Transgenic Expression of a Human Polyreactive Ig Expressed in Chronic Lymphocytic Leukemia Generates Memory-Type B Cells That Respond to Nonspecific Immune Activation

Abstract

We generated transgenic mice, designated SMI, expressing unmutated H and L chain Ig genes encoding a low-affinity, polyreactive human (h)IgM/κ rheumatoid factor. These animals were compared with control AB29 transgenic mice expressing a hIgM/κ rheumatoid factor specific for human IgG, with no detectable reactivity with mouse proteins. SMI B cells expressed significantly lower levels of surface hIgM/κ than did the B cells of AB29 mice, but still could be induced to proliferate by surface Ig cross-linking in vitro and could be deleted with anti-Id mAb in vivo. Transgene-expressing B cells of AB29 mice had a B-2 phenotype and were located in the primary follicle. In contrast, a relatively high proportion of hIgM-expressing B cells of SMI mice had the phenotype of B-1 B cells in the peritoneum or marginal zone B cells in the spleen, where they were located in the periarteriolar sheath, marginal zone, and interfollicular areas that typically are populated by memory-type B cells. Although the relative proportions of transgene-expressing B cells in both types of transgenic mice declined with aging, SMI mice experienced progressive increases in the serum levels of IgM transgene protein over time. Finally, SMI transgene-expressing B cells, but not AB29 transgene-expressing B cells, were induced to secrete Ab when cultured with alloreactive T cells. These results indicate that expression of polyreactive autoantibodies can allow for development of B cells that are neither deleted nor rendered anergic, but instead have a phenotype of memory-type or Ag-experienced B cells that respond to nonspecific immune activation.

Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins

“…Evidence for this comes from transgenic mice that express the SMI IgM/ antibody. 40 Transgenic expression of the SMI IgM/ induced mouse B cells to differentiate into nonnaive, memory-type B cells that were hyperresponsive to nonspecific T-cell help. SMI mice, but not control mice that express a human Ig in the absence of specific antigen, had increased numbers of human Ig transgene-expressing B1 and marginal zone (MZ) B cells.…”

“…Although the B cells expressing the SMI IgM/ transgenes expressed relatively low levels of surface human Ig, these transgene-expressing B cells still could be selectively deleted in vivo by treatment with mAbs specific for the CRI of the SMI IgM/. 40 Conceivably, anti-idiotypic mAbs could be used during early pathogenesis to target cells that express CRI of Ig associated with an increased risk for neoplastic transformation. In addition, vaccine strategies also could be developed to induce cellular immune responses against peptide epitopes of common motifs found within the CDR3 of Ig frequently expressed in CLL.…”

Immunoglobulin light chain repertoire in chronic lymphocytic leukemia

“…[72][73][74][75][76] A recent study on transgenic expression of a human IgM polyreactive rheumatoid factor from a patient with CLL demonstrated that expression of polyreactive autoantibodies can allow for development of B cells that are neither deleted nor rendered anergic but have a phenotype of antigen-experienced B cells that respond to nonspecific activation. 77 The similarity between B cells producing natural autoantibodies and CLL B cells could mean that the process of positive selection of natural autoreactive B cells may carry a risk for malignant transformation. 77,78 The results of the present study emphasize the close relationship between autoreactivity and CLL with similarities both in IGKV/IGLV repertoire and CDR3 formation, alluding to a different pathway of B-cell activation, not involving a classical germinal center (GC) reaction response to T-independent antigens.…”

Analysis of Expressed and Non-Expressed IGK Locus Rearrangements in Chronic Lymphocytic Leukemia

“…Furthermore, CLL cells frequently produce "natural" or polyreactive IgM autoantibodies (32)(33)(34)(35)(36)(37). Altogether, the similarity between B cells producing natural autoantibodies and CLL malignant B cells could mean that the process of positive selection of natural autoreactive B cells may carry a risk for malignant transformation (38).…”