Elevated Concentrations of Serum Immunoglobulin Free Light Chains in Systemic Lupus Erythematosus Patients in Relation to Disease Activity, Inflammatory Status, B Cell Activity and Epstein-Barr Virus Antibodies

Abstract

ObjectiveIn this study, we examined the concentration of serum immunoglobulin free light chains (FLCs) in systemic lupus erythematosus (SLE) patients and investigated its association with various disease parameters in order to evaluate the role of FLCs as a potential biomarker in SLE. Furthermore, FLCs’ association with Epstein-Barr virus (EBV) antibodies was examined.MethodsUsing a nephelometric assay, κFLC and λFLC concentrations were quantified in sera from 45 SLE patients and 40 healthy controls. SLE patients with renal insufficiency were excluded in order to preclude high concentrations of serum FLCs due to decreased clearance.ResultsSerum FLC concentrations were significantly elevated in SLE patients compared to healthy controls (p<0.0001) also after adjusting for Ig levels (p<0.0001). The concentration of serum FLCs correlated with a global disease activity (SLE disease activity index (SLEDAI)) score of the SLE patients (r = 0.399, p = 0.007). Furthermore, concentrations of FLCs correlated with titers of dsDNA antibodies (r = 0.383, p = 0.009), and FLC levels and SLEDAI scores correlated in the anti-dsDNA-positive SLE patients, but not in anti-dsDNA-negative SLE patients. Total immunoglobulin (IgG and IgA) concentrations correlated with FLC concentrations and elevated FLC levels were additionally shown to associate with the inflammatory marker C-reactive protein and also with complement consumption determined by low C4 in SLE patients. Collectively, results indicated that elevated serum FLCs reflects increased B cell activity in relation to inflammation. SLE patients had an increased seropositivity of EBV-directed antibodies that did not associate with elevated FLC concentrations. An explanation for this could be that serum FLC concentrations reflect the current EBV activity (reactivation) whereas EBV-directed antibodies reflect the extent of previous infection/reactivations.ConclusionSLE patients have elevated concentrations of serum FLCs that correlate with global disease activity scores and especially serologic markers for active disease. These findings are suggestive of circulating FLCs having potential as a new supplementary serologic biomarker in SLE.

Serum immunoglobulin free light chains and their association with clinical phenotypes, serology and activity in patients with IgG4-related disease: a cross-sectional study.

“…As has been described for other systemic autoimmune diseases such as SLE, SS, RA and SSc [4,5,6,7], measurement of sFLC may be a useful biomarker to assess systemic activity in IgG4-RD, as demonstrated by our ndings of higher levels of k sFLC and k/λ ratio in patients with active vs. inactive IgG4-RD. Interestingly, only one patient with inactive disease had an elevated k/λ ratio.…”

“…The increase levels of sFLC in patients with IgG4-RD is undoubtedly related to the increase synthesis of immunoglobulins by the B cell lineage which also could explain why we found a positive correlation between sFLC and IgG1 and IgG4 levels. This phenomenon is well described in systemic autoimmune diseases in which B cell over-activation is a component of the pathogenesis of the disease such as SS and SLE [4,5]. It was noteworthy that a considerable proportion of our IgG4-RD cohort (28.9%) had an abnormal k/λ ratio, in contrast to the lower frequencies found in SS and SLE [4,28].…”

“…For instance, a recent study including 100 patients with SS disclosed that 64% had abnormal sFLC levels and 11% had a high k/λ ratio; furthermore, sFLC levels correlated with systemic activity and their levels were modi ed by treatment with rituximab and abatacept, showing a sensitivity to change [4]. Other studies in patients with SLE, rheumatoid arthritis (RA) and systemic sclerosis (SSc) have reported abnormal levels of sFLC and a potential utility as biomarkers of disease activity as well [5,6,7].…”

How compelling are the data for Epstein–Barr virus being a trigger for systemic lupus and other autoimmune diseases?

“…Known predisposing congenital and/or acquired immuno-deficiencies comprise complement deficiencies (especially, C1q and C4), impaired cytokine regulation, T-cell proliferation and B-cell functions including altered immunoglobulin production (Table 1) [1,4,5]. Together with external factors, predominantly infections, development of SLE is elicited.…”

Elevated serum free light chains predict cardiovascular risk in type 1 diabetes mellitus

“…1 Monoclonal FLC -or Bence Jones proteins -are elevated in multiple myeloma 1 whereas increased polyclonal cFLC is associated with inflammatory conditions and disease activity, as demonstrated in rheumatoid arthritis and systemic lupus erythematosus. [2][3][4] Indeed, elevated polyclonal serum FLC can arise by two principal mechanisms: renal impairment and/or chronic immune stimulation, as observed in diabetes patients with cardiovascular disease, 5 which are all prominent complications of diabetes. Furthermore, FLC have been shown to exert independent biological functions rather than conferring simple bystander effects.…”