title: Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment.
abstract: BACKGROUND
  Mutations in Janus kinase 3 (JAK3) are a cause of severe combined immunodeficiency, but hypomorphic JAK3 defects can result in a milder clinical phenotype, with residual development and function of autologous T cells. Maternal T-cell engraftment is a common finding in infants with severe combined immunodeficiency but is not typically observed in patients with residual T-cell development.
  
  
  OBJECTIVE
  We sought to study in detail the molecular, cellular, and humoral immune phenotype and function of 3 patients with hypomorphic JAK3 mutations.
  
  
  METHODS
  We analyzed the distribution and function of T and B lymphocytes in 3 patients and studied the in vitro and in vivo responses of maternal T lymphocytes in 1 patient with maternal T-cell engraftment and residual production of autologous T lymphocytes.
  
  
  RESULTS
  B cells were present in normal numbers but with abnormal distribution of marginal zone-like and memory B cells. B-cell differentiation to plasmablasts in vitro in response to CD40 ligand and IL-21 was abolished. In 2 patients the T-cell repertoire was moderately restricted. Surprisingly, 1 patient showed coexistence of maternal and autologous T lymphocytes. By using an mAb recognizing the maternal noninherited HLA-A2 antigen, we found that autologous cells progressively accumulated in vivo but did not compete with maternal cells in vitro.
  
  
  CONCLUSIONS
  The study of 3 patients with hypomorphic JAK3 mutations suggests that terminal B-cell maturation/differentiation requires intact JAK3 function, even if partially functioning T lymphocytes are present. Maternal T-cell engraftment can occur in patients with JAK3 mutations despite the presence of autologous T cells.
authors: Division of Hematology-Oncology, the Manton Center for Orphan Disease Research, Department of Laboratory Medicine, Boston Children's Hospital, and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors: Federica
authors: F
authors: Cattaneo
authors: Mike
authors: M
authors: Recher
authors: Stefania
authors: S
authors: Masneri
authors: Sachin N
authors: SN
authors: Baxi
authors: Claudia
authors: C
authors: Fiorini
authors: Francesca
authors: F
authors: Antonelli
authors: Christian A
authors: CA
authors: Wysocki
authors: Jose G
authors: JG
authors: Calderon
authors: Hermann
authors: H
authors: Eibel
authors: Angela R
authors: AR
authors: Smith
authors: Francisco A
authors: FA
authors: Bonilla
authors: Erdyni
authors: E
authors: Tsitsikov
authors: Silvia
authors: S
authors: Giliani
authors: Luigi D
authors: LD
authors: Notarangelo
authors: Sung-Yun
authors: SY
authors: Pai
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D001483:Base Sequence; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002675:Child, Preschool; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D014644:Genetic Variation / Q000276:immunology*; D006801:Humans; D007112:Immunity, Maternally-Acquired; D007223:Infant; D053616:Janus Kinase 3 / Q000235:genetics* / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D061251:Primary Cell Culture; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*
chemical_list: C507933:JAK3 protein, human; D053616:Janus Kinase 3
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