; 59(6): 655-660, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28207965

RESUMO

BACKGROUND: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is the most frequent repetitive fever syndrome in childhood. It is characterized by fever episodes lasting for approximately 3-6 days, once every 3-8 weeks. METHODS: Clinical and laboratory data for PFAPA syndrome patients between January 2010 and December 2014 followed up at a tertiary pediatric care hospital were reviewed. RESULTS: Four hundred children (256 male, 144 female; mean age at diagnosis, 4.2 ± 2.2 years), were enrolled in the study. During the episodes, mean leukocyte number was high (12 725/mm3 ) with predominant neutrophils. The mean number of monocytes was 1256/mm3 , and 90.2% had monocytosis. Serum amyloid A and C-reactive protein were high in 84.6% and in 77.8% of the patients, respectively. Mediterranean fever (MEFV) gene heterozygous mutation was identified in 57 of the 231 patients (24.7%) in whom genetic analysis had been performed. The most frequent mutation was heterozygous M694V (10%, n = 23). Extension of between-episode interval following prophylaxis was noted in 85% of those on regular colchicine treatment (n = 303). In the colchicine group, between-episode interval was prolonged from 18.8 ± 7.9 days (before colchicine treatment) to 49.5 ± 17.6 days on prophylactic colchicine therapy; also, prophylactic treatment was more effective in reducing episode frequency in patients with MEFV gene variant (n = 54, 96%) than in those without (n = 122, 80%; P = 0.003). CONCLUSIONS: This study has involved the largest number of PFAPA syndrome patients in the literature. It is particularly important to assess and to demonstrate the high rate of response to colchicine prophylaxis in PFAPA syndrome patients, especially those with MEFV variant. On blood screening, neutrophilia associated with monocytosis and low procalcitonin could contribute to diagnosis.


Assuntos
Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre/prevenção & controle , Linfadenite/prevenção & controle , Faringite/prevenção & controle , Estomatite Aftosa/prevenção & controle , Moduladores de Tubulina/uso terapêutico , Criança , Pré-Escolar , Esquema de Medicação , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Feminino , Febre/diagnóstico , Febre/genética , Seguimentos , Marcadores Genéticos , Humanos , Lactente , Linfadenite/diagnóstico , Linfadenite/genética , Masculino , Mutação , Pescoço , Faringite/diagnóstico , Faringite/genética , Pirina/genética , Estudos Retrospectivos , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/genética , Síndrome , Resultado do Tratamento
14.
J Clin Invest ; 126(11): 4289-4302, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27701145

RESUMO

Patients with mutations in AICDA, which encodes activation-induced cytidine deaminase (AID), display an impaired peripheral B cell tolerance. AID mediates class-switch recombination (CSR) and somatic hypermutation (SHM) in B cells, but the mechanism by which AID prevents the accumulation of autoreactive B cells in blood is unclear. Here, we analyzed B cell tolerance in AID-deficient patients, patients with autosomal dominant AID mutations (AD-AID), asymptomatic AICDA heterozygotes (AID+/-), and patients with uracil N-glycosylase (UNG) deficiency, which impairs CSR but not SHM. The low frequency of autoreactive mature naive B cells in UNG-deficient patients resembled that of healthy subjects, revealing that impaired CSR does not interfere with the peripheral B cell tolerance checkpoint. In contrast, we observed decreased frequencies of SHM in memory B cells from AD-AID patients and AID+/- subjects, who were unable to prevent the accumulation of autoreactive mature naive B cells. In addition, the individuals with AICDA mutations, but not UNG-deficient patients, displayed Tregs with defective suppressive capacity that correlated with increases in circulating T follicular helper cells and enhanced cytokine production. We conclude that SHM, but not CSR, regulates peripheral B cell tolerance through the production of mutated antibodies that clear antigens and prevent sustained interleukin secretions that interfere with Treg function.


Assuntos
Linfócitos B/imunologia , Pontos de Checagem do Ciclo Celular/imunologia , Citidina Desaminase/deficiência , Tolerância Imunológica , Memória Imunológica , Mutação , Hipermutação Somática de Imunoglobulina/imunologia , Linfócitos B/patologia , Pontos de Checagem do Ciclo Celular/genética , Citidina Desaminase/imunologia , Feminino , Humanos , Masculino , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
15.
Haematologica ; 101(10): 1180-1189, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27612988

RESUMO

Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically, these were homozygous variants in USB1 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements.


