Serum Free Immunoglobulins Light Chains: A Common Feature of Common Variable Immunodeficiency?

Serum free light chain (sFLC) is a recently proposed biomarker for CVID diagnosis. Most CVID patients present low or undetectable sFLC up to 10-fold lower compared to other primary antibody deficiencies. Given that kappa and lambda light chains are normally secreted in excess with respect to immunoglobulins, this finding points to an intrinsic defect of B cell differentiation in CVID. sFLC levels were prospectively evaluated in a cohort of 100 primary immunodeficiency (PID) patients and in 49 patients with secondary immunodeficiency to haematological malignancy (SID). CVID patients had significantly lower kappa and/or lambda values (mean: kappa: 1.39 +/- 1.7 mg/L and lambda: 1.97 +/- 2.24 mg/L) compared to "other PIDs" (kappa: 13.97 +/- 5.88 mg/L and lambda: 12.92 +/- 7.4 mg/L, respectively,p< 0.001 both), and SID (kappa 20.9 +/- 22.8 mg/L and lambda 12.8 +/- 8.7 mg/L, respectively,p< 0.001 both). The sum of kappa and lambda (sum kappa + lambda) in CVID patients (7.25 +/- 7.90 mg/L) was significantly lower respect to other PIDs (26.44 +/- 13.25 mg/L,p< 0.0001), and to SID patients (28.25 +/- 26.24 mg/L,p= 0.0002). ROC analysis of the sum kappa + lambda disclosed an area under the curve (AUC) of 0.894 for CVID diagnosis (SD 0.031; 95% CI: 0.83-0.95,p< 0.0001), with optimal cut-off of 16.7 mg/L, giving the highest combination of sensitivity (92%), specificity (75%) and NPV (98%). The Relative Risk (RR) for patients presenting a sum kappa + lambda below 16.7 mg/L was 20.35-fold higher (95%, CI: 5.630-75.93) for CVID than below this threshold. A similar behavior of the sFLC in our CVID cohort with respect to previously published studies was observed. We propose a cut-off of sum kappa + lambda 16.7 with diagnostic application in CVID patients, and discuss potential specific defects converging in low or undetectable sFLC.