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1.
Blood ; 143(24): 2504-2516, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38579284

RESUMO

ABSTRACT: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.


Assuntos
Genótipo , Síndrome de Wiskott-Aldrich , Humanos , Adolescente , Criança , Masculino , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/diagnóstico , Síndrome de Wiskott-Aldrich/terapia , Feminino , Pré-Escolar , Adulto , Estudos Retrospectivos , Lactente , Adulto Jovem , Biomarcadores , Transplante de Células-Tronco Hematopoéticas , Índice de Gravidade de Doença , Proteína da Síndrome de Wiskott-Aldrich/genética , Seguimentos , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
2.
Clin Immunol ; 244: 109131, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36179983

RESUMO

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD.


Assuntos
Doenças da Imunodeficiência Primária , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Criança , Pré-Escolar , Egito , Feminino , Humanos , Masculino , Doenças da Imunodeficiência Primária/genética , Sistema de Registros , Estudos Retrospectivos , Tunísia , Turquia , Proteínas de Transporte Vesicular/genética , Proteínas rab27 de Ligação ao GTP/genética
3.
Allergy ; 77(10): 3108-3123, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35491430

RESUMO

BACKGROUND: Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency and cytotoxic T-lymphocyte protein-4 (CTLA-4) insufficiency are recently described disorders that present with susceptibility to infections, autoimmunity, and lymphoproliferation. Clinical and immunological comparisons of the diseases with long-term follow-up have not been previously reported. We sought to compare the clinical and laboratory manifestations of both diseases and investigate the role of flow cytometry in predicting the genetic defect in patients with LRBA deficiency and CTLA-4 insufficiency. METHODS: Patients were evaluated clinically with laboratory assessments for lymphocyte subsets, T follicular helper cells (TFH ), LRBA expression, and expression of CD25, FOXP3, and CTLA4 in regulatory T cells (Tregs) at baseline and 16 h post-stimulation. RESULTS: LRBA-deficient patients (n = 29) showed significantly early age of symptom onset, higher rates of pneumonia, autoimmunity, chronic diarrhea, and failure to thrive compared to CTLA-4 insufficiency (n = 12). In total, 29 patients received abatacept with favorable responses and the overall survival probability was not different between transplanted versus non-transplanted patients in LRBA deficiency. Meanwhile, higher probability of survival was observed in CTLA-4-insufficient patients (p = 0.04). The T-cell subsets showed more deviation to memory cells in CTLA-4-insufficiency, accompanied by low percentages of Treg and dysregulated cTFH cells response in both diseases. Cumulative numbers of autoimmunities positively correlated with cTFH frequencies. Baseline CTLA-4 expression was significantly diminished in LRBA deficiency and CTLA-4 insufficiency, but significant induction in CTLA-4 was observed after short-term T-cell stimulation in LRBA deficiency and controls, while this elevation was less in CTLA-4 insufficiency, allowing to differentiate this disease from LRBA deficiency with high sensitivity (87.5%) and specificity (90%). CONCLUSION: This cohort provided detailed clinical and laboratory comparisons for LRBA deficiency and CTLA-4 insufficiency. The flow cytometric approach is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide rapid diagnosis and treatment for these diseases impacting the CTLA-4 pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Lipopolissacarídeos , Abatacepte/metabolismo , Abatacepte/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos
4.
J Clin Immunol ; 41(8): 1804-1838, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34390440

RESUMO

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers.


Assuntos
Candidíase Mucocutânea Crônica/genética , Síndrome de Job/genética , Adolescente , Adulto , Candidíase Mucocutânea Crônica/sangue , Criança , Pré-Escolar , Estudos de Coortes , Eczema/genética , Eosinofilia/genética , Feminino , Humanos , Imunoglobulina E/sangue , Lactente , Síndrome de Job/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Adulto Jovem
5.
J Clin Immunol ; 41(8): 1878-1892, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34477998

RESUMO

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).


Assuntos
Ataxia Telangiectasia/imunologia , Ataxia Telangiectasia/mortalidade , Linfócitos B/imunologia , Deficiência de IgA/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Deficiência de IgA/mortalidade , Deficiência de IgG/imunologia , Deficiência de IgG/mortalidade , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Lactente , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
J Allergy Clin Immunol ; 145(6): 1664-1672.e10, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31945408

RESUMO

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. OBJECTIVE: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. CONCLUSIONS: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.


