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Purpose: This paper aims to explore structural and systemic influences in the development of competence models and qualifications systems at sectoral and national levels across Europe, considering the influences of different socio-economic models of skill formation on the processes of design and provision of qualifications. Design/methodology/approach: The paper is based on a meta analysis of three European projects that used literature review, documentary analysis and interviews with practitioners and policy makers. Findings: The main methodological and practical challenges posed by varieties of competence and qualifications to inter-country comparability of qualifications are shown to be related to different socio-economic models of skill formation. Research limitations/implications: The research is limited to 13 countries and four sectors but these were carefully selected to maximise coverage of European diversity with respect to competence models, training regimes and approaches to qualifications. There is clearly a need for further research involving more countries and sectors. Practical implications: The paper offers recommendations for improving the potential of the European Qualifications Framework to promote comparability of qualifications and hence mobility of labour. These recommendations will be of interest to policy makers and practitioners involved in using the EQF and similar instruments. Originality/value: This is the first systematic attempt to explore the methodological and practical difficulties of establishing comparability between qualifications. (Contains 4 tables.)

Author(s): Stéphanie Rigaud [1, 5]; Marie-Claude Fondanèche [1, 5]; Nathalie Lambert [1, 2]; Benoit Pasquier [1]; Véronique Mateo [1]; Pauline Soulas [1]; Lionel Galicier [3]; Françoise Le Deist [1, 2]; [...]

Research has been conducted on the variable, diversity, joining gene segments expressed by a mechanism known as V(D)J recombination. The cloning of the gene Artemis which encodes a protein involved in the V(D)J recombination /DNA repair has been carried out and the results of the protein sequence analysis suggest that this gene belongs to the metallo-beta-lactamase superfamily.

Severe combined immunodeficiency-X1 (SCID-X1) is an X-linked inherited disorder characterized by an early block in T and natural kilter (NK) lymphocyte differentiation. This block is caused by mutations of the gene encoding the [Gamma]c cytokine receptor subunit of interteukin-2, -4, -7, -9, and -15 receptors, which participates in the delivery of growth, survival, and differentiation signals to early lymphoid progenitors. After preclinical studies, a gene therapy trial for SCID-X1 was initiated, based on the use of complementary DNA containing a defective [Gamma]c Moloney retrovirus-derived vector and ex vivo infection of [CD34.sup.+] cells. After a 10-month follow-up period, [Gamma]c transgene-expressing T and NK cells were detected in two patients. T, B, and NK cell counts and function, including antigen-specific responses, were comparable to those of age-matched controls. Thus, gene therapy was able to provide full correction of disease phenotype and, hence, clinical benefit., In considering diseases that might be ameliorated by gene therapy, a setting in which a selective advantage is conferred by transgene expression, in association with long-lived transduced cells such as [...]

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, rapidly fatal, autosomal recessive immune disorder characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines. Linkage analyses indicate that FHL is genetically heterogeneous and linked to 9q21.3-22, 10q21-22, or another as yet undefined locus. Sequencing of the coding regions of the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients. Cultured lymphocytes from patients had defective cytotoxic activity, and immunostaining revealed little or no perforin in the granules. Thus, defects in perforin are responsible for 10q21-22-[inked FHL Perforin-based effector systems are, therefore, involved not only in the lysis of abnormal cells but also in the down-regulation of cellular immune activation., FHL is a hemophagocytic lymphohistiocytic disorder in which previously healthy young children present with fever, splenomegaly, hepatomegaly, pancytopenia, coagulation abnormalities, neurological abnormalities, and high serum concentrations of interferon-[Gamma] (IFN-[Gamma]) and [...]

One form of autoimmune lymphoproliferative syndrome II (ALPS II) involves a mutation in the gene for CASP 10. CASP 10 is involved in lymphocyte apoptosis, and the resulting defect in apoptosis causes an abnormal accumulation of T and B cells and autoimmune disease.

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the gene encoding NEMO/IKKgamma, the regulatory subunit of the IkappaB kinase (IKK) complex. IKK normally phosphorylates the IkappaB-inhibitors of NF-kappaB at specific serine residues, thereby promoting their ubiquitination and degradation by the proteasome. This allows NF-kappaB complexes to translocate into the nucleus where they activate their target genes. Here, we describe an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense mutation at serine 32 of IkappaBalpha. This mutation is gain-of-function, as it enhances the inhibitory capacity of IkappaBalpha by preventing its phosphorylation and degradation, and results in impaired NF-kappaB activation. The developmental, immunologic, and infectious phenotypes associated with hypomorphic NEMO and hypermorphic IKBA mutations largely overlap and include EDA, impaired cellular responses to ligands of TIR (TLR-ligands, IL-1beta, and IL-18), and TNFR (TNF-alpha, LTalpha1/beta2, and CD154) superfamily members and severe bacterial diseases. However, AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell immunodeficiency. Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro. Our report highlights both the diversity of genotypes associated with EDA-ID and the diversity of immunologic phenotypes associated with mutations in different components of the NF-kappaB signaling pathway. [ABSTRACT FROM AUTHOR]

We have previously described the identification of Artemis, a factor involved in the nonhomologous end joining (NHEJ) phase of V(D)J recombination of T and B cell receptor genes. Null mutations of the Artemis gene result in a complete absence of T and B lymphocytes that is associated with increased cell radiosensitivity, causing the radiosensitive T(-)B(-) SCID (RS-SCID) condition. We presently report the occurrence of hypomorphic mutations of the Artemis gene in four patients from two kindreds. Partially preserved in vivo activity of Artemis is associated with the presence of polyclonal T and B lymphocyte populations, albeit in reduced numbers, along with chromosomal instability and development of EBV-associated lymphoma in two of four patients. This syndrome emphasizes the role of Artemis in the NHEJ pathway of DNA repair and suggests that other, yet ill-defined, conditions associating immunodeficiency and lymphoma could be caused by mutations in genes encoding NHEJ factors. [ABSTRACT FROM AUTHOR]

Examines the linkage of familial hemophagocytic lymphohistiocytosis (FHL) to 10q21-22. Characteristic of FHL; Relevance of T cell and marcophages on FHL; Correlation between neurological abnormalities and pancytopenia.

Immune function has been restored in 9 of 10 children with X-linked severe combined immunodeficiency by gamma c gene transfer in CD34+ cells. The distribution of both T-cell receptor (TCR) V beta family usage and TCR V beta complementarity-determining region 3 (CDR3) length revealed a broadly diversified T-cell repertoire. Retroviral integration site analysis in T cells demonstrated a high number of distinct insertion sites, indicating polyclonality of genetically corrected cell clones, in all patients. Detection of gamma c transgene expression on patients' mature myeloid cells has prompted us to investigate the nature of the most immature transduced hematopoietic precursor cells. Insertion sites shared by T and B lymphocytes as well as highly purified granulocytes and monocytes demonstrate the correction of common multipotent progenitor cells. Moreover, our data show that differentiated leukocytes share the same exact insertion sites with CD34+ cells that we obtained 8 months later and that were able to generate long-term culture-initiating cells (LTC-ICs). This finding demonstrates the initial transduction of very primitive multipotent progenitor cells with self-renewal capacity. These results provide a first evidence in the setting of a clinical trial that CD34+ cells maintain both lymphomyeloid potential as well as self-renewal capacity after ex vivo manipulation.