Anti‐B cell autoantibodies encoded by VH 4–21 genes in human fetal spleen do not require in vivo somatic selection

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Abstract
We isolated immunoglobulin (Ig) VH4 genes that were rearranged in the genomic DNA of 160 day human fetal spleen. Productively rearranged VH 4‐21 genes were cloned into pRTM1, a human IgM expression vector. This allowed us to generate IgMϰK‐expressing transfectomas by co‐transfecting each of these constructs with pSVG‐VϰK3, an Ig ϰK light‐chain expression vector that has a variable region encoded Humkv325, a conserved VϰK gene that is frequently expressed early B cell ontogeny. We find that all transfectomas expressing IgMϰK encoded by VH 4‐21 make IgM autoantibodies reactive with i, a linear poly‐N‐acetyllactosamine determinant present on neonatal red blood cells and a B cell‐restricted isoform of the CD45 surface molecule. In contrast, a transfectoma expressing pSVG‐VϰK3 and pRTM1 containing a rearranged VH4‐59 (V71‐4) gene isolated from a chronic lymphocytic leukemia B cell population, designated WIL, produced IgMϰK antibodies that had no detectable anti‐i binding activity. However, transfectomas expressing VH 4‐21 fused onto the Ig heavy‐chain third complementarity determining region (CDR3) of WIL are found to make anti‐B cell autoantibodies with anti‐i activity. These studies indicate that VH 4‐21 genes rearranged in human fetal B cell ontogeny can encode anti‐B cell autoantibodies with a binding specificity that does not require in vivo somatic selection.

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