T cell receptor repertoire and function in patients with DiGeorge syndrome and velocardiofacial syndrome

Pierdominici, Marina; Marziali, Marco; Giovannetti, Antonello; Oliva, Alessandra; Rosso, Rosamaria; Marino, Bruno; Digilio, M. Cristina; Giannotti, Aldo; Novelli, Giuseppe; Dallapiccola, Bruno; Aiuti, F; Pandolfi, Franco

doi:10.1046/j.1365-2249.2000.01247.x

Cited by 27 publications

(22 citation statements)

References 42 publications

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“…Indeed, that was the case, with patients having both more oligoclonal peaks and V␤ family dropouts than controls. V␤ family dropout has been previously reported in several young patients with the deletion, 41 suggesting that the T-cell repertoire alterations may begin very early in life. In our older population, the increase in oligoclonal peaks and V␤ family dropouts was comparable with what has been seen in HIV-infected patients.…”

Section: Discussionmentioning

confidence: 89%

T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome

Piliero

Sanford

McDonald‐McGinn

et al. 2004

Blood

125

115

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Patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) typically exhibit thymic hypoplasia, conotruncal cardiac defects, and hypoparathyroidism. The immunodeficiency that results from the thymic hypoplasia has been extensively described and consists primarily of T-cell lymphopenia. A curious feature of the T-cell lymphopenia is that the age-related rate of decline of T-cell numbers is slower in patients than controls. This leads to T-cell numbers in adulthood that are minimally decreased compared with controls. This suggests that homeostatic mechanisms might be acting to preserve the peripheral blood T-cell numbers in patients. We characterized changes in CD4/ CD45RA and CD4/CD45RO T-cell populations in patients and controls of various ages and determined T-cell recombination excision circles and telomere length within the CD4/CD45RA population. Patients had evidence of accelerated conversion of naive to memory cells and had evidence of more extensive replicative history within the CD4/CD45RA compartment compared with controls. Oligoclonal T-cell receptor (TCR) V␤ families and missing V␤ families were seen more often in patients than controls. These data are consistent with homeostatic proliferation of T cells in patients with limited T-cell production due to thymic hypoplasia. ( IntroductionChromosome 22q11.2 deletion syndrome is a disorder that is classically associated with conotruncal cardiac anomalies, thymic hypoplasia, and hypoparathyriodism. 1 DiGeorge syndrome, velocardiofacial syndrome, Opitz/GBBB syndrome, Coloboma, heart defects, atresa of choanae, retardation of growth and development, genital anomalies, ear anomalies (CHARGE) syndrome, and conotruncal anomaly face syndrome have been associated with the deletion. The thymic hypoplasia is seen in more than 80% of the patients with the deletion regardless of the other clinical manifestations of the syndrome. The immunodeficiency arising as a consequence of the thymic hypoplasia in patients with the deletion syndrome has been studied for nearly 50 years, and it is now known to be extremely variable. [2][3][4][5] The spectrum of immunodeficiency ranges from absent T cells due to thymic aplasia to normal T-cell numbers. 2,6 T-cell function is typically preserved, although standard mitogen proliferation assays are usually diminished when the T-cell count is very low, corresponding to the diminished numbers of cells competent to respond to the stimulus. 4 Immunoglobulin A (IgA) deficiency, hypogammaglobulinemia, and defects in functional antibody production have been occasionally described and are thought to be secondary to the T-cell defect. [7][8][9] The clinical picture for patients with chromosome 22q11.2 deletion syndrome is similarly diverse. Early descriptions of the syndrome emphasized life-threatening infections; however, most of these patients were ascertained due to absent or nearly absent T cells. 3,10 Recent descriptions of populations with the deletion have noted that the very severe immunodeficiency...

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Section: Discussionmentioning

confidence: 89%

T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome

Piliero

Sanford

McDonald‐McGinn

et al. 2004

Blood

125

115

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“…In addition, RAG2 -/-mice reconstituted with CrkL -/-fetal liver cells showed normal thymic cellularity. It has been proposed that the T cell deficit seen in infants with DGS/VCFS corrects over time, and selectively affects CD8 + cells vs. CD4 + cells [48]. As we analyzed our mice at 6 weeks of age, it is conceivable that evaluation at an earlier age may have detected small differences between mice.…”

Section: Discussionmentioning

confidence: 98%

“…The DGS/VCFS seen in humans results from a deletion in Ch 22q11. Phenotypes vary and the genetic mechanisms that contribute to this syndrome are not fully known, but thymic hypoplasia can be seen which can result in a T cell deficiency [48]. The frequency of thymic anomalies in embryonic day 16.5 embryos was 40% [41].…”

Section: Discussionmentioning

confidence: 99%

T cell development and function in CrkL‐deficient mice

et al. 2003

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The adapter protein CrkL has been implicated in multiple signal transduction pathways in hematopoietic cells. In T lymphocytes, the recruitment of CrkL-C3G complexes has been correlated with hyporesponsiveness, implicating CrkL as a potential negative regulator. To test this hypothesis we examined T cell activation in CrkL-deficient mice. The CrkL -/-genotype was partially embryonic lethal. In viable CrkL -/-mice, peripheral blood counts were normal. The thymus from CrkL -/-mice had 40% fewer cells compared to littermates, but the proportion of thymocyte subsets was comparable. There was no discernable alteration in T cell function as reflected by T cell numbers, expression of memory markers, IL-2 production, proliferation, and differentiation into Th1/Th2 phenotypes. Immunization induced comparable levels of IgG2a and IgG1 antibodies. Chimeric mice, generated by transfer of CrkL -/-fetal liver cells into irradiated RAG2-/-recipients, also showed normal T cell function, arguing against selection via partial embryonic lethality. Our results indicate that CrkL is not absolutely required for T cell development or function, and argue against it being an essential component of a negative regulatory pathway in TCR signaling.

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“…22 All experiments were done using anticoagulant-treated peripheral blood obtained by venipuncture. This study was conducted according to the good clinical practice guidelines of the Italian Ministry of Health.…”

Section: Patientsmentioning

confidence: 99%

“…The pelleted RNA was resuspended in diethyl-pyrocarbonate-treated water and the poly-(A) ϩ portion of total RNA was converted into cDNA using 2. To analyze the TCRBV transcript size patterns cDNA samples were amplified by using a TCRB C1/C2-specific primer (CGG GCT GCT CCT TGA GGG GCT GCG) and a set of 24 TCRBV-specific primers (BV 1, 2, 3, 4, 5.1, 5.3, 6.1, 6.2, 7,8,9,11,12,13,14,15,16,17,18,20,21,22,24). 24 Briefly, 2 L of the RT product was brought to a final reaction volume of 50 L containing 50 mM KCl, 10 mM Tris-HCl 1,5 mM MgCl 2 , 0,2 mM of each dNTPs, 25 pmol of each oligonucleotide, and 2 U Taq DNA polymerase (AmpliTaq; Applied Biosystems).…”

Section: Molecular Studiesmentioning

confidence: 99%

Skewed T-cell receptor repertoire, decreased thymic output, and predominance of terminally differentiated T cells in ataxia telangiectasia

Giovannetti

Mazzetta

Caprini

et al. 2002

Blood

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T cell receptor repertoire and function in patients with DiGeorge syndrome and velocardiofacial syndrome

Cited by 27 publications

References 42 publications

T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome

T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome

T cell development and function in CrkL‐deficient mice

Skewed T-cell receptor repertoire, decreased thymic output, and predominance of terminally differentiated T cells in ataxia telangiectasia

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