Actin polymerisation after FCγR stimulation of human fibroblasts is BCL10 independent.

B-cell lymphoma 10 (BCL10) is not essential for actin polymerisation after FcγR stimulation in human fibroblasts.

Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity.

Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). These 3 CARD-BCL10-MALT1 (CBM) complexes activate nuclear factor κB in both the innate and adaptive arms of immunity. Human inherited defects of the 3 components of the CBM complex, including the 2 adaptors CARD9 and CARD11 and the 2 core components BCL10 and MALT1, have recently been reported. Biallelic loss-of-function mutant alleles underlie several different immunologic and clinical phenotypes, which can be assigned to 2 distinct categories. Isolated invasive fungal infections of unclear cellular basis are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1, and BCL10 deficiencies. Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice. Moreover, germline and somatic gain-of-function mutations of MALT1, BCL10, and CARD11 have also been found in patients with other lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including loss-of-function and gain-of-function mutations, highlights the contribution of each of the components of the CBM complex to human immunity.

Clinical Features Before Hematopoietic Stem Cell Transplantation or Enzyme Replacement Therapy of Children With Combined Immunodeficiency.

BACKGROUND: Survival of children with combined immunodeficiency is strongly related to patient's age and clinical situation at the time of hematopoietic stem cell transplantation (HSCT). We describe the clinical features before HSCT or enzyme replacement therapy (ERT) in a cohort of children treated in a National Reference Unit. METHODS: A retrospective study of children with CIDs treated in our Hospital during a 20-year period (1995-2014) was performed, analyzing their clinical situation before HSCT/ERT. RESULTS: Thirty-one children were included. Risk factors such as family history or consanguinity were present in 35% of cases, but only 3 children (9%) were initially studied because of family history. Median ages at clinical onset, diagnosis and HSCT/ERT were 3.3, 5.6 and 8.1 months, respectively. All patients had lymphopenia before HSCT/ERT. At the time of admission to our unit, 68% of cases had abnormal lung auscultation, 72% were malnourished, 45% reported chronic gastroenteritis and 35% had hepatosplenomegaly. Before HSCT/ERT, respiratory infections and sepsis episodes were documented in 80% and 42% of cases, respectively. In 23% of children, a viral systemic infection was confirmed. The mortality rate was 35%, and 72% of children who died had Gram-negative bacterial sepsis or a viral infection. CONCLUSIONS: The present study shows the characteristics and outcome of children with CIDs in the absence of neonatal screening. Although all our patients had lymphopenia and most of them had suffered relevant infections or had a positive family history, these factors were not identified early. Respiratory and systemic viral infections were the main source of infection with important implications in clinical outcome. Our results highlight the importance of the implementation of neonatal screening, to improve survival rates.

A genotype-phenotype correlation study in a group of 54 patients with X-linked agammaglobulinemia.

BACKGROUND: X-linked (Bruton's) agammaglobulinemia (XLA) is a rare immunodeficiency caused by a block in B-cell development caused by mutations in the Bruton's tyrosine kinase (BTK) gene. Many aspects of XLA and BTK function remain unresolved; atypical presentations have been reported, and no clear genotype-phenotype correlation has been established. OBJECTIVES: We sought to contribute to the understanding of XLA through the phenotypic and biochemical characterization of a large group of Spanish patients with agammaglobulinemia. We also sought to classify the mutations according to their severity to analyze a genotype-phenotype correlation. METHODS: Clinical and analytic data were collected from the clinical records. We studied the BTK gene, protein expression, and function, and the findings were correlated with the phenotypic information. RESULTS: Fifty-four patients were given diagnoses of XLA. We identified 38 different mutations in BTK, 26 not described in other patients, and several uncommon clinical phenotypes or analytic characteristics were found. The statistical analysis shows that less severe mutations or minimal detection of protein by means of flow cytometry are associated with decreased severity in clinical and analytic data, demonstrating a clear relation between the type of mutation and the disease expressivity. However, some exemptions to this rule were noted. CONCLUSIONS: XLA is a variable disease. Globally, a genotype-phenotype correlation is observed, but individual discrepancies between the severity of the mutation and the clinical and analytic phenotype suggest that other loci or ambient factors significantly influence the disease presentation and evolution.