Reduced memory B‐cell populations in boys with B‐cell dysfunction after bone marrow transplantation for X‐linked severe combined immunodeficiency

Abstract

X‐linked severe combined immunodeficiency (XSCID) is a lethal disease resulting in death in infancy. In many instances, haploidentical bone marrow transplantation (BMT) offers reconstitution of T‐cell immunity alone, with residual hypogammaglobulinaemia. The exact nature of B‐cell dysfunction in these patients is unclear, although differentiation arrest of the B cells is a potential explanation. To ascertain the differentiation status of peripheral blood B lymphocytes from XSCID patients after BMT, the surface expression of CD19, CD10, CD34, CD5, serum immunoglogulin (sIg)M, sIgD, sIgG and CD27 on these B cells was investigated using three‐colour flow cytometry. CD27 is a marker of memory B cells. Populations of CD19+IgM−D− B cells, CD19+IgM‐only, CD19+IgG+CD27+ and CD19+IgM+ CD27+ B cells were found to be diminished in the XSCID patients after BMT with persistent hypogammaglobulinaemia, compared with both post‐BMT patients with B‐cell function and age‐matched normal controls. This indicated the lack of CD19+IgM−D− B cells, which represent Ig isotype‐switched B cells, as well as CD19+IgM‐only and CD19+IgG+CD27+ or CD19+IgM+CD27+ memory B‐cell populations. Interaction between CD27 and its ligand CD70 has been shown to induce IgG and IgM production by CD27+ B cells. Therefore, the lack of CD27/70 interaction is a probable explanation for the hypogammaglobulinaemia in these patients after BMT.

IL-21 is the primary common γ chain-binding cytokine required for human B-cell differentiation in vivo

“…12,23 The proportions of memory B cells that had undergone isotype switching to IgG and IgA was significantly reduced in group 2 X-SCID/ JAK3-deficient patients compared with healthy controls and group 1 patients (Figure 1C-D), consistent with previous findings. 20 Thus, a likely explanation for poor humoral immune responses in vivo, and requirement for IgRT, in group 2 SCID patients is an inability to generate a normal pool of memory B cells.…”

“…17 However, despite normalization of T-cell numbers, B-cell dysfunction persists in a substantial proportion of transplanted patients who subsequently require Ig replacement therapy (IgRT). [17][18][19][20] This impaired reconstitution of humoral immunity is more often associated with split chimerism, that is, the presence of donor-derived T cells and the persistence of autologous, genetically defective B lymphocytes. [17][18][19][20] Robust in vivo B-cell function is often observed in patients with IL7R, ADA, or CD3 deficiency who also develop split chimerism after HCT, 17,19 indicating that the specific nature of the genetic defect may affect the quality of humoral immune reconstitution among SCID patients who retain autologous B cells post-HCT.…”

Severe Papillomavirus Infection Progressing to Metastatic Squamous Cell Carcinoma in Bone Marrow-Transplanted X-Linked SCID Dogs

“…Although T-cell depletion makes BMT possible for virtually all SCID patients, long-term immune reconstitution and survival are less favorable than those after histocompatible BMT, with 60 to 78% of patients surviving for 3 to 6 months posttransplantation (10,22). The most common immunologic problems in human XSCID patients following both histocompatible and haploidentical BMT are a failure to engraft donor B cells and poor humoral immune reconstitution that can be managed by intravenous immunoglobulin therapy (18,23,53,55). A recent retrospective study of 41 SCID patients who have survived for more than 10 years following BMT reported that 50% of XSCID and Jak3-deficient SCID patients (9/18) developed chronic severe papillomavirus infections, with a median age of onset of 8 years post-BMT, while patients with other forms of SCID did not develop cutaneous papillomas (30).…”

Abnormal T cell–dependent B-cell responses in SCID mice receiving allogeneic bone marrow in utero

“…19,20 In spite of this, many SCID recipients of haploidentical stem cells exhibit prolonged humoral deficiency. [19][20][21][22][23][24][25] Several studies have demonstrated that humoral dysfunction is attributed to the lack of donor B-cell engraftment. 21,[23][24][25] This suggests that host B cells in SCID patients are dysfunctional or only partially functional and may not be able to appropriately respond to donor T-cell signals.…”

“…[19][20][21][22][23][24][25] Several studies have demonstrated that humoral dysfunction is attributed to the lack of donor B-cell engraftment. 21,[23][24][25] This suggests that host B cells in SCID patients are dysfunctional or only partially functional and may not be able to appropriately respond to donor T-cell signals. The reason for poor donor B-cell engraftment is unclear, but it may reflect the inability of donor B-cell precursors to compete for space with the host B-cell pool.…”