Posttransplant B cell development and function in patients with B cell positive SCID caused by pathogenic variants in IL2RG and JAK3

Abstract Genetic defects in IL2RG or JAK3 can cause the phenotype of severe combined immunodeficiency (SCID) with absent T- and non-functional B-lymphocytes (T-B+ SCID). B cell function and the need for immunoglobulin replacement after hematopoietic stem cell transplantation (HSCT) depends on the engraftment of donor B-lymphocytes. In a retrospective study we describe B-lymphocyte reconstitution after HSCT with the objective to identify B cell subpopulations as an early predictor for the maturation and function of B cells after HSCT. All patients included underwent HSCT in a single institution between 1980 and 2017. First, we studied B cell maturation in cryopreserved blood samples of 12 long-term surviving patients with B+ SCID (IL2RG-deficiency) after haploidentical HSCT and mixed B cell chimerism. Recipient and donor B cell subpopulations were identified by HLA-staining using flow cytometry. In a consecutive step we compared B cell subpopulations irrespective of chimerism between patients with or without post-transplant B cell function. Samples for this study had been obtained between day +90 to +250 after HSCT from 25 post-transplant long-term survivors with B-positive (9 with genetic variants in JAK3, 16 in IL2RG) SCID, 9/25 were dependent and 16/25 independent of Ig-substitution. We demonstrate that a proportion of less than 2% of donor B cells is sufficient for posttransplant B cell function and that a proportion of more than 4.7% of switched memory (IgM-) B cells in the memory B cell population (CD19+CD27+) between days +90 and +250 after HSCT correlates with normal B cell function and independence from immunoglobulin substitution.