Abstract
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 κ and λ 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 κ and/or λ values (mean: κ: 1.39 ± 1.7 mg/L and λ: 1.97 ± 2.24 mg/L) compared to “other PIDs” (κ: 13.97 ± 5.88 mg/L and λ: 12.92 ± 7.4 mg/L, respectively, p < 0.001 both), and SID (κ 20.9 ± 22.8 mg/L and λ 12.8 ± 8.7 mg/L, respectively, p < 0.001 both). The sum of kappa and lambda (sum κ + λ) 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 κ + λ 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 κ + λ 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 κ + λ 16.7 with diagnostic application in CVID patients, and discuss potential specific defects converging in low or undetectable sFLC.
Highlights
IMMUNOGLOBULIN, THE MASTER KEY OF MANY LOCKSGiven the high clinical variability and immunological heterogeneity in clinical manifestations of common variable immunodeficiency (CVID), several researchers have proposed combinations of clinical and immunological biomarkers in order to refine the diagnosis and to provide more personalized followup and treatment strategies that may improve the prognosis of the individual patient [1,2,3,4]
Production in excess of L chains occurs throughout B-cell development till plasma cells, where they bind to H chains, excess L chains enter the bloodstream as FLCs
We studied serum free light chain (sFLC) in 100 patients with different primary immunodeficiency (PID) as part as routine immunological work-up
Summary
IMMUNOGLOBULIN, THE MASTER KEY OF MANY LOCKSGiven the high clinical variability and immunological heterogeneity in clinical manifestations of common variable immunodeficiency (CVID), several researchers have proposed combinations of clinical and immunological biomarkers in order to refine the diagnosis and to provide more personalized followup and treatment strategies that may improve the prognosis of the individual patient [1,2,3,4]. The key-shaped structure of immunoglobulins (Ig) as originally described by Ehrlich [9], consists of four polypeptide chains, two pairwise identical copies of both heavy (H) and light (L) chains, the latter being named kappa (κ) or lambda (λ) chains [10]. This “key” opens up a wide range of processes associated with innate and adaptive immunity. Large pre-B cells express a pre-BCR that is assembled from antibody μ H chains and surrogate L chain (VPREB1 and IGLL1). Secretion of L chains would reflect B cell activation [13, 14]
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