Intrinsic defects of B cell function in X-linked severe combined immunodeficiency

Abstract

The cytokine receptor common gamma chain mutation in X‐linked SCID results in a failure of T and NK cell development and an as yet undefined defect of B cells. Using immunoglobulin isotype‐specific reverse transcription‐PCR we show that although hematopoietic stem cell transplantation restores a diverse repertoire of class‐switched B cell clones, on further analysis these are almost all of donor origin. This suggests that host B cells, which predominate after unconditioned transplantation, are still defective even in the presence of normal T cells. These studies imply that effective humoral reconstitution can only be achieved by the engraftment of normal donor B cells.

Long-term immune reconstitution and clinical outcome after stem cell transplantation for severe T-cell immunodeficiency

“…In the absence of CR, recipients of MMRD-HSCT for B 1 SCID most often retain autologous B cells, and this is usually associated with the need for lifelong immunoglobulin replacement therapy. 3,[18][19][20] In our series Bcell engraftment was strongly associated with use of CR. Previous data from the European experience with HSCT for B 1 SCID had failed to disclose a significant effect of use of CR in promoting B-cell engraftment.…”

Long-term immune reconstitution after anti-CD52–treated or anti-CD34–treated hematopoietic stem cell transplantation for severe T-lymphocyte immunodeficiency

“…18 Recipient B lymphocytes in IL-7Ra-deficient SCID are functionally normal, whereas those from CgC-or JAK3-deficient SCID are intrinsically defective. 19 Therefore unless donor B-lymphocyte chimerism is achieved in patients with CgC-or JAK3-deficient SCID, normal humoral function is unlikely because interaction with donor T lymphocytes does not result in immunoglobulin class switching and antigen-specific IgG production in recipient B lymphocytes. 20 Our results are difficult to interpret because more patients in the anti-CD34-treated HSC group had CgC/ JAK3 SCID with recipient B lymphocytes.…”

“…More sensitive methods of detecting microchimerism might detect donor cells in this patient. 19 Patient 8, with IL-7Ra deficiency, does not make immunoglobulin, although donor T lymphocytes would be expected to interact with recipient B lymphocytes. In this patient T-lymphocyte engraftment is poor, with few TEE cells and a restricted T-lymphocyte repertoire (data not shown); there might be too few T-and B-lymphocyte interactions for effective humoral immunity.…”

Severe Combined Immunodeficiency Disorders

“…About half of survivors continue to require immunoglobulin replacement, 62% of whom have IL2RG deficiency, for which B-cell reconstitution is known to be challenging. 12 More than 80% of patients with RAG1 and RAG2 deficiency also continue to require immunoglobulin replacement therapy. However, patients with IL7R (94%), ADA (78%), and CD3 component deficiencies (100%) develop normal B-cell function and are able to discontinue immunoglobulin infusions.…”