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Clin Exp Immunol ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31799703


In addition to their detection in typical X-linked severe combined immunodeficiency, hypomorphic mutations in the IL-2 receptor common gamma chain gene (IL2RG) have been described in patients with atypical clinical and immunological phenotypes. In this leaky clinical phenotype, the diagnosis is often delayed, limiting prompt therapy in these patients. Here, we report the biochemical and functional characterization of a nonsense mutation in exon 8 (p.R328X) of IL2RG in 2 siblings: a 4-year-old boy with lethal Epstein Barr virus-related lymphoma and his asymptomatic 8-month-old brother with a Tlow B+ NK+ immunophenotype, dysgammaglobulinemia, abnormal lymphocyte proliferation, and reduced levels of T cell receptor excision circles. After confirming normal IL2RG expression (CD132) on T lymphocytes, STAT5 phosphorylation was examined to evaluate the functionality of the common gamma chain (γc ), which showed partially preserved function. Co-immunoprecipitation experiments were performed to assess the interaction capacity of the R328X mutant with JAK3, concluding that R328X impairs JAK3 binding to γc . Here, we describe how the R328X mutation in IL2RG may allow partial phosphorylation of STAT5 through a JAK3-independent pathway. We identified a region of 3 amino acids in the γc intracellular domain that may be critical for receptor stabilization and allow this alternative signaling. Identification of the functional consequences of pathogenic IL2RG variants at the cellular level is important to enable better understanding of partial defects leading to leaky phenotypes.

Artigo em Inglês | MEDLINE | ID: mdl-31887391


BACKGROUND: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentations of lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data for non-transplanted patients beyond previous patient reports or meta-reviews are scarce. OBJECTIVE: This international, retrospective study was conducted to elucidate the longitudinal clinical course of transplanted and non-transplanted LRBA-deficient patients. METHODS: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity (IDDA) score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. RESULTS: Twenty-four of 76 LRBA-deficient patients from 29 centers (10 years median follow-up, range: 1-52) underwent HSCT from 2005 to 2019. Overall survival after HSCT (median follow-up 20 months) was 70.8% (17/24 patients); all deaths were due to non-specific, early, transplant-related mortality. Currently, 82.7% (43/52) of non-transplanted patients (aged 3-69 years) are alive. Of 17 HSCT survivors, seven are in complete and five in good partial remission without treatment (12/17, 70.6%). Only five of 43 non-transplanted patients (11.6%) are without immunosuppression. IDDA scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P=0.005) or in patients who received abatacept or sirolimus as compared to other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. CONCLUSIONS: The life-long disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.

Front Immunol ; 10: 2406, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695692


Severe combined immunodeficiency (SCID), the most severe form of T-cell immunodeficiency, can be screened at birth by quantifying T-cell receptor excision circles (TRECs) in dried blood spot (DBS) samples. Early detection of this condition speeds up the establishment of appropriate treatment and increases the patient's life expectancy. Newborn screening for SCID started in January 2017 in Catalonia, the first Spanish and European region to universally include this testing. The results obtained in the first 2 years of experience are evaluated here. All babies born between January 2017 and December 2018 were screened. TREC quantification in DBS (1.5 mm diameter) was performed with the Enlite Neonatal TREC kit from PerkinElmer (Turku, Finland). In 2018, the retest cutoff in the detection algorithm was updated based on the experience gained in the first year, and changed from 34 to 24 copies/µL. This decreased the retest rate from 3.34 to 1.4% (global retest rate, 2.4%), with a requested second sample rate of 0.23% and a positive detection rate of 0.02%. Lymphocyte phenotype (T, B, NK populations), expression of CD45RA/RO isoforms, percentage and intensity of TCR αß and TCR γδ, presence of HLA-DR+ T lymphocytes, and in vitro lymphocyte proliferation were studied in all patients by flow cytometry. Of 130,903 newborns screened, 30 tested positive, 15 of which were male. During the study period, one patient was diagnosed with SCID: incidence, 1 in 130,903 births in Catalonia. Thirteen patients had clinically significant T-cell lymphopenia (non-SCID) with an incidence of 1 in 10,069 newborns (43% of positive detections). Nine patients were considered false-positive cases because of an initially normal lymphocyte count with normalization of TRECs between 3 and 6 months of life, four infants had transient lymphopenia due to an initially low lymphocyte count with recovery in the following months, and three patients are still under study. The results obtained provide further evidence of the benefits of including this disease in newborn screening programs. Longer follow-up is needed to define the exact incidence of SCID in Catalonia.

Front Immunol ; 9: 2397, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386343


LRBA deficiency was first described in 2012 as an autosomal recessive disorder caused by biallelic mutations in the LRBA gene (OMIM #614700). It was initially characterized as producing early-onset hypogammaglobulinemia, autoimmune manifestations, susceptibility to inflammatory bowel disease, and recurrent infection. However, further reports expanded this phenotype (including patients without hypogammaglobulinemia) and described LRBA deficiency as a clinically variable syndrome with a wide spectrum of clinical manifestations. We present the case of a female patient who presented with type 1 diabetes, psoriasis, oral thrush, and enlarged liver and spleen at the age of 8 months. She later experienced recurrent bacterial and viral infections, including pneumococcal meningitis and Epstein Barr viremia. She underwent two consecutive stem cell transplants at the age of 8 and 9 years, and ultimately died. Samples from the patient and her parents were subjected to whole exome sequencing, which revealed a homozygous 1-bp insertion in exon 23 of the patient's LRBA gene, resulting in frameshift and premature stop codon. The patient's healthy mother was heterozygous for the mutation and her father tested wild-type. This finding suggested that either one copy of the paternal chromosome 4 bore a deletion including the LRBA locus, or the patient inherited two copies of the mutant maternal LRBA allele. The patient's sequencing data showed a 1-Mb loss of heterozygosity region in chromosome 4, including the LRBA gene. Comparative genomic hybridization array of the patient's and father's genomic DNA yielded normal findings, ruling out genomic copy number abnormalities. Here, we present the first case of LRBA deficiency due to a uniparental disomy (UPD). In contrast to classical Mendelian inheritance, UPD involves inheritance of 2 copies of a chromosomal region from only 1 parent. Specifically, our patient carried a small segmental isodisomy of maternal origin affecting 1 Mb of chromosome 4.

Proteínas Adaptadoras de Transdução de Sinal/deficiência , Cromossomos Humanos Par 4 , Estudos de Associação Genética , Predisposição Genética para Doença , Homozigoto , Mutação , Dissomia Uniparental , Hibridização Genômica Comparativa , Estudos de Associação Genética/métodos , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Sequenciamento Completo do Exoma