Assuntos
Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Transtornos da Insuficiência da Medula Óssea/genética , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação/genética , Fenótipo , Aplasia Pura de Série Vermelha/genética , Vasculite/genética
7.
J Clin Immunol ; 37(6): 524-528, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28681255

RESUMO

PURPOSE: Homozygous mutations in the HAX1 gene cause an autosomal recessive form of severe congenital neutropenia (SCN). There are limited data on cases of gonadal insufficiency that involve the HAX1 gene mutation. We aimed to evaluate the pubertal development and gonadal functions of our patients with a p.Trp44X mutation in the HAX1 gene. METHOD: Pubertal development, physical and laboratory findings of one male and seven female patients with HAX1 deficiency were evaluated. RESULTS: The age of the patients was between 13 and 25 years. All female patients were diagnosed with primary ovarian insufficiency (POI) based on amenorrhea and elevated gonadotropins. The ovary volumes in female patients were determined to be smaller than normal for their age through sonographic studies. Short stature associated with gonadal insufficiency was also observed in three patients. CONCLUSION: The HAX1 gene is important for ovarian development, in which a p.Trp44X mutation may cause POI in female patients. It is crucial to follow up and evaluate the gonadal functions of female patients in such cases.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação/genética , Neutropenia/congênito , Ovário/fisiologia , Puberdade Tardia/genética , Adolescente , Adulto , Transtornos Cromossômicos , Síndrome Congênita de Insuficiência da Medula Óssea , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Masculino , Neutropenia/genética , Linhagem , Adulto Jovem
8.
J Pediatr Hematol Oncol ; 38(2): e75-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26535771

RESUMO

Dyskeratosis congenita (DC) is a rare inherited disorder characterized by reticular skin pigmentation, oral cavity leukoplakia, and nail dystrophy. A variety of noncutaneous (dental, pulmonary, gastrointestinal, neurological, genitourinary, ophthalmic, and skeletal) abnormalities also have been reported. An 8-year-old boy with DC developed juvenile idiopathic inflammatory myopathy. C16orf57 mutation was identified as a genetic cause of DC. Treatment with methylprednisolone was initiated, followed with methotrexate, prednisolone, and high-dose intravenous immunoglobulin treatment. This is the first report on a patient with juvenile idiopathic inflammatory myopathy and DC.


Assuntos
Disceratose Congênita/complicações , Disceratose Congênita/genética , Mutação , Miosite/genética , Diester Fosfórico Hidrolases/genética , Criança , Humanos , Masculino
9.
Blood ; 119(17): 3997-4008, 2012 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-22403255

RESUMO

T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rß1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.


Assuntos
Diferenciação Celular , Interleucina-12/farmacologia , Mutação/genética , Receptores de Interleucina-12/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Linfócitos T Auxiliares-Indutores/citologia , TYK2 Quinase/genética , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Humanos , Hospedeiro Imunocomprometido , Ativação Linfocitária , Camundongos , Receptores de Interleucina-12/deficiência , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/deficiência , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , TYK2 Quinase/metabolismo , Fatores de Transcrição/metabolismo
10.
Proc Natl Acad Sci U S A ; 108(28): 11554-9, 2011 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-21700883

RESUMO

Impaired immune functions leading to primary immunodeficiencies often correlate with paradoxical autoimmune complications; patients with hyper-IgM syndromes who are deficient in activation-induced cytidine deaminase (AID), which is required for class-switch recombination and somatic hypermutation, are prone to develop autoimmune diseases. To investigate the impact of AID-deficiency on early B-cell tolerance checkpoints in humans, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from AID-deficient patients. New emigrant/transitional and mature naive B cells from AID-deficient patients express an abnormal Ig repertoire and high frequencies of autoreactive antibodies, demonstrating that AID is required for the establishment of both central and peripheral B-cell tolerance. In addition, B-cell tolerance was further breached in AID-deficient patients as illustrated by the detection of anti-nuclear IgM antibodies in the serum of all patients. Thus, we identified a major and previously unsuspected role for AID in the removal of developing autoreactive B cells in humans.


