Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis - PubMed (original) (raw)

Case Reports

doi: 10.1172/JCI16774.

Christophe Pannetier, Régina de Chasseval Rd, Françoise le Deist Fl, Marina Cavazzana-Calvo, Serge Romana, Elizabeth Macintyre, Danielle Canioni, Nicole Brousse, Alain Fischer, Jean-Laurent Casanova, Jean-Pierre de Villartay

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Case Reports

Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis

Despina Moshous et al. J Clin Invest. 2003 Feb.

Abstract

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.

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Figures

Figure 1

Figure 1

Immunohistological analysis of B cell lymphomas in P68 and P69. (a) Lymphoproliferation in the liver of P69, showing a lymphoid infiltration with a mixture of large and small lymphocytes. (b–f) Lymphoproliferation in lymph node of P68 stained with H&E (b), CD20 (c), Ki67 (d), LMP1 (e), and EBER (f). ×40.

Figure 2

Figure 2

Clonality of B cell lymphomas in P68 and P69. IgH V(D)J genescan profiles from liver biopsy (top, clonal monoallelic) and peripheral blood lymphocytes (PBL) (bottom, polyclonal) from P69 and lymph node (middle, clonal biallelic) from P68 DNA, amplified with FR1 primer. The size of PCR products is indicated.

Figure 3

Figure 3

Cell cycle analysis following γ-ray irradiation. Primary skin fibroblasts from a control (a), a P70 (b), and an AT patient (c) were analyzed for the presence of the S and G2 cell cycle checkpoints following 5 Gy IR. Results are expressed as the percentage of cells present in each phase of the cell cycle during BrdU pulse staining 10 hours after irradiation. The various phases of the cell cycle were determined by measurement of DNA content (propidium iodide staining).

Figure 4

Figure 4

TCR-β junction analysis. (a) TCR CDR3-length profile of Vβ2, Vβ5, and Vβ6 cell populations in lymphocytes from P69 and P70 (solid lines) and control (dashed lines). Determination was performed by the Immunoscope method. The relative intensity of the bands (y axis) was plotted as a function of CDR3 size. (b) Sequence of TCR-β V(D)J junctions for Vβ2 in lymphocytes from P69, P70, and control. P nucleotides are represented in italics.

Figure 5

Figure 5

Complementation of IR sensitivity. (a) Fibroblasts from P70 were complemented with WT Artemis. The selective advantage of transduced cells after 3 Gy IR was assessed over time. The control curves, (vector 0 Gy) and (vector 3 Gy), are superimposed. (b) Fibroblasts from an Artemis-deficient patient were complemented with either the WT or the P70-specific truncated form of Artemis. The selective advantage of transduced cells after 4 Gy IR was assessed over time. Results are expressed as the GFP+/GFP– cell ratio over time following irradiation.

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