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Immunoglobulins free light chains (FLCs) are assayable in several biological fluids. Currently, there are no reports on FLCs in seminal plasma. The aims of our study were to investigate the presence and detectability of FLCs in seminal plasma and to evaluate the usefulness of this assay in the diagnostic approach to infertile patients. We enrolled 61 patients aged 18-50 years. Semen analysis was performed. They were divided into four groups: controls-normozoospermic, 10 patients, mean ± SEM age 35 ± 1.5 years; varicoceles (VAR), 18 patients aged 24.3 ± 0.96 years; inflammatory (INF) seminal fluids, 24 patients, aged 38.8 ± 2.2 years; and varicoceles and inflammatory (VAR/INF) seminal fluids, 9 patients, aged 29.5 ± 0.71 years. A trend towards higher λ FLCs levels was evidenced in the INF and VAR/INF groups. κ FLCs were higher in normozoospermic patients with lower levels in VAR, both isolated and associated with inflammatory parameters. This differential pattern of the two types of FLCs reached statistical significance when comparing κ/λ ratio, with significant lower levels in VAR vs controls. This is the first report of FLCs assay in seminal plasma. We can hypothesize that λ FLCs are increased in inflammatory processes, whether κ FLCs seem to be influenced by other molecular mechanisms related to varicocele., (© 2021 Wiley-VCH GmbH.)

Circulating free light chains (FLCs), considered biomarkers of B cell activity, are frequently elevated in patients affected by systemic inflammatory autoimmune diseases. As the systemic sclerosis (SSc) clinical course can be variable, this study is aimed at evaluating FLCs levels in affected individuals as biomarkers of disease activity. We assessed FLC levels in serum and urine of 72 SSc patients and 30 healthy controls (HC). Results were analyzed in comparison with overall clinical and laboratory findings, disease activity index (DAI) and disease severity scale (DSS). SSc patients displayed increased levels of κ and λ FLC in serum significantly higher than HC (p = 0.0001) alongside the mean values of free κ/λ ratio and κ + λ sum (p = 0.0001). SSc patients showed increased free κ in urine with a κ/λ higher than HC (p = 0.0001). SSc patients with increased κ + λ in serum showed that erythro-sedimentation rate (p = 0.034), C-reactive protein (p = 0.003), DAI (p = 0.024) and DSS (p = 0.015) were higher if compared to SSc patients with normal levels of FLC. A positive linear correlation was found between serum levels of free κ and DAI (r = 0.29, p = 0.014). In addition, SSc patients with increased free κ in urine had higher DAI (p = 0.048) than SSc patients with normal κ levels. Our results strengthen the role of serum FLC as useful biomarker in clinical practice to early diagnosis and monitor disease activity, showing for the first time that also urine FLC levels correlated with disease activity in SSc patients., (© 2021 British Society for Immunology.)

Objective: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and hyperinsulinemia that contribute to create a state of chronic low-grade inflammation. We performed an observational case-control study to investigate inflammatory and immunological parameters, such as IgG subclasses and free light chains (FLCs) and hemolytic complement activity (CH50) in non-obese PCOS, evaluating their relations with metabolic and hormonal parameters., Patients and Methods: 36 subjects were studied: 16 PCOS patients (mean±SEM 27.13±1.82 age; BMI 24.1±0.9 kg/m2); 20 controls (aged 26.05±0.73; BMI 20.8 ± 0.4 kg/m2). The blood sample was collected for metabolic and hormonal parameters, IgG subclasses, k and λ FLCs, CH50. Hormones were measured by immunochemiluminometric assays; metabolic parameters by enzymatic assays; subclasses of IgG, FLCs, and CH50 were evaluated by the turbidimetric method., Results: PCOS patients showed vs. controls lower IgG1, IgG2, IgG3 (mean±SEM 3.76±0.29 g/l, 2.63±0.20, 0.62±0.06, 0.34±0.08 vs. 6.49±0.35, 4.28±0.25, 0.84±0.07, 0.33±0.04, respectively) and higher levels of FLCs (k 12.22±0.71 vs. 6.03±0.30, λ 10.10±0.79 vs. 8.04±0.48 g/l) and CH50 (48.64±2.65 vs. 36.51±1.38 U/ml); we found correlation between IgG2 and free-testosterone (r=0.72, p=0.005) and CH50 and vitamin D (r=0.54, p=0.04); an inverse correlation was found between IgG1 and, respectively, ACTH (r=-0.57, p=0.02) and cortisol (r=0.78, p=0.001) in PCOS., Conclusions: In the complex scenario of low-grade inflammation in non-obese PCOS, we showed lower levels of main subclasses of IgG and higher CH50 levels, suggesting the involvement of other mechanisms other than the "classical" pathway of complement activation; FLCs could be attractive to monitor inflammation degree, disease activity and influence on hormonal status.