Assuntos
Linfócitos B/enzimologia , Linfócitos B/imunologia , Citidina Desaminase/imunologia , Tolerância a Antígenos Próprios/imunologia , Adolescente , Adulto , Sequência de Aminoácidos , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/genética , Fator Ativador de Células B/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Citidina Desaminase/deficiência , Citidina Desaminase/genética , Feminino , Humanos , Imunoglobulina M/sangue , Imunoglobulina M/genética , Síndrome de Job/enzimologia , Síndrome de Job/genética , Síndrome de Job/imunologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Células Precursoras de Linfócitos B/enzimologia , Células Precursoras de Linfócitos B/imunologia , Tolerância a Antígenos Próprios/genética , Linfócitos T Reguladores/enzimologia , Linfócitos T Reguladores/imunologia , Adulto Jovem
11.
BMC Immunol ; 14: 3, 2013 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-23336327

RESUMO

BACKGROUND: The T cell antigen receptors (TCR) of αß and γδ T lymphocytes are believed to assemble in a similar fashion in humans. Firstly, αß or γδ TCR chains incorporate a CD3δε dimer, then a CD3γε dimer and finally a ζζ homodimer, resulting in TCR complexes with the same CD3 dimer stoichiometry. Partial reduction in the expression of the highly homologous CD3γ and CD3δ proteins would thus be expected to have a similar impact in the assembly and surface expression of both TCR isotypes. To test this hypothesis, we compared the surface TCR expression of primary αß and γδ T cells from healthy donors carrying a single null or leaky mutation in CD3G (γ+/-) or CD3D (δ+/-, δ+/leaky) with that of normal controls. RESULTS: Although the partial reduction in the intracellular availability of CD3γ or CD3δ proteins was comparable as a consequence of the mutations, surface TCR expression measured with anti-CD3ε antibodies was significantly more decreased in γδ than in αß T lymphocytes in CD3γ+/- individuals, whereas CD3δ+/- and CD3δ+/leaky donors showed a similar decrease of surface TCR in both T cell lineages. Therefore, surface γδ TCR expression was more dependent on available CD3γ than surface αß TCR expression. CONCLUSIONS: The results support the existence of differential structural constraints in the two human TCR isotypes regarding the incorporation of CD3γε and CD3δε dimers, as revealed by their discordant surface expression behaviour when confronted with reduced amounts of CD3γ, but not of the homologous CD3δ chain. A modified version of the prevailing TCR assembly model is proposed to accommodate these new data.


Assuntos
Complexo CD3/imunologia , Haploinsuficiência/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Membrana Celular/metabolismo , Humanos , Modelos Imunológicos , Linfócitos T/imunologia
12.
J Clin Immunol ; 33(1): 74-83, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22983506

RESUMO

PURPOSE: Primary immunodeficiency diseases (PIDs) are inherited disorders of the immune system resulting in increased susceptibility to unusual infections and predisposition to autoimmunity and malignancies. The European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This study aimed to provide a minimum estimate of the prevalence of each disorder and to determine the clinical characteristics and outcomes of patients with PID in Turkey. METHODS: Clinical features of 1435 patients with primary immunodeficiency disorders are registered in ESID Online Patient Registry by the Pediatric Immunology Departments of the Medical Faculties of Uludag University and Ege University Between 2004 and 2010. These two centers are the major contributors reporting PID patients to ESID database from Turkey. RESULTS: Predominantly antibody immunodeficiency (73.5 %) was the most common category followed by autoinflammatory disorders (13.3 %), other well defined immunodeficiencies (5.5 %), congenital defects of phagocyte number, function or both 3.5 %), combined T and B cell immunodeficiencies (2 %), defects in innate immunity (1 %), and diseases of immune dysregulation (0.7 %). Patients between 0 and 18 years of age constitued 94 % of total and the mean age was 9.2 ± 6 years. The consanguinity rate within the registered patients was 14.3 % (188 of 1130 patients). The prevalance of all PID cases ascertained from the registry was 30.5/100.000. The major cause of the mortality was severe infection which was seen in forty-two of seventy five deceased patients. The highest mortality was observed in patients with severe combined immunodeficiencies and ataxia-telangiectasia. CONCLUSION: Promoting the awareness of PID among the medical professionals and the general public is required if premature death and serious morbidity occurs due to late diagnosis of the wider spectrum of PID are to be avoided.


Assuntos
Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/imunologia , Bases de Dados Factuais , Feminino , Hospitais Universitários , Humanos , Lactente , Masculino , Prevalência , Sistema de Registros , Turquia/epidemiologia , Adulto Jovem
13.
J Pediatr ; 160(6): 1055-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22402565

RESUMO

We describe a Turkish patient with tyrosine kinase 2 deficiency who suffered from disseminated Bacille Calmette-Guerin infection, neurobrucellosis, and cutaneous herpes zoster infection. Tyrosine kinase 2 deficiency should be considered in patients susceptible to herpes viruses and intramacrophage pathogens even in the absence of atopy, high serum IgE, and staphylococcal disease.


