Development of B-lineage cells in immunoglobulin-transgenic scid mice

Michal Reichman-Fried, University of Pennsylvania


Severe combined immune deficiency in mice results from a single autosomal recessive mutation (scid). Although mice homozygous for scid (scid mice) show evidence of early lymphoid cells committed to the B- or T- cell pathway, these cells generally fail to differentiate into pre-B, B and T cells. It has been hypothesized that this developmental arrest reflects a defect in the mechanism responsible for rearrangement of immunoglobulin (Ig) and T-cell receptor genes. The present work was designed to test this hypothesis by introducing functionally rearranged Ig transgenes (i.e., Ig-$\mu$ heavy-chain gene alone or both Ig-$\mu$ and Ig-$\kappa$ light chain genes) into the scid mouse genome to ascertain whether this results in further differentiation of scid B-lineage committed cells (pro B cells). It was found that scid mice with a functional $\mu$-heavy chain gene alone ($\mu$-transgenic scid mice) develop normal numbers of pre-B cells in their bone marrow; however, these cells do not differentiate into IgM$\sp+$ B cells. In mice carrying both a functional Ig-$\mu$ and Ig-$\kappa$ transgene ($\mu\kappa$-transgenic scid mice), low numbers of transgene-expressing IgM$\sp+$ cells are detected in the bone marrow, but these cells do not migrate to the peripheral lymphoid tissues and do not become Ig-secreting plasma cells. Further studies have indicated that pre-B cells of $\mu$-transgenic scid mice rarely attempt rearrangement of Ig-$\kappa$ light chain genes. Moreover, the frequency of rearrangements at the endogenous Ig-heavy chain genes in scid pro-B and pre-B cells was markedly reduced relative to that in pro-B and pre-B cells from normal mice. Together, these results confirm the linkage between scid and antigen-receptor gene recombination and suggest that this process might be prematurely terminated in developing scid lymphocytes, thus resulting in their developmental arrest. If other differentiative processes, which are critical for B-cell development and function, were to depend on the occurrence of endogenous Ig-gene rearrangements, then the rarity of these rearrangements in scid cells could account for the impaired generation of B cells in $\mu\kappa$-transgenic scid mice.

Subject Area

Cellular biology|Molecular biology|Immunology

Recommended Citation

Reichman-Fried, Michal, "Development of B-lineage cells in immunoglobulin-transgenic scid mice" (1991). Dissertations available from ProQuest. AAI9125735.