Objective: Chronic Hepatitis C virus (HCV) infection can cause severe extrahepatic manifestations, such as mixed cryoglobulins (MC), up to the development of B cell nonHodgkin's lymphoma (B-NHL). Mechanisms transforming of HCV infection into lymphoproliferative and/or autoimmune disorders are still poorly understood. In course of HCV infection, the sustained virus-driven antigenic stimulation may probably induce a B-cell clonal expansion. Measurements of serum free light chains (FLCs) levels, considered as a direct marker of B cell activity, are analyzed with increasing interest in clinical practice, for diagnosis, monitoring and follow-up of plasma cell dyscrasia. Syndecan-1 (CD138) is a transmembrane heparan sulfate proteoglycan expressed and actively shed by most myeloma cells. Membrane CD138 represents the major receptor protein for HCV attachment to the hepatocyte surface and high levels of circulating sCD138 levels are detected in patients at early stage of B-cell chronic lymphocytic leukemia. This study is aimed to evaluate sCD138 and FLC levels as diagnostic biomarkers of HCV-related MC with B-NHL., Patients and Methods: We enrolled 35 HCV-MC-NHL patients, characterized for the specific type of cryoglobulins, and 25 healthy blood donors (HBD) as negative control. Serum sCD138 levels were determined using ELISA kits specific for human sCD138. Serum FLCs were assessed by means of the turbidimetric assay., Results: We found that serum levels of sCD138, as well as FLCs, were significantly higher in patients than in HBD (p<0.001)., Conclusions: In agreement with the definition of HCV-driven lymphoproliferative disorders as the consequence of a multifactorial and multistep pathogenetic process, we suggest that sCD138 and FLCs could be considered putative independent markers of worsening progression of the disease.

Objective: A still uncertain association between vitamin D levels and HCV chronic liver diseases has been reported. Increased levels of serum-free light chains (FLCs) and an altered k/λ FLC ratio correlate with Mixed Cryoglobulinemia (MC) vasculitis and/or B-cell non-Hodgkin's lymphoma in HCV-positive patients. We aimed to investigate the possible role of vitamin D, vitamin D Binding Protein (DBP), and FLCs levels as a tool for discriminating different stages of HCV- related MC and chronic liver diseases., Patients and Methods: Sixty-five untreated patients were retrospectively enrolled and 21 healthy blood donors (HBD) were used as controls. Vitamin D, DBP, FLCs, and cryoglobulins levels were measured. Based on cryoglobulins, patients were divided in three subgroups (without cryoglobulins, type II, and type III)., Results: We didn't find any significant differences in vitamin D and DBP levels between HCV patients' main groups and HBD. Serum FLCs levels were significantly higher in HCV patients than in HBD. FLCs ratio among patients' subgroups did not reveal differences., Conclusions: Our results confirm the presence of an increased serum level of FLCs in HCV patients and suggest that nor vitamin D and DBP or FLC levels can be considered reliable biomarkers for discriminating different stages of HCV-associated chronic liver diseases and/or HCV-associated extrahepatic manifestation. We confirm that serological FLCs levels are significantly higher in patients than in HBD as a signature of B cell activation in course of HCV infection.