Assuntos
Síndromes de Imunodeficiência/enzimologia , TYK2 Quinase/deficiência , Criança , Diagnóstico Diferencial , Seguimentos , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndrome de Job/diagnóstico , Imageamento por Ressonância Magnética , Masculino , TYK2 Quinase/sangue
14.
J Exp Med ; 219(10)2022 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-36094518

RESUMO

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/ß (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.


Assuntos
Síndrome de Job , TYK2 Quinase , Humanos , Interferon gama/metabolismo , Interleucina-23 , Síndrome de Job/genética , TYK2 Quinase/deficiência , TYK2 Quinase/genética , TYK2 Quinase/metabolismo
15.
Am J Hum Genet ; 83(1): 64-76, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18606301

RESUMO

Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.


Assuntos
Agamaglobulinemia/sangue , Osteoclastos/patologia , Osteopetrose/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Fosfatase Ácida/metabolismo , Actinas/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Argentina , Arginina/metabolismo , Biópsia , Estudos de Casos e Controles , Linhagem Celular Transformada , Proliferação de Células , Transformação Celular Viral , Células Cultivadas , Estudos de Coortes , Consanguinidade , Cisteína/metabolismo , Análise Mutacional de DNA , Dendritos/fisiologia , Feminino , Genes Recessivos , Herpesvirus Humano 4/fisiologia , Heterozigoto , Homozigoto , Humanos , Ílio/cirurgia , Isoenzimas/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/patologia , Lipopolissacarídeos/farmacologia , Fator Estimulador de Colônias de Macrófagos/farmacologia , Masculino , Modelos Imunológicos , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Osteoclastos/metabolismo , Osteoclastos/ultraestrutura , Osteopetrose/diagnóstico , Osteopetrose/diagnóstico por imagem , Osteopetrose/patologia , Osteopetrose/fisiopatologia , Osteoprotegerina/metabolismo , Paquistão , Linhagem , Polimorfismo Genético , Estrutura Terciária de Proteína , Ligante RANK/metabolismo , Radiografia Torácica/métodos , Receptor Ativador de Fator Nuclear kappa-B/química , Receptor Ativador de Fator Nuclear kappa-B/imunologia , Receptores de Vitronectina/metabolismo
16.
J Ocul Pharmacol Ther ; 37(4): 236-240, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33512278

RESUMO

Purpose: Management of uveitis displays a particular challenge in childhood. This study aims to compare the efficacy and safety of infliximab (IFX) and adalimumab (ADA) in pediatric noninfectious uveitis that were refractory to conventional immunosuppresives. Methods: This retrospective single-center study included 33 patients who were treated with anti-tumor necrosis factor (TNF) agents (16 with IFX and 17 with ADA). Patients had diverse etiologies, including juvenile idiopathic arthritis, idiopathic uveitis, and Behçet's disease. Demographic characteristics, systemic diagnosis, findings of the ophthalmological examination, control of ocular inflammation, response to treatment, and the rate of clinical remission were studied. Results: Fourteen (87.5%) patients receiving IFX and 10 (58.8%) patients receiving ADA achieved response to treatment during the follow-up (P = 0.118). The agents were discontinued with complete clinical remission in 6 (37.5%) patients receiving IFX and in 2 (11.8%) patients receiving ADA (P = 0.118). Baseline visual acuities and parameters of inflammation improved significantly in both groups after anti-TNF therapy. Conclusion: Both IFX and ADA are safe and effective for pediatric noninfectious uveitis.


Assuntos
Adalimumab/efeitos adversos , Infliximab/efeitos adversos , Doenças não Transmissíveis/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Uveíte/tratamento farmacológico , Adalimumab/administração & dosagem , Adalimumab/uso terapêutico , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Oftalmopatias/patologia , Feminino , Seguimentos , Humanos , Inflamação/tratamento farmacológico , Infliximab/administração & dosagem , Infliximab/uso terapêutico , Masculino , Indução de Remissão , Estudos Retrospectivos , Segurança , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Uveíte/diagnóstico , Uveíte/etiologia , Acuidade Visual/efeitos dos fármacos
17.
Clin Cancer Res ; 27(2): 575-584, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33082212

