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Serum Free Immunoglobulins Light Chains: A Common Feature of Common Variable Immunodeficiency?
Kissy Guevara-Hoyer1,2,3, Juliana Ochoa-Grullón1,2,3, Miguel Fernández-Arquero1,2,3
1Department of Immunology, IML and IdSSC, Hospital Clínico San Carlos, Madrid, Spain.
Insights
Serum free light chain (sFLC) levels are significantly lower in Common Variable Immunodeficiency (CVID) patients compared to other primary immunodeficiencies. A sum of kappa and lambda sFLC below 16.7 mg/L strongly indicates CVID.
Area of Science:
- Immunology
- Biochemistry
Background:
- Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by impaired antibody production.
- Serum free light chains (sFLC), specifically kappa (κ) and lambda (λ) chains, are typically secreted in excess and can serve as biomarkers.
- Previous studies suggest low sFLC levels in CVID, hinting at intrinsic B cell defects.
Purpose of the Study:
- To evaluate serum free light chain (sFLC) levels as a diagnostic biomarker for CVID.
- To compare sFLC levels in CVID patients with those in other primary immunodeficiencies (PIDs) and secondary immunodeficiencies (SID).
- To establish an optimal sFLC cut-off value for CVID diagnosis.
Main Methods:
- Prospective evaluation of sFLC levels (κ and λ) in 100 PID patients and 49 SID patients.
- Comparison of mean sFLC levels between CVID, other PIDs, and SID groups.
- Receiver Operating Characteristic (ROC) analysis to determine the optimal diagnostic cut-off for the sum of κ and λ sFLC.
Main Results:
- CVID patients exhibited significantly lower mean κ and λ sFLC levels compared to both other PIDs and SID patients (p < 0.001).
- The sum of κ + λ sFLC was significantly lower in CVID patients (7.25 ± 7.90 mg/L) versus other PIDs (26.44 ± 13.25 mg/L) and SID (28.25 ± 26.24 mg/L).
- ROC analysis yielded an Area Under the Curve (AUC) of 0.894 for CVID diagnosis, with an optimal cut-off of 16.7 mg/L, demonstrating 92% sensitivity, 75% specificity, and 98% negative predictive value.
Conclusions:
- A sum of κ + λ sFLC cut-off of 16.7 mg/L is proposed as a valuable diagnostic tool for CVID.
- Low sFLC levels in CVID patients likely reflect an intrinsic defect in B cell differentiation.
- This biomarker offers high sensitivity and specificity for CVID diagnosis, aiding in differentiating it from other immunodeficiencies.
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.
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