Assuntos
Disceratose Congênita/diagnóstico , Disceratose Congênita/genética , Exoma/genética , Variação Genética/genética , DNA Ligase Dependente de ATP/genética , Proteínas de Ligação a DNA/genética , Humanos , Linhagem , Diester Fosfórico Hidrolases/genética , Análise de Sequência de DNA , Síndrome , Fatores de Transcrição/genética
16.
J Allergy Clin Immunol ; 138(1): 210-218.e9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27221134

RESUMO

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases. OBJECTIVES: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. METHODS: The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. RESULTS: Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications. CONCLUSION: APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/etiologia , Fenótipo , Adolescente , Adulto , Alelos , Biópsia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Humanos , Síndromes de Imunodeficiência/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Sítios de Splice de RNA , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
18.
Immunity ; 43(5): 884-95, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26546282

RESUMO

Activation-induced cytidine deaminase (AID), the enzyme-mediating class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes, is essential for the removal of developing autoreactive B cells. How AID mediates central B cell tolerance remains unknown. We report that AID enzymes were produced in a discrete population of immature B cells that expressed recombination-activating gene 2 (RAG2), suggesting that they undergo secondary recombination to edit autoreactive antibodies. However, most AID+ immature B cells lacked anti-apoptotic MCL-1 and were deleted by apoptosis. AID inhibition using lentiviral-encoded short hairpin (sh)RNA in B cells developing in humanized mice resulted in a failure to remove autoreactive clones. Hence, B cell intrinsic AID expression mediates central B cell tolerance potentially through its RAG-coupled genotoxic activity in self-reactive immature B cells.


Assuntos
Tolerância Central/genética , Tolerância Central/imunologia , Citidina Desaminase/genética , Ativação Linfocitária/imunologia , Células Precursoras de Linfócitos B/imunologia , Adolescente , Adulto , Idoso , Animais , Apoptose/genética , Apoptose/imunologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Feminino , Genes de Imunoglobulinas/genética , Genes de Imunoglobulinas/imunologia , Humanos , Ativação Linfocitária/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Recombinação Genética/genética , Recombinação Genética/imunologia , Hipermutação Somática de Imunoglobulina/genética , Hipermutação Somática de Imunoglobulina/imunologia , Adulto Jovem
19.
J Clin Immunol ; 35(6): 538-49, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26271390

RESUMO

PURPOSE: Nijmegen Breakage Syndrome (NBS) is a rare inherited condition, characterized by microcephaly, chromosomal instability, immunodeficiency, and predisposition to malignancy. This retrospective study, characterizing the clinical and immunological status of patients with NBS at time of diagnosis, was designed to assess whether any parameters were useful in disease prognosis, and could help determine patients qualified for hematopoietic stem cell transplantation. METHODS: The clinical and immunological characteristics of 149 NBS patients registered in the online database of the European Society for Immune Deficiencies were analyzed. RESULTS: Of the 149 NBS patients, 91 (61%), of median age 14.3 years, remained alive at the time of analysis. These patients were clinically heterogeneous, with variable immune defects, ranging from negligible to severe dysfunction. Humoral deficiencies predisposed NBS patients to recurrent/chronic respiratory tract infections and worsened long-term clinical prognosis. Eighty malignancies, most of lymphoid origin (especially non-Hodgkin's lymphomas), were diagnosed in 42% of patients, with malignancy being the leading cause of death in this cohort. Survival probabilities at 5, 10, 20 and 30 years of age were 95, 85, 50 and 35%, respectively, and were significantly lower in patients with than without malignancies. CONCLUSIONS: The extremely high incidence of malignancies, mostly non-Hodgkin's lymphomas, was the main risk factor affecting survival probability in NBS patients. Because treatment of NBS is very difficult and frequently unsuccessful, the search for an alternative medical intervention such as hematopoietic stem cell transplantation is of great clinical importance.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome de Quebra de Nijmegen/diagnóstico , Fatores de Tempo , Adolescente , Adulto , Criança , Pré-Escolar , Instabilidade Cromossômica , Feminino , Humanos , Síndromes de Imunodeficiência , Lactente , Linfoma não Hodgkin , Masculino , Microcefalia , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/terapia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
20.
J Exp Med ; 212(10): 1641-62, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26304966

RESUMO

Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/ß, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/ß. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.


Assuntos
Síndrome de Job/etiologia , TYK2 Quinase/deficiência , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Interferon gama/metabolismo , Interleucina-10/farmacologia , Interleucina-12/metabolismo , Interleucina-12/farmacologia , Interleucina-23/farmacologia , Interleucina-6/farmacologia , Síndrome de Job/complicações , Síndrome de Job/genética , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Mutação , Infecções por Mycobacterium/etiologia , Linfócitos T/metabolismo , Linfócitos T/patologia , TYK2 Quinase/genética , TYK2 Quinase/metabolismo , Viroses/etiologia , Adulto Jovem
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