Differences in kappa to lambda (κ:λ) ratios of serum and urinary free light chains

Abstract

SUMMARY: Free light chains (FLC) are a natural product of B lymphocytes and, as such, represent a quantifiable biomarker of cellular proliferation. Accurate measurement of the concentrations of these components in serum and urine provides a unique means of ascertaining B cell immunoglobulin synthesis during physiologic and, especially, pathologic states, where such information has important diagnostic and therapeutic implications. Previously, use of such quantitative assays has been limited due to the lack of potent serologic reagents specific for these components. We have immunized mice with κ- and λ-type monoclonal human light chains (Bence Jones proteins (BJP)) and have obtained monoclonal antibodies (MoAbs) that differentiate between unbound and bound light chains. These highly specific MoAbs were used to measure by ELISA the concentrations of FLC in the serum of 22 normal individuals and in urine from 16 of these subjects. The mean serum κ and λ FLC concentrations were found to be 16.6 ± 6.1 μg/ml and 33.8 ± 14.8 μg/ml, respectively. In contrast, the values for urinary κ and λ FLC were 2.96 ± 1.84 μg/ml and 1.07 ± 0.69 μg/ml, respectively. In each case studied, the serum κ:λ ratio was consistently less than that of urine (mean values, serum ≈ 1:2; urine ≈ 3:1). That the rate of synthesis of λ-type FLC exceeded that of κ was evidenced in assays of culture fluid supernatants of unstimulated normal peripheral blood mononuclear cells (PBMC), where the mean κ:λ ratio was determined to be 1:1.4. Metabolic studies in which mice were injected with pools of κ- and λ-type BJP prepared in ratios of 1:1, 1:2 and 1:4 demonstrated that, regardless of the proportion, κ FLC were preferentially excreted. Our studies provide the first evidence that λ FLC are secreted by normal PBMC at a greater rate than are κ FLC, as evidenced in biosynthetic studies and by measurement of their serum concentrations. Further, we posit that quaternary structural differences between the two light-chain isotypes may account for the predominance of κversusλ components in urine.