RESUMO

PURPOSE: Nijmegen breakage syndrome (NBS) is a DNA repair disorder with a high predisposition to hematologic malignancies. EXPERIMENTAL DESIGN: We describe the natural history of NBS, including cancer incidence, risk of death, and the potential effectiveness of hematopoietic stem cell transplantation (HSCT) in preventing both pathologies: malignancy and immunodeficiency. RESULTS: Among 241 patients with NBS enrolled in the study from 11 countries, 151 (63.0%) patients were diagnosed with cancer. Incidence rates for primary and secondary cancer, tumor characteristics, and risk factors affecting overall survival (OS) were estimated. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively. Most of the tumors n = 95 (62.9%) were non-Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignancies occurred at a median age of 18 (interquartile range, 13.7-21.5) years. The probability of 20-year overall survival (OS) for the whole cohort was 44.6% ± 4.5%. Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; P < 10-5). A total of 49 patients with NBS underwent HSCT, including 14 patients transplanted before malignancy. Patients with NBS with diagnosed cancer who received HSCT had higher 20-year OS than those who did not (42.7% vs. 30.3%; P = 0.038, respectively). In the group of patients who underwent preemptive transplantation, only 1 patient developed cancer, which is 6.7 times lower as compared with nontransplanted patients [incidence rate ratio 0.149 (95% confidence interval, 0.138-0.162); P < 0.0001]. CONCLUSIONS: There is a beneficial effect of HSCT on the long-term survival of patients with NBS transplanted in their first complete remission of cancer.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Neoplasias/epidemiologia , Neoplasias/terapia , Síndrome de Quebra de Nijmegen/epidemiologia , Adolescente , Adulto , Criança , Estudos de Coortes , Comorbidade , Seguimentos , Humanos , Incidência , Estimativa de Kaplan-Meier , Polônia/epidemiologia , Prevalência , Adulto Jovem
18.
J Clin Immunol ; 29(1): 117-22, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18709451

RESUMO

INTRODUCTION: Leukocyte adhesion deficiency (LAD) type III is a rare syndrome characterized by severe recurrent infections, leukocytosis, and increased bleeding tendency. All integrins are normally expressed yet a defect in their activation leads to the observed clinical manifestations. MATERIALS AND METHODS: Less than 20 patients have been reported world wide and the primary genetic defect was identified in some of them. Here we describe the clinical features of patients in whom a mutation in the calcium and diacylglycerol-regulated guanine nucleotide exchange factor 1 (CalDAG GEF1) was found and compare them to other cases of LAD III and to animal models harboring a mutation in the CalDAG GEF1 gene. DISCUSSION: The hallmarks of the syndrome are recurrent infections accompanied by severe bleeding episodes distinguished by osteopetrosis like bone abnormalities and neurodevelopmental defects.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Síndrome da Aderência Leucocítica Deficitária/genética , Osso e Ossos/anormalidades , Osso e Ossos/diagnóstico por imagem , Feminino , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Lactente , Síndrome da Aderência Leucocítica Deficitária/diagnóstico , Síndrome da Aderência Leucocítica Deficitária/patologia , Masculino , Mutação/genética , Radiografia
19.
J Allergy Clin Immunol Pract ; 7(8): 2790-2800.e15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31238161

RESUMO

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency.


Assuntos
Abatacepte/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Síndromes de Imunodeficiência/tratamento farmacológico , Imunossupressores/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Terapia de Alvo Molecular , Resultado do Tratamento , Adulto Jovem
20.
Int Arch Allergy Immunol ; 146(3): 190-4, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18268386

RESUMO

Hyper IgE syndromes (HIES) are primary immunodeficiency disorders of unknown pathogenesis. Patients are typically affected with 'cold' abscesses of the skin, recurrent cyst-forming pneumonia, chronic mucocutaneous candidiasis and other less frequent features such as progressive skeletal abnormalities. Defective signaling in the Toll-like receptor (TLR) pathways has been suggested as a responsible pathologic mechanism, however, in previous reports, 10 patients revealed no defect in inflammatory cytokine responses to different TLR ligands. Here, we report the increase in pro-inflammatory cytokines TNF-alpha and IL-8, following TLR2 and TLR4 stimulation in a larger cohort of 25 additional patients with HIES, and provide a meta-analysis of the TLR data in HIES.


Assuntos
Interleucina-8/imunologia , Síndrome de Job/imunologia , Leucócitos Mononucleares/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/imunologia , Estudos de Coortes , Feminino , Humanos , Interleucina-8/sangue , Lipopolissacarídeos/imunologia , Masculino , Transdução de Sinais , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/sangue
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