The M167 mu+kappa Immunoglobulin Transgene Increases Susceptibility to Pristane-Induced Plasmacytomas In BALB/c Mice

Abstract

The goal of this research was to investigate the role of Ig transgenes (Tgs) in plasma cell tumor development as a useful means of examining potential antigen-specific B cell precursors. The Ig Tg M167mk (V1 mu plus Vk24) on a genetically PCT-susceptible BALB/c background was used to determine if B cells expressing anti-phosphorylcholine (PC) B cell receptors are more susceptible than non-Tg littermates to pristane induction of plasma cell tumors. The M167mk Tg mice, which express the anti-PC M167 BCR on >97% of B cells, developed a higher percentage of plasma cell tumors (63%) compared to non-Tg BALB/cAnPt littermates (35%), p<0.01, and had a reduced latent period from 240 to 200 days. Serologic and nucleic acid analysis of Igs expressed by Tg tumors revealed co-expression of the M167-id V1-mu/Vk24 transgenes and a rearranged endogenous VH-alpha/Vk Ig. In an attempt to learn something of the natural history of the PCT precursor B cell, the M167mk transgene and endogenous VH/VL Ig mRNA from Tg PCT cells were sequenced for evidence of somatic hypermutation, a hallmark of T-cell dependent germinal center activity. M167mu and k Tg mRNA transcripts revealed no evidence of mutation of the transgenes; however, sequencing of endogenous Ig mRNA from M167mk Tg PCTs showed that 80% contained somatic hypermutation (SHM) and 20% had germline Ig genes. PCTs from control groups, BALB/c non-Tg littermates and C.B20 mice, also contained 80% SHM and 20% germline Ig genes.

M167mk Tg mice have an increased (MZ) B cell population (15-25% B220+), a hyper-activated TI responsive B cell phenotype, compared to non-Tg WT mice (5-10% B220+). These data suggest that PC-responsive M167mk B cells are a PCT-susceptible subset, as the M167mk Tg BCR generates B cell clones that are responsive to bacterial PC antigen that likely enhances overall proliferation of B cells during PCT development, thereby increasing the chances of a neoplastic B cell clone to expand and increasing the susceptibility of M167mk Tg mice to the induction of PCTS.