Severe combined immunodeficiency. A model disease for molecular immunology and therapy. Immunol Rev

INSERM U429, Hôpital Necker-Enfants Malades, Paris, France.
Immunological Reviews (Impact Factor: 10.12). 03/2005; 203(1):98-109. DOI: 10.1111/j.0105-2896.2005.00223.x
Source: PubMed


Severe combined immunodeficiencies (SCIDs) consist of genetically determined arrest of T-cell differentiation. Ten different molecular defects have now been identified, which all lead to early death in the absence of therapy. Transplantation of allogeneic hematopoietic stem cells (HSCT) can restore T-cell development, thus saving the lives of SCID patients. In this review, the different characteristics of HSCT are discussed along with the available data regarding the long-term outcome. Transient thymopoiesis caused by an exhaustion of donor progenitor cells and possibly a progressive loss of thymus function can lead to a progressive decline in T-cell functions. The preliminary results of gene therapy show the correction of two SCID conditions. Based on the assumption that long-lasting pluripotent progenitor cells are transduced, these data suggest that gene therapy could overcome the long-term recurrence of the T-cell immunodeficiency. SCID is thus a disease model for experimental therapy in the hematopoietic system.

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    • "At the time of activation of naive T-cell into cytotoxic or T-helper cells, the population of naive T-cells has to pass through the pattern recognition process of the identification of antigenic peptide sequences (self or non-self antigen), which in turn decides whether the naive T-cells will be converted into the active T-cells (which will further proliferate) or inactive Tcells (no further proliferation but the cells will survive) or dead T-cells (which will further trigger apoptotic pathway and cell death) (Carter 2000; Coombs and Goldstein 2005). Hence, certain deregulation of this sensitive mechanism can destabilize our body's immune system and can trigger various diseases, like auto-immune diseases, severe combined immune deficiency syndrome (SCID), etc. (Shlomchik et al. 1987; Fischer et al. 2005; Baecklund et al. 2014). However, the complete activation of the T-cell responses and the expression of the major interleukin molecules cannot be achieved by T-cell receptor (TCR) and MHC class II protein interaction alone, but requires the successful interaction of the various co-stimulator molecules with its coreceptors and the activation of the calcium channel as well (Chen and Flies 2013). "
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    ABSTRACT: Various T-cell co-receptor molecules and calcium channel CRAC play a pivotal role in the maintenance of cell’s functional responses by regulating the production of effector molecules (mostly cytokines) that aids in immune clearance and also maintaining the cell in a functionally active state. Any defect in these co-receptor signalling pathways may lead to an altered expression pattern of the effector molecules. To study the propagation of such defects with time and their effect on the intracellular protein expression patterns, a comprehensive and largest pathway map of T-cell activation network is reconstructed manually. The entire pathway reactions are then translated using logical equations and simulated using the published time series microarray expression data as inputs. After validating the model, the effect of in silico knock down of co-receptor molecules on the expression patterns of their downstream proteins is studied and simultaneously the changes in the phenotypic behaviours of the T-cell population are predicted, which shows significant variations among the proteins expression and the signalling routes through which the response is propagated in the cytoplasm. This integrative computational approach serves as a valuable technique to study the changes in protein expression patterns and helps to predict variations in the cellular behaviour.
    Full-text · Article · Sep 2015 · Journal of Biosciences
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    • "Affected patients suffer from life-threatening recurrent infections, chronic diarrhea and failure to thrive. Treatments include hematopoietic stem cell transplantation or gene therapy, to correct gene defects [1]. "
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    ABSTRACT: Here we describe a novel, spontaneous, 4035 basepairs long deletion in the DNA cross-link repair 1C (Dclre1c)-locus in C57BL/6-mice, which leads to loss of exons 10 and 11 of the gene encoding for Artemis, a protein involved into V(D) J-recombination of antigen receptors of T and B cells. While several spontaneous mutations of Artemis have been described to cause SCID in humans, in mice, only targeted deletions by knockout technology are known to cause the same phenotype so far. The deletion we observed causes a loss of Artemis function in the C57BL/6 strain and, consequently, the absence of T and B cells, in presence of normal numbers of NK cells and cells of the myeloid lineage. Thus, for the first time we present T(-)B(-)NK(+) severe combined immunodeficiency (SCID) phenotype after spontaneously occurring modification of Artemis gene in mice. Our mouse model may serve as a valuable tool to study mechanisms as well as potential therapies of SCID in humans.
    Preview · Article · Sep 2013 · PLoS ONE
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    • "These rare, genetically determined disorders, which characteristically manifest during infancy and childhood with increased frequency of infections caused by unusual pathogens, are often accompanied by immunoregulatory defects [28]. Severe combined immunodeficiency (SCID), the most serious and lethal form of PID, is characterized by profound deficiencies of T- and B-cell functions and a low number of natural killer (NK) cells [29,30]. Infants with SCID develop failure to thrive, chronic diarrhea, and infections in the first few months of life. "
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    ABSTRACT: T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) are circular DNA segments generated in T and B cells during their maturation in the thymus and bone marrow. These circularized DNA elements persist in the cells, are unable to replicate, and are diluted as a result of cell division, thus are considered markers of new lymphocyte output. The quantification of TRECs and KRECs, which can be reliably performed using singleplex or duplex real-time quantitative PCR, provides novel information in the management of T- and B-cell immunity-related diseases. In primary immunodeficiencies, when combined with flow cytometric analysis of T- and B-cell subpopulations, the measure of TRECs and KRECs has contributed to an improved characterization of the diseases, to the identification of patients' subgroups, and to the monitoring of stem cell transplantation and enzyme replacement therapy. For the same diseases, the TREC and KREC assays, introduced in the newborn screening program, allow early disease identification and may lead to discovery of new genetic defects. TREC and KREC levels can also been used as a surrogate marker of lymphocyte output in acquired immunodeficiencies. The low number of TRECs, which has in fact been extensively documented in untreated HIV-infected subjects, has been shown to increase following antiretroviral therapy. Differently, KREC number, which is in the normal range in these patients, has been shown to decrease following long-lasting therapy. Whether changes of KREC levels have relevance in the biology and in the clinical aspects of primary and acquired immunodeficiencies remains to be firmly established.
    Full-text · Article · May 2013 · Journal of Translational Medicine
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