B-cell differentiation and IL-21 response in IL2RG/JAK3 SCID patients after hematopoietic stem cell transplantation

Alexandra M. Miggelbrink, Brent R. Logan, Rebecca H. Buckley, Roberta E. Parrott, Christopher C. Dvorak, Neena Kapoor, Hisham Abdel-Azim, Susan E. Prockop, David Shyr, Hélène Decaluwe, Imelda C. Hanson, Alfred Gillio, Blachy J. Dávila Saldaña, Hermann Eibel, Gregory Hopkins, Jolan E. Walter, Jennifer S. Whangbo, Donald B. Kohn, Jennifer M. Puck, Morton J. Cowan, Linda M. Griffith, Elie Haddad, Richard J. O’Reilly, Luigi D. Notarangelo and Sung-Yun Pai

Key Points

  • IL2RG/JAK3-deficient B cells remain intrinsically defective posttransplant despite follicular helper T-cell reconstitution.

  • In vitro response of B cells to IL-21 is a potential biomarker for humoral immunity in patients with IL2RG/JAK3 SCID after transplantation.


Allogeneic hematopoietic stem cell transplant (HSCT) typically results in donor T-cell engraftment and function in patients with severe combined immunodeficiency (SCID), but humoral immunity, particularly when using donors other than matched siblings, is variable. B-cell function after HSCT for SCID depends on the genetic cause, the use of pre-HSCT conditioning, and whether donor B-cell chimerism is achieved. Patients with defects in IL2RG or JAK3 undergoing HSCT without conditioning often have poor B-cell function post-HSCT, perhaps as a result of impairment of IL-21 signaling in host-derived B cells. To investigate the effect of pre-HSCT conditioning on B-cell function, and the relationship of in vitro B-cell function to clinical humoral immune status, we analyzed 48 patients with IL2RG/JAK3 SCID who were older than 2 years after HSCT with donors other than matched siblings. T follicular helper cells (TFH) developed in these patients with kinetics similar to healthy young children; thus, poor B-cell function could not be attributed to a failure of TFH development. In vitro differentiation of B cells into plasmablasts and immunoglobulin secretion in response to IL-21 strongly correlated with the use of conditioning, donor B-cell engraftment, freedom from immunoglobulin replacement, and response to tetanus vaccine. Patients receiving immunoglobulin replacement who had normal serum immunoglobulin M showed poor response to IL-21 in vitro, similar to those with low serum IgM. In vitro response of B cells to IL-21 may predict clinically relevant humoral immune function in patients with IL2RG/JAK3 SCID after HSCT.

  • Submitted October 30, 2017.
  • Accepted April 26, 2018.
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