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J Clin Immunol ; 2018 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-29934865


PURPOSE: Signal transducer and activator of transcription 1 gain-of-function (STAT1 GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC). We aim to report the effect of oral ruxolitinib, the Janus kinase (JAK) family tyrosine kinase inhibitor, on clinical and immune status of a 12-year-old boy with severe CMC due to a novel STAT1 GOF mutation. METHODS: Clinical features and laboratory data were analyzed, particularly lymphocyte subsets, ex vivo IFNγ- and IFNα-induced STAT1, 3, 5 phosphorylation dynamics during the course of JAK1/2 inhibition therapy, and Th17-related, STAT1- and STAT3-inducible gene expression before and during the treatment. Sanger sequencing was used to detect the STAT1 mutation. Literature review of ruxolitinib in treatment of CMC is appended. RESULTS: A novel STAT1 GOF mutation (c.617T > C; p.L206P), detected in a child with recalcitrant CMC, was shown to be reversible in vitro with ruxolitinib. Major clinical improvement was achieved after 8 weeks of ruxolitinib treatment, while sustained suppression of IFNγ- and IFNα-induced phosphorylation of STAT1, STAT3, and STAT5, as well as increased STAT3-inducible and Th17-related gene expression, was demonstrated ex vivo. Clinical relapse and spike of all monitored phosphorylated STAT activity was registered shortly after unplanned withdrawal, decreasing again after ruxolitinib reintroduction. No increase of peripheral CD4+ IL17+ T cells was detected after 4 months of therapy. No adverse effects were noted. CONCLUSION: JAK1/2 inhibition with ruxolitinib represents a viable option for treatment of refractory CMC, if HSCT is not considered. However, long-term administration is necessary, as the effect is not sustained after treatment discontinuation.

Horm Res Paediatr ; 88(2): 160-166, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28253502


BACKGROUND: Germline STAT3 gain-of-function (GOF) mutations cause multiple endocrine and haematologic autoimmune disorders, lymphoproliferation, and growth impairment. As the JAK-STAT pathway is known to transduce the growth hormone (GH) signalling, and STAT3 interacts with STAT5 in growth regulation, we hypothesised that short stature in STAT3 GOF mutations results mostly from GH insensitivity via involving activation of STAT5. CASE REPORT: A boy with a novel STAT3 c.2144C>T (p.Pro715Leu) mutation presented with short stature (-2.60 SD at 5.5 years). He developed diabetes mellitus at 11 months, generalised lympho-proliferation, autoimmune thyroid disease, and immune bicytopenia in the subsequent years. At 5.5 years, his insulin-like growth factor-1 (IGF-I) was 37 µg/L (-2.22 SD) but stimulated GH was 27.7 µg/L. Both a standard IGF-I generation test (GH 0.033 mg/kg/day sc; 4 days) and a high-dose prolonged IGF-I generation test (GH 0.067 mg/kg/day sc; 14 days) failed to significantly increase IGF-I levels (37-46 and 72-87 µg/L, respectively). The boy underwent haematopoietic stem cell transplantation at 6 years due to severe neutropenia and massive lymphoproliferation, but unfortunately deceased 42 days after transplantation from reactivated generalised adenoviral infection. CONCLUSIONS: Our findings confirm the effect of STAT3 GOF mutation on the downstream activation of STAT5 resulting in partial GH insensitivity. 

Doenças Autoimunes/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/metabolismo , Mutação , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Doenças Autoimunes/metabolismo , Criança , Pré-Escolar , Evolução Fatal , Transtornos do Crescimento/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Fator de Transcrição STAT3/metabolismo , Gêmeos
Clin Immunol ; 176: 77-86, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28104464


BACKGROUND: Mutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway. METHODS: We studied precursor and peripheral B-cell differentiation and apoptosis via flowcytometry. Furthermore, we performed AKT-phosphorylation assays and somatic hypermutations (SHM) and class switch recombination (CSR) analysis. RESULTS: We identified 13 patients of whom 3 had new mutations in PIK3CD or PIK3R1. Patients had low total B-cell numbers with increased frequencies of transitional B cells and plasmablasts, while the precursor B-cell compartment in bone marrow was relatively normal. Basal AKT phosphorylation was increased in lymphocytes from APDS patients and natural effector B cells where most affected. PI3K mutations resulted in altered SHM and CSR and increased apoptosis. CONCLUSIONS: The B-cell compartment in APDS patients is affected by the mutations in PI3K. There is reduced differentiation beyond the transitional stage, increased AKT phosphorylation and increased apoptosis. This B-cell phenotype contributes to the clinical phenotype.

Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Diferenciação Celular/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/genética , Adolescente , Adulto , Diferenciação Celular/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Switching de Imunoglobulina/genética , Switching de Imunoglobulina/imunologia , Infecção/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Mutação/genética , Mutação/imunologia , Fosforilação/genética , Plasmócitos/imunologia , Células Precursoras de Linfócitos B/imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Recidiva , Transdução de Sinais/genética , Hipermutação Somática de Imunoglobulina/genética , Hipermutação Somática de Imunoglobulina/imunologia , Adulto Jovem
Med Sci Monit ; 11(4): CR182-7, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15795698


BACKGROUND: diGeorge syndrome is a relatively common congenital disorder with developmental defects, including hypoplasia or pathologic migration of the thymus, associated with deletion of contiguous genes on chromosome 22. We prospectively followed a cohort of children with confirmed 22q11.2 deletion. MATERIAL/METHODS: One to six repeated examination were performed in 13 boys and 21 girls, age 4 days to 19 years. Due to the proposed role of the thymus in T lymphocyte selection, we studied T lymphocytes and their function, and also the presence of double positive CD4+CD8+ and gamma/delta T lymphocytes in peripheral blood. RESULTS: A low number of T lymphocytes was detected in the majority of patients before the age of 2 years. Both spontaneous and PHA-induced proliferation were unexpectedly higher than in normal samples from children <2 years old. Both T cell numbers and function normalized thereafter in the majority of patients. Double positive T cells were detected in one boy, together with transient positivity of antinuclear antibodies. Gamma/delta T cells were greater than 5% in 21% of the children. In our 5-year prospective study we have not yet observed serious clinical signs of immunodeficiency or autoimmunity in these patients, except for repeated respiratory infections. CONCLUSIONS: All patients classified as partial diGeorge syndrome presented with delayed but gradual development of immune function against a background of impaired support by the thymus.

Síndrome de DiGeorge/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Envelhecimento/imunologia , Autoanticorpos/sangue , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Lactente , Recém-Nascido , Ativação Linfocitária , Masculino