Chantal Lagresle-Peyrou1, Michèle Millili2, Sonia Luce3, Annie Boned2, Hanem Sadek1, Julien Rouiller1, Pierre Frange4, Guilhem Cros5, Marina Cavazzana1, Isabelle André-Schmutz6, Claudine Schiff7. 1. CIC-BT 502 Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; INSERM, U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France. 2. Centre d'Immunologie de Marseille-Luminy, Faculté des Sciences de Luminy, Aix Marseille Université, UM2, Marseille, France; INSERM, U1104, Marseille, France; Centre National de la Recherche Scientifique, UMR7280, Marseille, France. 3. INSERM, U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France. 4. Unité d'Immunologie, Hématologie et Rhumatologie pédiatriques, Hôpital Necker-Enfants Malades, Paris, France; EA 3620, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 5. Unité d'Immunologie, Hématologie et Rhumatologie pédiatriques, Hôpital Necker-Enfants Malades, Paris, France. 6. INSERM, U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France. Electronic address: isabelle.andre-schmutz@inserm.fr. 7. Centre d'Immunologie de Marseille-Luminy, Faculté des Sciences de Luminy, Aix Marseille Université, UM2, Marseille, France; INSERM, U1104, Marseille, France; Centre National de la Recherche Scientifique, UMR7280, Marseille, France. Electronic address: schiff@ciml.univ-mrs.fr.
Abstract
BACKGROUND: Expression of the pre-B-cell receptor (pre-BCR) by pre-BII cells constitutes a crucial checkpoint in B-cell differentiation. Mutations that affect the pre-B-cell receptor result in early B-cell differentiation blockades that lead to primary B-cell immunodeficiencies. BLNK adaptor protein has a key role in the pre-B-cell receptor signaling cascade, as illustrated by the abnormal B-cell development in the 4 patients with BLNK gene defects reported to date. However, the BLNK protein's precise function in human B-cell differentiation has not been completely specified. METHODS: B-cell development, including IgVH and Vk chain repertoires analysis, was studied in the bone marrow of a new case of BLNK deficiency in vitro and in vivo. RESULTS: Here, we report on a patient with agammaglobulinemia, with a total absence of circulating B cells. We detected a homozygous mutation in BLNK, which leads to the complete abrogation of BLNK protein expression. In the bone marrow, we identified a severe differentiation blockade at the pre-BI- to pre-BII-cell transition. IgVH gene rearrangements and selection of the IgH repertoire were normal, whereas the patient's pre-BI cells showed very restricted usage of the IgVκ repertoire. Complementation of bone marrow progenitors from the patient with the BLNK gene and transplantation into NOD/SCID/γcko mice allowed the complete restoration of B-cell differentiation and a normal usage of the IgVκ genes.
BACKGROUND: Expression of the pre-B-cell receptor (pre-BCR) by pre-BII cells constitutes a crucial checkpoint in B-cell differentiation. Mutations that affect the pre-B-cell receptor result in early B-cell differentiation blockades that lead to primary B-cell immunodeficiencies. BLNK adaptor protein has a key role in the pre-B-cell receptor signaling cascade, as illustrated by the abnormal B-cell development in the 4 patients with BLNK gene defects reported to date. However, the BLNK protein's precise function in human B-cell differentiation has not been completely specified. METHODS: B-cell development, including IgVH and Vk chain repertoires analysis, was studied in the bone marrow of a new case of BLNK deficiency in vitro and in vivo. RESULTS: Here, we report on a patient with agammaglobulinemia, with a total absence of circulating B cells. We detected a homozygous mutation in BLNK, which leads to the complete abrogation of BLNK protein expression. In the bone marrow, we identified a severe differentiation blockade at the pre-BI- to pre-BII-cell transition. IgVH gene rearrangements and selection of the IgH repertoire were normal, whereas the patient's pre-BI cells showed very restricted usage of the IgVκ repertoire. Complementation of bone marrow progenitors from the patient with the BLNK gene and transplantation into NOD/SCID/γcko mice allowed the complete restoration of B-cell differentiation and a normal usage of the IgVκ genes.
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