The BLNK adaptor protein has a nonredundant role in human B-cell differentiation

  • J Allergy Clin Immunol. 2014 Jul;134(1):145-54. doi: 10.1016/j.jaci.2013.12.1083.
Chantal Lagresle-Peyrou  1 ,  Michèle Millili  2 ,  Sonia Luce  3 ,  Annie Boned  2 ,  Hanem Sadek  1 ,  Julien Rouiller  1 ,  Pierre Frange  4 ,  Guilhem Cros  5 ,  Marina Cavazzana  1 ,  Isabelle André-Schmutz  6 ,  Claudine Schiff  7
Affiliations
  • 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: [email protected].
  • 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: [email protected].
PMID: 24582315 DOI: 10.1016/j.jaci.2013.12.1083
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.

Keywords
Agammaglobulinemia; B-lymphocyte; BLNK protein; SCID-hu mouse; gene rearrangement; gene therapy; lymphopoiesis; pre–B-cell receptor.