G Di Matteo

The impact of TACI mutations: from hypogammaglobulinemia in infancy to autoimmunity in adulthood.

Common variable immunodeficiency (CVID) is considered the most common symptomatic antibody deficiency and, although mainly reported in adults, it may present from childhood. Few data on the impact of TACI defects on the clinical and immunological status of children are available. We screened 42 hypogammaglobulinemia children to investigate the frequency and mutational features of TACI defects. The genetic, clinical and immunological characterization was extended to 31 relatives of 11 children with TACI mutations. Of interest, our analysis showed a considerably higher mutation frequency in hypogammaglobulinemic children (13/42; 31%) than in other cohorts of adult patients. In seven out of nine families with the C104R variant, the prevalence of autoimmunity was significantly higher in C104R heterozygous relatives (8/15; 53%) than in those with no C104R mutation (1/11; 9%). Our data suggest a different impact of TACI mutations, from hypogammaglobulinemia in children to autoimmune disease in adulthood.

Insight into B cell development and differentiation

The main topic of this article is B cell development and differentiation, with a special focus on the mechanisms and molecules that regulate the expression of humoral immunity. Molecular epidemiological analysis was performed on the genes responsible for the X‐linked agammaglobu‐linemia (XLA) phenotype of the majority of Italian patients and their distinct mutations were characterized. Mutations in Brutons tyrosine kinase (BTK), a member of Tec Family of protein tyrosine kinases, have been found to be mainly responsible for XLA disease. The exact function of BTK in signal transduction is not yet known; thus, the specific role of BTK in receptor‐dependent calcium signaling and the pro‐antiapoptotic regulatory activity was addressed by transfecting RAMOS‐1, a BTK‐deficient human Burkitts/B cell leukemia line with wild‐type and mutant constructs. This work may provide clues about critical sites in the molecule and give support for gene therapy as a potential successful approach to XLA. Another aspect of this research is the identification and dissection of the molecular events that are likely to be directly related to the ability to express various isotypes of immunoglobulin with differing function and certain B cell immunodeficiency, mainly common variable disease and non‐X‐linked hyperIgM. B cell development and maturation steps in different compartments of the immune system are tracked by the analysis of cell‐surface molecules and components of the signal transduction pathways, i.e. CD40, CD30, CD27, CD38, CD22 and CD24. A few components involved in B cell development, maturation and differentiation and their specific functional role are at least partially known, but these are far from fitting into an understandable pathway at present.

Visceral leishmaniasis revealing chronic granulomatous disease in a child.

We report the first description of visceral leishmaniasis (VL) infection as a harbinger of chronic granulomatous disease (CGD) in a 3-year old child. Although VL is not frequently suspected in CGD patients, our case emphasises the importance of a complete evaluation of the immune system in children presenting with VL in order to exclude underlying immunodeficiency states. As the prognosis of CGD is poor, with high morbidity and mortality, establishing an early diagnosis has important practical implications in the successful treatment of these patients. Following the diagnosis, the patient received Human Leukocyte Antigen (HLA) identical sibling bone marrow transplantation (BMT). The child is now 2 years post-transplant and is in good general conditions with normal blood counts, and evidence of full-donor chimerism in repeated fluorescence in situ hybridization (FISH) studies.