Polycystic ovary syndrome (PCOS), as systemic disease, is accompanied by different indexes of inflammation. Free light chains of immunoglobulins (FLCs), produced by plasmacells, are released in slight excess for the immune requests, with still poorly defined physiological role but surely they represent a marker of inflammation. In order to evaluate their levels and correlate them with hyperandrogenism, we have studied a group of PCOS patients, age range 18-37 yrs, mean ± SEM body mass index (BMI) 24.1 ± 0.9 kg/m 2 ), compared with age- and BMI-matched controls, with assay of k and λ FLCs, by turbidimetric method, and their ratio in blood plasma. PCOs exhibited higher levels vs. controls: (mean ± SEM λ : 10.0 ± 0.85 mg/L vs. 8.41 ± 0.45 mg/L; k : 12.45 ± 0.72 mg/L vs. 6.41 ± 0.34 mg/L; k / λ : 1.31 ± 0.07 vs. 0.78 ± 0.04). A significant direct correlation was observed between λ -FLCs and testosterone levels, no correlation was indeed found with HOMA-IR index. These data confirm high levels of FLCs in PCOS, suggesting systemic inflammatory state and a possible role in the pathophysiology of such complex syndrome.

The study of free light chains (FLCs) has grown as area of enormous interest for many clinicians with the aim of disclosing the exact biological role and potential use of FLCs in the clinical routine. Moreover, the attention given to immunological functions of FLCs has sparked a new light into their pathogenic contribution in different chronic autoimmune-based inflammatory diseases. The release of intracellular antigens following cell death or ineffective clearance of apoptotic debris, modification of self-antigens, and molecular mimicry may trigger the production of immunoglobulins after activation and polyclonal expansion of B cells, by which FLCs are released. The discovery of polyclonal FLCs as potential biomarkers started with the observation of their increased concentrations in a variety of biological fluids related to patients with autoimmune diseases. This review deals with the use of polyclonal FLCs for identifying severity and monitoring outcome after treatment in some autoimmune diseases, namely systemic lupus erythematosus, myasthenia gravis, systemic sclerosis, rheumatoid arthritis and Sjögren's syndrome, as supported by the fact that levels of FLCs correlate with both B cell activation markers and other specific markers of disease activity. In a near future, following the evidence shown, FLCs might probably work as early prognostic markers of severity and also as indicators of response to treatment or early assessment of relapse in selected autoimmune diseases., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Atherosclerosis and ischemic heart disease (IHD) are the major cause of morbidity and mortality but their inflammatory pathogenesis is still unclear. In this scenario, the role of serum free light chains (sFLC) has never been fully evaluated. The aim of the present study is to assess the clinical and pathogenetic role of sFLC in patients with IHD and to propose their use as a new biomarker for cardiovascular disease., Patients and Methods: We enrolled 117 patients, divided into 5 cohorts: 15 healthy controls, non-diabetic and without ischemic heart disease; 19 patients with type 2 diabetes (T2DM), without ischemic heart disease at recruitment; 39 patients with stable chronic angina; 27 patients with NSTEMI, 17 patients with acute STEMI. Serum sFLC and high-sensitive C-reactive protein (hs-CRP) were measured. Patients also underwent a transthoracic echocardiographic study., Results: sFLC were higher in patients with IHD and T2DM. However, we did not find statistically significant differences in sFLC concentration among subgroups. No correlation resulted between sFLC and hs-CRP levels. The median value of the sFLC κ/λ ratio in the population was 0.63, therefore stratifying it into two groups according to their levels. We found that an increase in left ventricular ejection fraction at 12 months was detected in 77% of patients with κ/λ ratio higher than 0.63 and 25% of patients with κ/λ ratio lower of 0.63 (p=0.016, OR=10.0 [1.8-55.6])., Conclusions: Our study suggests that the sFLC, produced by the B-lymphocytes in the context of generalized immune activation, could play a pathogenetic role in acute coronary syndromes and that they could represent a novel risk biomarker of cardiovascular disease.

