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

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 cutoff 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 cutoff of sum κ + λ 16.7 with diagnostic application in CVID patients, and discuss potential specific defects converging in low or undetectable sFLC.

An Exploratory Approach of Clinically Useful Biomarkers of Cvid by Logistic Regression

“…Interestingly, IgG levels do not correlate with sBCMA in our cohort, highlighted by the findings first published by Maglione et al [ 17 ], or sFLC levels (Guevara-Hoyer et al) [ 16 ]. This distinctive characteristic contributes an important layer of information beyond traditional serum immunoglobulin measurements, underscoring the potential of sFLCs and sBCMA as diagnostic tools.…”

“…There has been considerable efforts on developing innovative biomarkers to bridge this diagnostic gap. Importantly, the aggregated levels of κ and λ light chains [ 14 – 16 ] alongside the soluble B-cell maturation antigen (sBCMA) [ 17 ], have emerged as potential markers. Both exhibit marked reductions in CVID compared to those with other primary (PID) and secondary immunodeficiencies (SID), suggesting their utility in distinguishing CVID from other immunological disorders.…”

Genomic crossroads between non-Hodgkin’s lymphoma and common variable immunodeficiency

“…Therefore, an exploratory analysis of germline CVID-related gene alterations was performed in NHL tumor samples. A key immune system feature is the recombination of the (VDJ) gene segment in the generation of T-and B-cell antigen receptor (TCR and BCR) repertoire, as well as SHM of B cells in the generation of immunoglobulin isotypes (124). These processes are orchestrated and tightly regulated by the expression of specific genes, as well as their resulting proteins, which also share a function within the DNA and transcription repair mechanisms (70, 125), the alteration of the latter being widely known as cancer-predisposing factors (10,71,(126)(127)(128).…”

Clinical Aspects of B Cell Immunodeficiencies: The Past, the Present and the Future

“…Another approach towards minimizing the delay in identification of primary B cell deficiencies involves the use of serum biomarkers that can play both a diagnostic and a prognostic role. Several potential candidates have been proposed, but perhaps the most promising is the B cell maturation antigen (BCMA) [ 75 , 76 , 77 , 78 ]. BCMA is a member of the tumor necrosis factor receptor superfamily, and it promotes the survival of plasma cells and plasmablasts [ 78 ].…”