T-B+NK+ Severe Combined Immunodeficiency Caused by Complete Deficiency of the CD3zeta Subunit of the T Cell Antigen Receptor Complex

Roberts, Joseph L.; Lauritsen, Jens Peter H.; Cooney, Myriah; Parrott, Roberta E.; Sajaroff, E.O.; Win, Chan M.; Keller, Michael D.; Carpenter, Jeffery H.; Sarzotti, Marcella; Zhong, Xiao‐Ping; Wiest, David L.; Bucley, R.H.

doi:10.1016/j.jaci.2006.11.298

Cited by 19 publications

(23 citation statements)

References 89 publications

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“…The abnormal levels of zeta chain expression could also account for the immune dysfunction observed in inflammation, systemic lupus erythematosus or aplastic anaemia [11][12][13]. There have also been case reports on immunodeficient children with mutations concerning the gene encoding the zeta chain [14,15]. However, apart from our preliminary results [16] and a study by Aviles et al [17], there are no data available on zeta expression in T lymphocytes in the peripheral blood of children with INS.…”

Section: Introductionmentioning

confidence: 67%

Zeta chain expression in T and NK cells in peripheral blood of children with nephrotic syndrome

et al. 2010

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The idiopathic nephrotic syndrome (INS) has been related to cellular immune disturbances. The zeta (zeta) chain, a component of the T-cell receptor/CD3 (TCR) complex and CD16 heterodimer in NK cells, plays a crucial role in T and NK cell activation and proliferation. The aim of our study was to examine zeta chain expression in CD4+, CD8+ T lymphocytes and NK cells in the peripheral blood of children with INS and to evaluate the effect of anti-CD3+rIL-2 stimulation on the level of zeta chain expression in the INS pediatric population. The study group consisted of 15 children with INS in relapse, 16 patients with INS in clinical remission, and 17 controls. The percentage of zeta-positive cells and the values of mean fluorescence intensity (MFI) were determined by flow cytometry. Compared with that in the controls, the percentage of zeta+ freshly isolated NK cells in children with INS in relapse was significantly lower, whereas, in CD3+/CD4+ and CD3+/CD8+ populations, no alteration was observed. There were no differences in the MFI values between the populations of freshly isolated cells either. Stimulation with anti-CD3+rIL-2 decreased the percentage of zeta+/CD4+ T cells and NKzeta+ cells in a significant way in all the groups analysed, whereas the percentage of zeta+/CD8+ T cells decreased significantly only in patients with INS in relapse. The altered pattern of zeta expression in fresh NK cells from children with INS in relapse, and the disturbed response of zeta+/CD8+ T cells to anti-CD3+rIL-2 stimulation in relapse, suggests the possible role of this chain in immune dysregulation in INS, particularly with regard to cytotoxic cells.

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Section: Introductionmentioning

confidence: 67%

Zeta chain expression in T and NK cells in peripheral blood of children with nephrotic syndrome

et al. 2010

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“…When a variable chain such as TCRα is affected, only αβ T cells are impaired, as shown recently (3). When an invariant chain is affected, both αβ and γδ T cells are either absent, as observed in CD3δ or CD3ε deficiency (4,5), or reduced, as reported for CD3γ or TCRζ deficiency (6,7). These immunophenotypes are described as T − B + NK + or T ± B + NK + , respectively.…”

Section: Introductionmentioning

confidence: 87%

A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a Tαβ–Tγδ+B+NK+ human SCID

Gil¹,

Busto²,

Garcillán³

et al. 2011

J. Clin. Invest.

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T cells recognize antigens via their cell surface TCR and are classified as either αβ or γδ depending on the variable chains in their TCR, α and β or γ and δ, respectively. Both αβ and γδ TCRs also contain several invariant chains, including CD3δ, which support surface TCR expression and transduce the TCR signal. Mutations in variable chains would be expected to affect a single T cell lineage, while mutations in the invariant chains would affect all T cells. Consistent with this, all CD3δ-deficient patients described to date showed a complete block in T cell development. However, CD3δ-KO mice have an αβ T cell-specific defect. Here, we report 2 unrelated cases of SCID with a selective block in αβ but not in γδ T cell development, associated with a new splicing mutation in the CD3D gene. The patients' T cells showed reduced CD3D transcripts, CD3δ proteins, surface TCR, and early TCR signaling. Their lymph nodes showed severe T cell depletion, recent thymus emigrants in peripheral blood were strongly decreased, and the scant αβ T cells were oligoclonal. T cell-dependent B cell functions were also impaired, despite the presence of normal B cell numbers. Strikingly, despite the specific loss of αβ T cells, surface TCR expression was more reduced in γδ than in αβ T cells. Analysis of individuals with this CD3D mutation thus demonstrates the contrasting CD3δ requirements for αβ versus γδ T cell development and TCR expression in humans and highlights the diagnostic and clinical relevance of studying both TCR isotypes when a T cell defect is suspected.

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“…In the United States, most cases of B-positive, NK-positive SCID occur as a result of IL7R (IL-7Ra) deficiency. 9,24 Rarer defects in components of the T-cell receptor have also been reported to cause SCID, including mutations in CD3D, [25][26][27][28] CD3E, 26 and CD247, 29,30 which encode the CD3 d, ε, and z chains, respectively. Defects in CD3G 31, 32 have not yet been observed to cause true SCID.…”

Section: B-positive Natural Killer-positive Severe Combined Immunodementioning

confidence: 99%

Severe Combined Immunodeficiency Disorders

Chinn

Shearer

2015

Immunology and Allergy Clinics of North America

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T-B+NK+ Severe Combined Immunodeficiency Caused by Complete Deficiency of the CD3zeta Subunit of the T Cell Antigen Receptor Complex

Cited by 19 publications

References 89 publications

Zeta chain expression in T and NK cells in peripheral blood of children with nephrotic syndrome

Zeta chain expression in T and NK cells in peripheral blood of children with nephrotic syndrome

A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a Tαβ–Tγδ+B+NK+ human SCID

Severe Combined Immunodeficiency Disorders

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