Background: Serological levels of free immunoglobulin light chains (FLCs), produced in excess of heavy chains during synthesis of immunoglobulins by plasma cells, can be considered a direct marker of B cell activity in different systemic inflammatory-autoimmune conditions and may represent a useful predictor of rituximab (RTX) therapeutic efficacy, as reported for rheumatoid arthritis and systemic lupus erythematosus. Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction with antibodies (abs) targeting the acetylcholine receptor (AChR) or the muscle-specific tyrosine kinase (MuSK), inducing muscle weakness and excessive fatigability. As MG course may be remarkably variable, we evaluated the possible use of FLCs as biomarkers of disease activity., Subjects and Methods: We assessed FLC levels in 34 sera from 17 AChR-MG and from 13 MuSK-MG patients, in comparison with 20 sera from patients with systemic autoimmune rheumatic diseases and 18 from healthy blood donors, along with titers of specific auto-abs and IgG subclass distribution., Results: We found a statistically significant increase in free κ chains in both AChR- and MuSK-MG patients, while free λ chain levels were increased only in AChR-MG. We also observed a significant reduction of both free κ and λ chains in 1/4 MuSK-MG patients along with specific abs titer, two months after RTX treatment., Conclusions: From our data, FLCs appear to be a sensitive marker of B cell activation in MG. Further investigations are necessary to exploit their potential as reliable biomarkers of disease activity.

Background: Serum free light chains detection assays are consistently meeting greater interest for the diagnosis and monitoring of monoclonal gammopathies and plasma cell dyscrasias. Nowadays, there are neither standardized methods nor reference material for the determination of free light chains; for this reason, it is important to compare two different assays used in clinical laboratory., Methods: We evaluated 300 serum samples from patients with B-cell disorders and compared the analytical performances of both assay. Each test was assayed on both testing platforms (Siemens Dade Behring BN II Nephelometer and SPAPLUS by The Binding Site). κ/λ ratios were determined and compared. Results were analyzed by Passing-Bablok and Bland-Altman plots to evaluate comparability of the two techniques and to determine bias., Results: The reproducibility of both assays is acceptable, reaching minimum and desirable analytical goals derived from biological variability. However, values are not interchangeable between systems. This study shows that the two systems do not allow results to be transferred from one method to the other even if they display good agreement., Conclusion: Our study highlights the importance of elaborating an international standard for free light chains quantification in order to offer homogeneous results as well as guarantee harmonization of values among laboratories. Moreover, the assays should be validated in specific patient groups to determine that they are clinically fit for purpose., (© 2017 Wiley Periodicals, Inc.)

The production of antibodies is accompanied by a slight excess of synthesis of κ and λ immunoglobulin light chains; small amounts of them are released in the peripheral blood and can also be found in various body fluids, such as synovial fluid, cerebrospinal fluid, urine and saliva. They are rapidly filtered by the glomerulus and >99% are reabsorbed from the cells of the proximal convoluted tubule, making them present in the urine in only trace amounts. The production of an excess of protein without a reason or a specific function in a biological system is rare. Free light chains, considered for years a waste product of Ig synthesis, are currently known to be very active molecules, able to bind antigens as well as whole immunoglobulin and helping to develop specific antibody affinity. The ability of free light chains to activate mast cells and then become an active part of the pathogenic mechanisms of chronic inflammatory diseases has increased interest in their clinical use, both as an attractive therapeutic target or as a biochemical marker of disease evolution or remission. This is an overview of relevant scientific interest that immunoglobulin light chains κ and λ have attracted over the years, a report on the progress in knowledge about their structure and function, with a special focus on their biological meaning and potential clinical utility in different diseases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In order to establish a diagnosis of monoclonal gammopathy, it is necessary to detect and identify monoclonal components. To confirm the immunological nature of the proteins, the next step is to define their composition in heavy and light chains using immunofixation. The purpose of this study was to compare two different instruments, one semiautomated and the other fully automated for serum and urine immunofixation., Methods: We selected 150 sera and 100 urines from patients admitted for routine analysis, which were analyzed by immunofixation to characterize monoclonal components., Results and Conclusion: Comparison study showed a difference in the identification of small monoclonal components and hypogammaglobulinemia, in serum and urine, between the two analyzers. We also observed a difference in the length of the electrophoretic pattern that is of considerable importance as it leads to a better resolution of the gamma region, allowing to identify even the smallest monoclonal component that can be easily hide in an oligoclonal pattern. For this reason, there is need to ameliorate commercial immunofixation assays. It is essential to improve data harmonization and standardize measurement procedures in order to guarantee a correct diagnosis for the right patient care., (© 2016 Wiley Periodicals, Inc.)

