Next Article in Journal
Cytokine Regulation and Oxidative Stress in Helicobacter Pylori-Associated Gastric Adenocarcinoma at Different Stages: Insights from a Cross-Sectional Study
Previous Article in Journal
Molecular Links Between Metabolism and Mental Health: Integrative Pathways from GDF15-Mediated Stress Signaling to Brain Energy Homeostasis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 26
Issue 15
10.3390/ijms26157607
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

B Cell-Derived and Non-B Cell-Derived Free Light Chains: From Generation to Biological and Pathophysiological Roles

by
Linyang Li
1,
Huining Gu
1,
Xiaoyan Qiu
1,2 and
Jing Huang
1,2,*
1
Department of Immunology, School of Basic Medical Sciences, and NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China
2
PUHSC Primary Immunodeficiency Research Center, School of Basic Medical Sciences, Peking University, Beijing 100191, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(15), 7607; https://doi.org/10.3390/ijms26157607
Submission received: 14 July 2025 / Revised: 31 July 2025 / Accepted: 1 August 2025 / Published: 6 August 2025
(This article belongs to the Section Molecular Biology)
Browse Figures
Review Reports Versions Notes

Abstract

Immunoglobulin light chains are essential components of intact immunoglobulins, traditionally believed to be produced exclusively by B cells. Physiologically, excess light chains not assembled into intact antibodies exist as free light chains (FLCs). Increasingly recognized as important biomarkers for diseases such as multiple myeloma, systemic amyloidosis, and light chain-related renal injuries, FLCs have also been shown in recent decades to originate from non-B cell sources, including epithelial and carcinoma cells. This review primarily focuses on novel non-B cell-derived FLCs, which challenge the conventional paradigms. It systematically compares B cell-derived and non-B cell-derived FLCs, analyzing differences in genetic features, physicochemical properties, and functional roles in both health and disease. By elucidating the distinctions and similarities in their nature as immune regulators and disease mediators, we highlight the significant clinical potential of FLCs, particularly non-B cell-derived FLCs, for novel diagnostic and therapeutic strategies.

1. Introduction

Free light chains (FLCs), a slight excess of kappa (κ) and lambda (λ) light chains (LCs) without binding to heavy chains (HCs) and therefore existing outside the tetrameric structure of intact immunoglobulins, have emerged as critical players in both physiological and pathological processes, though once regarded as mere byproducts of immunoglobulin synthesis. Traditionally, immunoglobulins, composed of heavy and light chains, were thought to be exclusively produced by B lymphocytes, serving as central mediators of humoral immunity. However, mounting evidence over the past two decades has challenged this paradigm, revealing that non-B cell lineages, including epithelial cells, neurons, and cardiomyocytes, also synthesize and secrete immunoglobulins and FLCs [1]. These discoveries not only redefine the biological origins of immunoglobulins but also underscore the need to re-evaluate the roles of FLCs in health and disease.
The story of FLCs began in 1845 with the serendipitous discovery of Bence Jones proteins as a peculiar urinary protein that precipitated upon heating and redissolved upon boiling from a patient with multiple myeloma (MM) by the British physician Henry Bence Jones [2]. This finding marked the very first observation of FLCs, though their nature as immunoglobulin light chains remained elusive until decades later in the 20th century [3,4]. Comprising κ or λ subtypes, FLCs are synthesized in slight excess during immunoglobulin assembly, existing as monomers or dimers (λ-FLC mostly dimeric, κ-FLCs dimeric or monomeric) with short serum half-lives of 2–6 h, specifically of 2–4 h for κ-FLC and 3–6 h for λ-FLC [5,6,7]. Their rapid clearance involves glomerular filtration and proximal tubule reabsorption via the megalin–cubulin receptor complex, followed by lysosomal degradation [6].
Clinically, monoclonal FLCs have become important biomarkers of certain diseases, including hematopoietic malignancies (e.g., multiple myeloma, lymphocytic leukemia), amyloidosis, and light-chain deposition diseases [8,9,10,11], while polyclonal elevations correlate with autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis) and neurological diseases (e.g., multiple sclerosis, myasthenia gravis) [12,13,14,15,16]. In the FLC-related diseases mentioned above, monoclonal or polyclonal FLCs are considered to be produced by a single clone or multiple clones of B-lineage cells. However, the recent identification of non-B cell-derived FLCs has introduced a transformative dimension to this field. Unlike their B cell counterparts, these ectopically expressed FLCs exhibit distinct genomic architectures, physicochemical properties, and pathophysiological mechanisms, potentially contributing to specific pathologies such as promoting inflammation and carcinogenesis.
This review systematically examines the dual origins of FLCs, contrasting the gene organization, physicochemical properties, functional roles, and disease implications of B cell-derived versus non-B cell-derived FLCs. By elucidating their divergent molecular profiles and clinical impacts, we aim to provide a framework for understanding these molecules as dual-edged entities—both guardians of immunity and instigators of disease—while charting future directions for research and therapeutic innovation.

2. B Cell-Derived Free Light Chains

2.1. Genomic Organization and Rearrangement of B Cell-Derived FLCs

2.1.1. Gene Structure of B Cell-Derived FLCs

Immunoglobulin light chains are composed of an N-terminal variable (V) region, which mediates antigen recognition through hypervariable sequences, and a C-terminal constant (C) region with conserved sequences within a species. Unlike heavy chain, light-chain V regions lack D segments and are encoded solely by V and J gene segments. During B cell development, V–J recombination assembles these segments, generating diverse light chains. This process is initiated by recombination signal sequences (RSS) flanking the V and J segments. Each RSS contains a conserved heptamer (5′-CACAGTG-3′) and nonamer (5′-ACAAAAACC-3′) motif separated by a 12- or 23-nucleotide spacer. The recombination-activating gene 1 (RAG1) and RAG2 recombinase induces double-strand breaks at these sites, enabling segment joining [17,18].
In humans, the immunoglobulin κ light-chain locus (IGK) is located at 2p11.2, and the λ light-chain locus (IGL) is located at 22q11.2. According to the IMGT databases (accessed 30 July 2025), the κ light-chain locus comprises IGKV genes grouped into seven subgroups (IGKV1–IGKV7, containing pseudogenes), followed by five functional IGKJ segments (IGKJ1–IGKJ5), and a single functional IGKC gene [19]. The λ light-chain locus comprises 11 subgroups of IGLV genes (IGLV1–IGLV11, containing pseudogenes), with seven downstream tandem IGLJ-IGLC cassettes, among which five are functional [19]. The genomic organization of V, J, and C gene segments in both light-chain loci, as well as the V–J recombination mechanism, is schematized in Figure 1.

2.1.2. Biased Gene Segment Usage in Health and Disease

Under physiological conditions, the V–J arrangement and gene usage vary in individuals, while a limited set of immunoglobulin gene segments are actively expressed in healthy individuals. In contrast, pathological states exhibit marked selectivity, with distinct diseases showing preferential usage of specific gene segments. Details of V–J segment usage are shown in Table 1.
In healthy individuals, although there is no consensus on certain biased usage of gene segments, some common trends have been observed. Physiologically, predominant usage of segment IGKV1, IGKV2, IGKV3, and IGKV4 in IGKV genes; IGKJ1, IGKJ2, and IGKJ4 in IGKJ genes; IGLV1, IGLV2, and IGLV3 in IGLV genes; and IGLJ7 in IGLJ genes has been noted [20,21,22,23].
While under diverse pathological conditions, the preponderance of gene segment usage in each disease was reported. In patients with multiple myeloma (MM), IGKV1, IGKV2, and IGKV3 are also widely observed for V–J arrangement. However, most studies do not indicate a preference for the usage of IGKJ or IGLJ genes [24,25,26,27]. In light-chain-derived (AL) amyloidosis, a preponderance of λ clones is observed, among which the three IGLV isotypes, including IGLV3 (IGLV3-1), IGLV6 (IGLV6-57), and IGLV1 (IGLV1-44), are significantly over-represented, accounting for approximately 70% of the amyloidogenic light chains (LCs) [28,29,30,31]. Notably, the λ6 (IGLV6-57) germline is responsible for about 30% of all λ-AL cases [30]. In light-chain deposition disease (LCDD), usage of IGKV4 (IGKV4-1), IGKV1 (IGKV1-5), IGKV3 (IGKV3-11 and IGKV3-15), and IGLV2 (IGLV2-23 and DPL12) has been observed in the rearrangement of light chains [32,33,34,35]. In light-chain Fanconi syndrome (FS), FLCs of the IGKV1 subgroup are most frequently found [46,47,48]. Regarding autoimmune diseases, naïve B cells in patients with juvenile rheumatoid arthritis (JRA) show decreased usage of the downstream IGKV4-1 segment and almost exclusive usage of the most upstream V gene segments [36]. Additionally, in patients with JRA and systemic lupus (SLE), predominant usage of IGKJ1 and IGKJ2 is widely observed [36,37,38].
In conclusion, though normal FLC diversity arises under physiological conditions within a pool of favored gene segments, pathological conditions exhibit disease-specific recombination patterns.

2.2. Physicochemical Properties of B Cell-Derived FLCs

Despite substantial disparities and mutations in gene segment combinations leading to high variation in the amino acid sequence, three-dimensional structure, and resultant physicochemical properties, certain characteristics are observed under physiological and specific pathological conditions. Physiologically, the FLCs mainly exist as monomers or dimers, with most κ-FLCs being monomeric and most λ-FLCs being dimeric [49]. The V region of FLC consists of four framework regions forming a hydrophobic core, within which are three scattered complementarity-determining regions (CDRs) containing amphipathic amino acids such as tyrosine and tryptophan [50,51,52]. When an FLC dimer is formed, two identical light chains are packed end-to-end with substantially hydrophobic VL–VL and CL–CL interfaces, which can occur through interchain disulfide bonds or non-covalently via intermolecular electrostatic, hydrophobic, and hydrogen bonds [53]. The production of κ light chains is more prevalent than λ light chains, as reflected in a serum κ/λ ratio of 1.8:1. This results in the dominance of monomeric FLCs, as most κ-FLCs, are monomeric [54].
An increase in the proportion of dimeric and multimeric FLC is observed in various diseases, such as AL amyloidosis, MM, and multiple sclerosis [1,55,56,57]. Amyloidogenic FLCs are caused by the deposition of insoluble, non-branched β-sheet-rich fibrils initiated by the aggregation of misfolded FLCs. Amyloidogenic FLCs have been shown to exhibit less inherent thermodynamic stability, which is possibly correlated with the C region, and higher protein dynamics compared to their non-pathological counterparts FLCs [58,59,60]. Unlike AL, where fibril synthesis may be related to electrostatic interactions between light chains, hydrophobic interactions enhance amorphous precipitation in LCDD. The CDRs of FLCs in LCDD display distinct features, such as the replacement of hydrophilic amino acid residues with non-polar ones and an abundance of positive net charge [61]. Additionally, unusual FLC size and increased N-linked glycosylation have also been observed, which may be correlated with the propensity of monoclonal Ig LC to cause LCDD [35,62,63]. Generally, as a result of the physicochemical features above, B-FLCs may assemble into different physical forms, e.g., crystalline precipitates, non-amyloid granular deposits, organized amyloid fibrils, and obstructive distal tubular casts. B-FLCs existing in different physical forms are shown in Figure 2A.

2.3. Biological Functions and Pathogenesis Features of B Cell-Derived FLCs

FLCs transcend their traditional role as inert byproducts of immunoglobulin synthesis, demonstrating multifaceted biological functions, which position FLCs not merely as disease biomarkers but as bioactive molecules that directly contribute to pathology by driving inflammation via immune cell activation and complement, acting as chemoattractants, forming cytotoxic aggregates or amyloid fibrils, mimicking pathogenic autoantibodies, and causing direct cellular damage, particularly to renal tubules. This positions them as active participants in disease mechanisms across nephrology, hematology, and rheumatology. Details about the biological functions and pathogenesis features of B-FLCs are listed in Table 2 and illustrated in Figure 3A.
First of all, the antigen-binding site in intact immunoglobulin involves both heavy and light chains; the autonomous antigen-binding ability of FLCs remains controversial. Most studies show that isolated FLCs lack antigen specificity or exhibit significantly reduced affinity compared to intact antibodies [91,92,93]. Reconstitution experiments reveal that separated HCs regain antigen-binding capacity when paired with unrelated LCs, whereas isolated LCs fail to do so, suggesting HCs dominate antigen recognition [64,65,66]. On the other hand, a subset of studies report the affinity of antigen–FLC interactions [94,95,96]. Monomeric κ-FLCs were reported to bind with antigens, e.g., actin, myoglobin, TNP25-BSA, with different affinity [94]. A monoclonal antibody solely consisting of κ-FLCs was observed to recognize and bind to an unidentified molecule expressed by the nevus cells [95]. Furthermore, Schechter proved the retained antigen-recognition ability of FLCs isolated from complete antibodies [96]. The inconsistency in the results concerning the antigen-binding ability of FLCs may lie in the inherent discrepancies among immunoglobulins.
Furthermore, FLCs modulate innate immunity through interactions with key effector cells, including mast cells (MCs) and neutrophils. MCs are innate immune cells present in almost all tissues and play a crucial role in human allergic reactions through degranulation upon activation. The IgE-mediated activation pathway is the most well-known mechanism for mast cell activation [97]. However, FLCs bind MCs via an unidentified receptor (distinct from FcεRI/FcγRIII), enabling antigen-mediated crosslinking that triggers degranulation—a pathway independent of classical IgE activation [67,68]. Neutrophils are the first-line cells that respond and function in the innate immune defense system after bacterial infection. FLCs impair neutrophil chemotaxis and hexose uptake while prolonging survival by inhibiting apoptosis, contributing to chronic inflammation in conditions like uremia [69,70,71]. In chronic obstructive pulmonary disease, FLC–neutrophil binding induces CXCL8 production, amplifying inflammatory cascades [98].
Notably, pathogenic FLCs induce tissue damage, which occurs not only through physical damage or structural remodeling caused by extracellular deposition but also through direct toxicity. Among the various systems affected, the cardiac and renal systems are most commonly involved in light-chain deposition-related diseases, such as AL amyloidosis and LCDD. Cardiotoxic FLCs directly bind to several intracellular proteins, such as mitochondrial optic atrophy-1 (APO1), like protein and peroxisomal acyl-coenzyme A oxidase 1 (ACOX1), related to the survival and metabolism of mitochondrial proteins, generating excessive ROS that impair mitochondrial integrity [72,74]. Moreover, high-level cellular ROS induced by FLCs were observed to be involved in the FLC-induced p38 MAPK signaling cascade, eventually leading to cell apoptosis [75]. Additionally, FLCs disrupt autophagy by compromising lysosomal function, ultimately triggering cardiomyocyte death [76]. Pathogenic FLCs are involved in renal injury, but the pathophysiological mechanisms vary depending on the specific renal structure affected. In the glomerulus, fibrillar FLCs in AL amyloidosis and granular FLCs in LCDD deposit in the mesangial space, transform normal mesangial cells to a macrophage phenotype or a myofibroblastic phenotype, respectively, causing damage through altering the mesangial matrix, irregular mesangial proliferation and fibrosis, and apoptosis caused a reduction in mesangial cells in the late phage of disease [78,79,80]. In the tubular nephrons, proximal tubule-residing FLCs activate NF-κB, ASK1, and JAK-STAT pathways, promoting oxidative stress via hydrogen peroxide, apoptosis, and tubulointerstitial fibrosis [81,82,83]. In the tubules of distal nephrons, FLCs bind uromodulin to form obstructive casts, exacerbating tubular damage through mechanical blockage and rupture of the tubules and ensuing immune response [77].

3. Non-B Cell-Derived Free Light Chains

Emerging evidence challenges the classical paradigm that immunoglobulins are exclusively produced by B lymphocytes. Non-B cells, including epithelial cells, cardiomyocytes, and tumor cells, exhibit “ectopic expression” of free light chains (non-B-FLCs) with distinct genomic and functional properties.

3.1. Genomic Features of Non-B Cell-Derived FLCs

Under physiological conditions, gene rearrangement of light chains derived from certain non-B cells and tissues exhibits distinct characteristics. Huang et al. demonstrated that Igκ is expressed in primary spermatocytes and isolated epididymis epithelial cells of adult mice. Among the VκJκ sequences derived from primary spermatocytes, dominant rearrangement patterns include Igkvbv9/Igkj1 and Igkv21-10/Igkj2, both of which exhibit >5% somatic hypermutation compared to germline sequences. In epididymal epithelial cells, the predominant rearrangement pattern was Igkvbw20/Igkj5 [39]. Zhu et al. proved the conserved VκJκ usage in cardiomyocytes of adult mice, with Igkv17-121, Igkv9-120, and Igkv14-100 being dominantly expressed [40]. Additionally, Igκ derived from primary hepatocytes of B cell-deficient μMT mice displayed distinct sequence characteristics, including preferential usage of Igkv1-135*01/Igkj1 and Igkv12–44*01/Igkj5 [41]. Furthermore, monocytes and neutrophils from patients with non-hematopoietic neoplasms frequently exhibited five rearrangement sets, including IGKV3-20*01/IGKJ1*01, IGKV3-20*01/IGKJ3*01, IGKV1-27*01/IGKJ1*01, IGKV1-27*01/IGKJ4*01, and IGKV1-5*03/IGKJ3*01 [42].
In carcinomas, soft tissue tumors, and hematologic malignancies, non-B-FLCs also exhibit tumor-specific gene rearrangement and hypermutation patterns. Wang et al. observed a unique IGKV4-1/IGKJ3 rearrangement pattern in Igκ light chains from multiple cancer cell lines, including HT-29 (colon cancer), A549 (lung cancer), HepG2 (hepatocellular carcinoma), HeLa MR (cervical cancer), and U2OS (osteosarcoma). These IGKV4-1/IGKJ3-FLCs show high homology to pathogenetic FLCs with identical rearrangements in LCDD and AL-AM [43]. Igκs derived from breast cancer, colon cancer, lung cancer, and hepatocellular carcinoma were further confirmed to predominantly utilize a unique IGKV4-1/IGKJ3 rearrangement pattern [44]. Additionally, Igκ sequences from fibrosarcoma, leiomyoma, rhabdomyosarcoma, and leiomyosarcoma tissues were highly homologous to IGKV3D-20*01, with all Jκ sequences belonging to IGKJ1 [45]. In acute myeloid leukemia (AML) myeloblasts, three recurrent IGKV/IGKJ rearrangements were identified, including IGKV15*03/IGKJ1*01, IGKV1-5*03/IGKJ3*01, and IGKV1-NL1*01/IGKJ5*01 [42]. Notably, the latter two show high inter-case homology.
Based on these findings, non-B cell-derived κ type FLCs exhibit cell-type-specific conserved rearrangement patterns under physiological conditions, accompanied by significant somatic hypermutation. Pathological FLCs display disease-characteristic rearrangements with IGKV4-1/IGKJ3 in carcinomas and IGKV3D-20*01 in soft tissue tumors, suggesting shared molecular mechanisms in a group of related pathological contexts. Details of V–J arrangement and gene segment usage are listed in Table 1.

3.2. Synthesis Regulation of Non-B Cell-Derived FLCs

Although mounting studies have validated the expression of Ig light chains in diverse non-B cell lineages, notably in almost all epithelial cancer cells, the genomic and molecular regulatory mechanisms underlying their production remain incompletely elucidated. Limited insights exist for light chains derived from nasopharyngeal carcinoma (NPC) cells and cardiomyocytes, with only few studies offering mechanistic clues.
A series of studies conducted by Cao et al. revealed the regulatory role of Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) on Ig light-chain expression. They identified functional regulatory elements, including the intronic enhancer (iEκ) and 3′ enhancer (3′Eκ), in specific NPC cell lines [99,100]. Mechanistically, LMP1 upregulates κ light-chain expression by enhancing 3′Eκ activity through ERK signaling-mediated activation of the transcription factor Ets-1 [100]. Concurrently, LMP1 promotes binding of heterodimeric NF-κB (p52/p65) and AP-1 (c-Jun/c-Fos) transcription factors to the iEκ enhancer region [101,102]. These findings challenge the classical view that Ig light-chain expression is strictly controlled by B cell lineage-restricted cis-regulatory elements, such as promoters/enhancers, thereby questioning the exclusivity of FLC production in B-lineage cells [99]. Interestingly, multiple immunoglobulins, such as Igκ-V8, Igκ-C, Igλ-V1, produced by cardiomyocytes were identified by Mehta‘s group. They demonstrated that light-chain expression is reduced in hearts of LOX-1 knockout mice, which is a cell surface lectin-like receptor for oxidized low-density lipoproteins (ox-LDL) critical in host defense. This loss was reversed upon exposure to angiotensin II-induced stress, implicating LOX-1 and hemodynamic stress in regulating cardiac Ig synthesis [103].

3.3. Physicochemical Properties and Morphological Forms of Non-B Cell-Derived FLCs

While the physicochemical properties of B cell-derived pathogenic FLCs in AL amyloidosis and LCDD are well characterized, non-B-FLCs remain understudied. Notably, Wang et al. reported that a free Igκ light chain with a unique Vκ4-1/Jκ3 rearrangement, derived from colon cancer, exhibits high homology to hydrophobic FLCs in AL amyloidosis and LCDD. These FLCs exist as monomers, dimers, and polymers, depositing both intracellularly and extracellularly in hydrophobic amorphous aggregates or fibrillar forms resembling extracellular matrix (ECM) proteins [43], suggesting their underlying pathological mechanisms and raising the question of whether these cancer-cell-deprived FLCs follow the similar regulation mechanism with their counterparts in AL amyloidosis and LCDD. In colitis and colitis-associated cancer, non-B-FLCs mainly exist as extracellular dimers [89]. Interestingly, in liver injury and hepatocellular carcinoma, dimeric and monomeric FLCs locate around the nucleus to form a point shape and display a filamentous network in hepatocytes and carcinoma cells [41,44]. Intracellular and extracellular pools of non-B-FLCs are depicted in Figure 2B.

3.4. Biological Functions and Pathogenesis Features of Non-B Cell-Derived FLCs

Non-B-FLCs exert diverse biological functions. Physiologically, non-B-FLCs are emerging as key players in tissue hemostasis, such as hepatocyte-derived Igκ in liver protection and lung epithelial Igκ in humoral immunity. Pathologically, non-B-FLCs drive tumor progression through multiple mechanisms, such as promoting inflammation and inflammation-mediated carcinogenesis, enhancing cancer cell survival, proliferation, invasion, and metastasis. Biological functions and pathogenesis features of non-B FLCs are listed in Table 2 and illustrated in Figure 3B.

3.4.1. Physiological Functions of Non-B Cell-Derived FLCs

Yin et al. demonstrated that hepatocyte-derived Igκ protects against concanavalin A (ConA)-induced acute liver injury. In a ConA-induced liver injury model, mitochondrial apoptosis is triggered by cytochrome c release and caspase activation [104,105]. Notably, Igκ expression at both the protein and mRNA level increased in hepatocytes of ConA-challenged mice. Igκ knockout exacerbated liver injury via enhanced mitochondrial apoptosis, NF-κB inactivation, and JNK activation, suggesting Igκ’s protective role in hepatocyte survival and its potential contribution to liver hemostasis [41].
Similarly, Gao et al. identified that lung epithelial cells secrete immunoglobulins (IgM, IgA, Igκ, and IgG3) under serum-free conditions. Using an adeno-associated virus (AAV-Cre) to knock down Igκ specifically in Clara cells, they immunized mice with the T cell-dependent antigen NP-KLH. Igκ-deficient mice showed reduced NP-specific antibody production in lung epithelial cells, revealing Igκ’s essential role in long-distance immune responses and antibody secretion by non-B cells [88].

3.4.2. Non-B Cell-Derived FLCs in Inflammation and Inflammation-Mediated Carcinogenesis

Nonallergic rhinitis (NAR) is an inflammatory disease lacking a clear allergic trigger from the history, with negative skin tests or negative specific IgE against common aeroallergens [106]. One possible explanation for this condition might be lie in non-IgE-mediated pathways involving FLCs. Redegeld et al. found that FLCs have a potential role in T cell-mediated immediate and delayed hypersensitivity immune responses, similar to IgE [87]. Significantly increased levels of FLCs in nasal secretions and enhanced FLC mRNA levels in nasal mucosa were discovered in NAR patients [107,108], which suggests that nasal mucosa cells may have the capacity to produce FLCs, although additional evidence is needed to confirm this possibility. Moreover, FLC expression showed concentrated localization in mast cells and a few distributions in eosinophils, indicating their possible role in local immune hypersensitivity and inflammation-mediated pathogenesis [107,108].
Chronic inflammation drives carcinogenesis through sustained tissue damage, oxidative stress, and dysregulated immune responses. Similarly, FLCs were found to promote murine colitis and colitis-associated cancer (CAC) carcinogenesis by inflammasome activation [89]. In both colitis and CAC mouse models, FLC was found to promote neutrophil activation. Moreover, active IL-1β and IL-18 levels are associated with increased FLC, along with more severe colitis damage and tumor formation. Conversely, using the FLC functional blocker peptide F991 significantly reduces activated IL-1β, IL-18, and activated caspase-1, while alleviating colitis progression and decreasing tumorigenesis [89]. Ig light-chain expression may serve as potential biomarkers of the stages in the process of inflammation-mediated carcinogenesis. Li et al. confirmed the Igκ light-chain constant region mRNA expressed by cervical epithelial cells and reported a significant increase in this mRNA level in dysplastic and carcinomatous cervical epithelial cells compared to cells with cervicitis, revealing a close association between Igκ constant region gene expression and cervical carcinogenesis development [109]. In addition, according to Kormelink et al., FLCs co-localized with mast cells in tumor-associated tissues from human breast, pancreas, lung, colon, skin, and kidney, but were absent in their healthy counterparts. Their study further revealed a positive correlation between FLC expression and aggressive tumor traits, such as increased proliferation, reduced apoptosis, and p53 mutation in basal-like breast cancers [110]. Moreover, research on a murine model of human malignant melanoma—which responds to anti-inflammatory therapy and is mast cell-dependent—suggests that FLCs promote tumor growth through FLC-activated mast cells, although specific mechanisms remain unclear [110,111,112,113].
Collectively, non-B-FLCs drive inflammation and tumor progression by activating inflammasome by enhancing the expression of cleaved caspase-1 and the maturation of IL-1β and IL-18. They also correlate with aggressive tumor traits and may serve as biomarkers or therapeutic targets to disrupt inflammation-to-cancer transitions.

3.4.3. Pathological Role of Non-B Cell-Derived FLCs in Malignancies

FLCs derived from non-B cells exhibit tumor-promoting roles across diverse malignancies through distinct molecular mechanisms. In colon cancer, FLCs stabilize the anti-apoptotic protein Bcl-xL by directly interacting with it, thereby inhibiting mitochondrial apoptosis and enhancing tumor cell survival [114]. Recently, the free Igκ chain with a unique Vκ4-1/Jκ3 has been widely detected in multiple cancer cells, such as colon cancer, lung cancer, cervical cancer, proven to act as an ECM protein and an integrin β1 ligand in colon cancer [43]. These FLCs activate the FAK/Src signaling cascade, upregulate MMP-2 and MMP-9 expression, and drive cancer cell migration and invasion. Structural analysis reveals that the CDR2 region of Vκ4-1/Jκ3-FLCs is critical for integrin β1 binding, highlighting a unique structure–function relationship [43]. In hepatocellular carcinoma (HCC), hepatocyte-derived Igκ promotes tumor progression by modulating fatty acid metabolism. Igκ interacts with electron transfer flavoprotein A (ETFA), stabilizing its expression to enhance β-oxidation—a metabolic process critical for energy production in proliferating HCC cells. Depletion of Igκ in hepatocytes suppresses HCC growth in murine models, confirming its oncogenic role [44]. In addition, Wang et al. reported that the expression level of Igλ in cervical adenocarcinoma and cervical squamous cell carcinoma was higher than that in normal cervical tissue, and they obtained four potential tumor-derived Igλ-interacting proteins, RPL7, RPS3, and histones H1-5 and H1-6 [90]. RPL7 and RPS3, crucial for DNA damage repair, belong to the L30P and S3 ribosomal protein families, respectively. RPS3 also plays a key role in apoptosis, inflammation, tumorigenesis, and transcriptional regulation [115,116], interacting with p53 and lactate dehydrogenase to promote colon cancer cell proliferation, survival, migration, and invasion while reducing apoptosis [117]. Histone H1, a chromatin linker protein, includes 12 subtypes [118], among which H1-5 stabilizes higher-order chromatin structure and regulates gene expression, DNA repair, cell differentiation, proliferation, and metastasis [119,120]. While H1-6 facilitates chromatin decondensation for gene activation [121]. Tumor-derived Igλ interaction with these proteins may enhance oncogenic gene activation and metastasis by disrupting DNA repair via RPL7/RPS3 interference, inhibiting p53-mediated apoptosis, and promoting chromatin relaxation through H1-5/H1-6 interactions [90].
Beyond epithelial cancers, mesenchymal tumors such as sarcomas show a strong correlation between Igκ expression and proliferation markers, such as PCNA, Ki-67, cyclin D1, suggesting a pro-proliferative role for Igκ in these malignancies, though mechanistic insights remain limited [45]. In hematologic cancers like acute myeloid leukemia (AML), the IGKV1-5/IGKJ3*01 rearrangement in myeloblasts upregulates fLMP and CXCL12, chemotactic factors that drive AML cell migration and dissemination [42].
In conclusion, non-B-FLCs drive tumor progression across diverse cancers via distinct mechanisms and correlate with aggressive traits in mesenchymal tumors and hematologic malignancies. Especially, their structural specificity with Vκ4-1/Jκ3 rearrangement pattern and cross-tissue oncogenic roles highlight FLCs as multifunctional mediators and potential therapeutic targets in cancer biology.

4. Comparative Analysis of B Cell-Derived FLCs vs. Non-B Cell-Derived FLCs

Both B- or non-B-FLCs originate from V–J recombination of Ig light-chain genes consisting of V and J segments. However, their genomic preferences and structural features diverge under physiological or pathological conditions. B-FLCs exhibit disease-specific gene segment biases, such as the dominance of IGLV6-57 (Vλ6) in AL [30]. However, non-B-FLCs lack consensus in gene segment usage among different lineages but frequently display a unique Vκ4-1/Jκ3 rearrangement pattern in various epithelial carcinomas, which is homologous to pathogenic B-FLCs in AL and LCDD [43]. Structurally, these Vκ4-1/Jκ3-FLCs can also form hydrophobic polymers that disrupt tissue architecture, similar to pathogenic B-FLCs.
Both B- and non-B-FLCs share similar roles in immune cell modulation, both involved in interacting with mast cells in diverse diseases, e.g., non-B-FLCs in tumor-associated inflammation, nonallergic rhinitis, and co-localization with mast cells in solid tumors (e.g., breast, lung), functionally echoing the role of B-FLCs in non-IgE-mediated mast cell activation [68,87,89,110]. However, significant divergence exists in the biological functions regarding other aspects. B-FLCs inhibit neutrophil apoptosis and exhibit enzymatic activities (e.g., anti-angiogenic, prothrombinase, and proteolytic functions), which have not been reported in non-B-FLCs [5,84,85,86]. Conversely, non-B-FLCs drive tumor progression via non-immunological pathways, such as stabilizing the anti-apoptotic protein Bcl-xL to enhance cancer cell survival or activating integrin β1/FAK/Src signaling to promote invasion and metastasis through MMP-mediated ECM remodeling [43,114].
Despite differences in disease associations, B- and non-B-FLCs share pathogenic mechanisms. Both induce extracellular deposition of hydrophobic aggregates, leading to structural damage like AL fibrils and tumor-associated ECM disruption [43,122]. In malignancies, the cellular origin of FLCs dictates their pathological impact. Non-B-FLCs in solid tumors (e.g., lung adenocarcinoma, colorectal cancer, and sarcomas) promote tumorigenesis by enhancing anti-apoptotic signaling via Bcl-xL stabilization, activating pro-invasive pathways via integrin β1/FAK/Src, rewiring metabolism via ETFA-dependent fatty acid oxidation, or disrupting DNA repair/epigenetic regulation via ribosomal/histone interactions and correlating with hyperproliferative phenotypes in mesenchymal tumors, etc. [43,44,45,89,90,110,114]. Conversely, B-FLCs in hematologic disorders serve as hallmarks of MM and Waldenström macroglobulinemia and directly cause organ damage through insoluble aggregate deposition, for example, tubular obstruction and tissue fibrosis, as well as molecular toxicity through activating NF-κB, complement pathways, and oxidative stress [49,122,123,124]. This dichotomy underscores the dual nature of FLC pathogenicity: non-B-FLCs drive epithelial/stromal tumor progression through oncogenic signaling, while B-FLCs mediate structural and inflammatory organ damage in hematologic malignancies.

5. Clinical and Therapeutic Perspectives

Currently, the clinical application of B-FLCs remains confined to their roles as a diagnostic, prognostic, and therapeutic marker in B cell clonal disorders, such as monoclonal gammopathy of undetermined significance (MGUS), MM, AL, and light-chain-related renal injuries. In these conditions, both the absolute levels of FLCs and the κ/λ ratio provide critical diagnostic and prognostic insights [125]. B-FLCs also show potential as biomarkers for autoimmune diseases (e.g., rheumatoid arthritis, primary Sjögren’s syndrome) and chronic inflammatory conditions, for example, chronic hepatitis B and diabetes, though further validation is required before clinical translation [126,127,128]. Emerging evidence suggests B-FLCs may serve as biomarkers for neurological disorders like myasthenia gravis and multiple sclerosis, but their routine use in these contexts is not yet established [13,14,15,16]. In contrast, non-B-FLCs remain poorly characterized pathologically, with no reported therapies targeting them to date.
Laboratory assessment of FLCs encompasses both qualitative and quantitative analyses of serum and urine samples. Qualitative or semi-quantitative methods primarily include protein electrophoresis and immunofixation electrophoresis [129]. For serum FLC quantification, the turbidimetry Freelite assay (The Binding Site), which employs with sheep polyclonal antibodies binding to hidden epitopes in the FLC constant region, was commercialized in 2001 [130]. Subsequent developments introduced alternative commercial serum FLC assays, including nephelometric methods like N-Latex FLC (Siemens; using monoclonal antibodies) and lateral flow methods like Seralite (Abingdon Health-Sebia; competitive inhibition lateral flow immunoassay), as well as the sandwich ELISA-based Sebia FLC assay (Sebia; using polyclonal antibody) [131,132]. Likely, urine FLC quantification is also possible using nephelometric and turbidimetric methods. However, the clinical utility of urinary FLC measurement remains limited. This is due to discordance between urinary FLC excretion patterns and serum FLC levels heavily influenced by renal function, combined with challenges in urine sample preparation and standardization [131]. Notably, mass spectrometry methods has recently demonstrated promising potential for the accurate and sensitive quantification of both serum and urine FLCs [133].
The focus and methodological considerations in FLC measurement vary significantly across diverse pathological contexts. In MM, the primary concerns are the absolute level of the involved FLCs reflecting selective κ or λ chain elevation due to plasma cell clonal expansion and the involved/uninvolved FLC ratio. Recommended laboratory testing includes serum and 24 h urine protein electrophoresis with immunofixation, alongside serum FLC quantification [131,132]. Crucially, when evaluating MM patients with chronic kidney disease (CKD), renal function must be factored into the interpretation of serum FLC levels, as these levels are influenced by renal clearance capacity. In multiple sclerosis (MS), the κFLC index calculated from cerebrospinal fluid (CSF) and serum FLC/albumin ratios is the validated diagnostic biomarker. Turbidimetric or nephelometric methods are recommended [133]. FLC measurement is not currently included in diagnostic guidelines, and specific methodological recommendations are lacking. However, it is worth noticing that for autoimmune diseases such as RA or SS, unlike the monoclonal FLCs observed in MM, the polyclonal FLC increase in autoimmune disorders necessitates assay compatibility with a broad range of light-chain epitopes.
With advancing research on both B- and non-B-FLCs, therapeutic strategies targeting these molecules hold significant promise. For B-FLC-associated diseases like MM and AL, current therapies focus on eliminating clonal plasma cells via alkylating agents, proteasome inhibitors, or anti-B cell antibodies, or reducing circulating FLCs via dialysis rather than directly targeting FLCs themselves, as their pathological effects largely stem from aggregation. However, recent breakthroughs include the anti-amyloid fibril antibody CAEL-101, which demonstrated organ response improvements in AL patients in Phase 1a/b trials, with ongoing Phase III studies, such as Mayo Stage IIIb [72,134,135]. Another promising avenue is blocking B-FLC interactions with mast cells to mitigate allergic and inflammatory responses [136]. Non-B-FLCs, however, represent a novel therapeutic frontier in oncology. These FLCs promote inflammation, carcinogenesis, and tumor progression in epithelial cancers. Among them, Vκ4-1/Jκ3-FLCs act as integrin β1 ligands, activating FAK/Src pathways and MMP-mediated ECM remodeling to drive metastasis; therefore, monoclonal antibodies targeting these FLCs show antitumor efficacy in preclinical models [43]. Moreover, Vκ4-1/Jκ3-FLCs interact with ETFA to enhance fatty acid β-oxidation, fueling tumor proliferation, and then disrupting the Igκ/ETFA axis suppresses HCC growth [44]. Targeting these interactions, such as integrin β1 or ETFA blockade, offers promising strategies for cancer treatment.
Therapies targeting B-FLCs and non-B-FLCs hold great translational promise for the future, yet several mechanistic questions need further exploration. For B-FLC-targeted therapies, challenges arise as the amino acid sequence and 3D structure of amyloid fibrils vary among patients, complicating the achievement of stable efficacy. Regarding non-B-FLCs, more research is needed to compare their structural properties and physicochemical characteristics with those of B-FLCs. Functionally, the exact interaction patterns and immune cell modulation mechanisms of B-FLCs and non-B-FLCs, particularly concerning mast cells and neutrophils, remain unclear. Moreover, the specific mechanisms by which FLCs promote cancer cell proliferation, metastasis, and immune escape need to be uncovered. For instance, in cervical cancers, how FLCs interact with proteins like RPL7, RPS3, H1-5, and H1-6, and the exact process of FLCs promoting sarcoma proliferation, are not yet fully understood [45,90]. In summary, while B-FLCs dominate hematologic disease management, non-B-FLCs represent untapped targets in solid tumors. Overcoming mechanistic and structural ambiguities will be pivotal to unlocking their full therapeutic potential.

6. Conclusions

B cell-derived and non-B cell-derived FLCs show both coherences and divergences in gene structures, physicochemical properties, biological functions, and pathogenic roles. They hold great clinical potential for accurate and sensitive diagnosis, targeted therapies, and timely monitoring of disease severity and prognosis across various diseases. However, research on FLCs is insufficient, particularly for non-B-FLCs, which have only garnered attention in recent decades. As exploration continues, a more in-depth understanding of FLCs and their translational potential is anticipated.

Author Contributions

Conceptualization, J.H. and L.L.; validation, L.L.; resources, J.H. and X.Q.; writing—original draft preparation, L.L.; writing—review and editing, J.H., L.L. and H.G.; visualization, L.L. and H.G.; supervision, J.H. and X.Q.; funding acquisition, J.H. and X.Q. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (82171806, 82371733, 82030044 and 82341227) and the Beijing Natural Science Foundation (Z220014 and 7222104).

Data Availability Statement

The data generated in this study are available upon reasonable request from the corresponding authors.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
3′E3′ enhancer
AAVadeno-associated virus
ACOX1peroxisomal acyl-coenzyme A oxidase 1
AL amyloidosislight chain-derived amyloidosis
AMLacute myeloid leukemia
APO1optic atrophy-1
ASK1Apoptosis Signal-regulating Kinase 1
Bcl-xLB cell Lymphoma-extra Large
B-FLCB cell-derived free light chain
CACColitis Associated Cancer
CDRcomplementarity-determining region
ConAconcanavalin A
CKDChronic Kidney Disease
CSFCerebrospinal Fluid
CXCLC-X-C Motif Chemokine Ligand
EBVEpstein–Barr virus
ECMExtracellular matrix
ERKExtracellular Signal-Regulated Kinase
ETFAElectron Transfer Flavoprotein A
FAK/SrcFocal Adhesion Kinase/Src Kinase
FcγRFc Gamma Receptor
FcεRFc Epsilon Receptor
FLCFree light chain
FSFanconi syndrome
HCHeavy chains
HCCHepatocellular carcinoma
iEIntronic enhancer
IGKImmunoglobulin κ light-chain locus
IGLImmunoglobulin λ light-chain locus
JAK-STATJanus Kinase-Signal Transducer and Activator of Transcription
JNKc-Jun N-terminal kinase
JRAJuvenile rheumatoid arthritis
LCLight chains
LCCNLight-chain cast nephropathy
LCDDLight-chain deposition disease
LCPTLight-chain proximal tubulopathy
LDLLow-density lipoprotein
LMPLatent membrane protein
LOX-1Lectin-like Oxidized LDL Receptor 1
MAPKMitogen-Activated Protein Kinase
MCMast cell
MGUSMonoclonal gammopathy of undetermined significance
MMMultiple myeloma
MMPMatrix Metalloproteinase
NARNonallergic rhinitis
NF-κBNuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells
NLRP3NOD-like receptor thermal protein domain associated protein 3
non-B-FLCNon-B cell-derived free light chain
NPCNasopharyngeal carcinoma
NP-KLH4-Hydroxy-3-nitrophenylacetyl-Keyhole Limpet Hemocyanin
PCNAProliferating Cell Nuclear Antigen
RAGRecombination-Activating Gene
ROSReactive Oxygen Species
RPL7/S3Ribosomal Protein L7/S3
RSSRecombination Signal Sequences
SLESystemic lupus erythematosus
TNP25-BSATrinitrophenyl 25-Bovine Serum Albumin

References

  1. Huang, J.; Zhang, J.; Zhang, L.; Wang, Z.; Fan, T.; Yin, S. The Structure Characteristics and Function of Non B Cell-Derived Immunoglobulin. In Non B Cell-Derived Immunoglobulins: The Structure, Characteristics and the Implication on Clinical Medicine; Qiu, X., Huang, J., Xu, X., Eds.; Springer Nature: Singapore, 2024; pp. 59–71. ISBN 978-981-97-0511-5. [Google Scholar]
  2. Jones, H.B. Some Account of a New Animal Substance Occurring in the Urine of a Patient Labouring under Mollities Ossium. Edinb. Med. Surg. J. 1850, 74, 357–368. [Google Scholar] [PubMed]
  3. Delman, G.M.; Gally, J.A. The nature of bence-jones proteins: Chemical similarities to polypeptide chains of myeloma globulins and normal γ-globulins. J. Exp. Med. 1962, 116, 207–227. [Google Scholar] [CrossRef]
  4. Schwartz, J.H.; Edelman, G.M. Comparisons of Bence-Jones Proteins and L Polypeptide Chains of Myeloma Globulins after Hydrolysis with Trypsin. J. Exp. Med. 1963, 118, 41–53. [Google Scholar] [CrossRef]
  5. Boivin, D.; Provençal, M.; Gendron, S.; Ratel, D.; Demeule, M.; Gingras, D.; Béliveau, R. Purification and Characterization of a Stimulator of Plasmin Generation from the Antiangiogenic Agent Neovastat: Identification as Immunoglobulin Kappa Light Chain. Arch. Biochem. Biophys. 2004, 431, 197–206. [Google Scholar] [CrossRef]
  6. Solomon, A.; Waldmann, T.A.; Fahey, J.L.; Mcfarlane, A.S. Metabolism of bence jones proteins. J. Clin. Investig. 1964, 43, 103–117. [Google Scholar] [CrossRef] [PubMed]
  7. Wochner, R.D.; Strober, W.; Waldmann, T.A. The Role of the Kidney in the Catabolism of Bence Jones Proteins and Immunoglobulin Fragments. J. Exp. Med. 1967, 126, 207–221. [Google Scholar] [CrossRef]
  8. Rajkumar, S.V. Multiple Myeloma: 2024 Update on Diagnosis, Risk-Stratification, and Management. Am. J. Hematol. 2024, 99, 1802–1824. [Google Scholar] [CrossRef]
  9. Glenn, M.J.; Madsen, M.J.; Davis, E.; Garner, C.D.; Curtin, K.; Jones, B.; Williams, J.A.; