Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment - 30/03/13
, Mike Recher, MD b, c, , Stefania Masneri, MS d, Sachin N. Baxi, MD c, Claudia Fiorini, PhD a, Francesca Antonelli, BS d, Christian A. Wysocki, MD, PhD e, Jose G. Calderon, MD e, Hermann Eibel, PhD f, Angela R. Smith, MD, MS g, Francisco A. Bonilla, MD, PhD c, Erdyni Tsitsikov, PhD h, Silvia Giliani, PhD d, Luigi D. Notarangelo, MD b, c, i, Sung-Yun Pai, MD a, j, ⁎ 
Corresponding author: Sung-Yun Pai, MD, Boston Children’s Hospital, One Blackfan Circle, Karp Family Research Laboratories, Rm 08214, Boston, MA 02115.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.
Conclusion |
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.
Le texte complet de cet article est disponible en PDF.Key words : Severe combined immunodeficiency, cytokine signaling, maternal engraftment
Abbreviations used : B-LCL, BMT, CD40L, CFSE, GVHD, JAK3, OS, SCID, STAT, TCR, TREC
Plan
| Supported by the Translational Investigator Service at Boston Children’s Hospital (to S.-Y.P.), the Manton Foundation (to L.D.N.), the National Institutes of Health (U54-AI082973 to S.-Y.P. and L.D.N.), and Fondazione Nocivelli (to S.G). M.R. was supported by the Swiss National Science Foundation (SNSF/SSMBS) grant PASMP3-127678. |
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| Disclosure of potential conflict of interest: M. Recher has been supported by one or more grants from the Swiss National Science Foundation (SNSF/SSMBS; Nrz PASMP3-127678). C. A. Wysocki has been supported by one or more grants from the National Institutes of Health. L. D. Notarangelo has received one or more grants from the National Institutes of Health and from the Manton Foundation, is a Board member for the Immune Disease Institute, is employed by Boston Children’s Hospital, has received one or more grants from or has one or more grants pending with the Wiskott-Aldrich Foundation and with the March of Dimes, and has received royalties from UpToDate. S.-Y. Pai has been supported by one or more grants from the National Institute of Allergy and Infectious Diseases and from Translational Research Program at Boston Children’s Hospital. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 4
P. 1136-1145 - avril 2013 Retour au numéro
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