Background: HCV can lead to both chronic liver disease and B-cell lymphoproliferative disorders. A strong association exists between HCV and mixed cryoglobulinaemia (MC)., Methods: Anti-nuclear antibodies (ANA), rheumatoid factor Ig-G (RF-IgG), free light chain κ and λ (FLC-κ, FLC-λ) levels and κ/λ ratio were evaluated in 50/420 subjects unexpectedly resulted anti-HCV positive after routine screenings for non-hepathological procedures., Results: Three/fifty patients had HCV-RNA undetectable in the serum and were excluded from the analysis. Thirty-nine/fifty patients had laboratory evidence of circulating cryoglobulins without liver disease and MC-related symptoms. Among them, 17 resulted ANA-positive. The mean cryocrit was higher in ANA-positive patients, while no other demographic/clinical differences were observed between the groups. Significantly higher levels of RF-IgG were observed in ANA-positive vs ANA-negative patients. κ and λ FLC were higher in ANA-positive patients. A ROC analysis, based on ANA-positivity vs ANA-negativity, confirmed a high sensitivity and specificity of RF-IgG test., Conclusions: Published data concerning MC come mostly from symptomatic vasculitis. We analyzed HCV-patients without MC symptoms, founding cryoglobulins in the majority of them. The increased levels of FR-IgG and FLC in CGs-ANA-positive patients, suggest these test could be used to identify a state of silent autoimmune and/or lymphoproliferative condition before the transition to a frank disease in naïve HCV-patients without symptoms of extrahepatic manifestations., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Monoclonal gammopathies encompass a wide range of diseases characterized by the monoclonal expansion of a B-cell clone. Despite emerging therapeutic strategies, chances of survival of patients who are affected are still scarce, which implies that new tools are necessary not only for the diagnosis but also for the follow-up of patients affected by such diseases. In this context, the use of free light chains (FLCs) has been incorporated into many guidelines. Likewise, tumor microenvironment is consistently gaining importance as role player in tumor pathogenesis. Specifically, Syndecan-1 (CD138), a heparan-sulfate proteoglycan is attracting interests as it is highly expressed and shed by myeloma plasma-cells. The aim of our study was to analyze CD138 levels in the serum of patients affected by multiple myeloma or light chain only disease, and to compare the values obtained with free light chain (FLC) kappa, lambda and FLC ratio in both groups of patients., Methods: 84 patients affected by Multiple Myeloma and Light Chain Myeloma were recruited for this study. Serum CD138 was assessed by ELISA (Diaclone Research, France) and FLC values were quantified by nephelometry (Freelite TM Human Kappa and Lambda Free Kits, The Binding Site, UK). Data was analyzed by GraphPad Prism software and Statgraph., Results: We observed higher CD138 mean values in myeloma patients compared to the light chain only myeloma group. A positive linear regression of CD138 and FLC was observed in the light chain only cohort as opposed to myeloma patients which show an inverse trend., Conclusions: The study highlighted an existing relationship between FLCs and CD138 and wishes to seek also a correlation in order to rapidly and efficiently perform diagnosis and different diagnostic schemes.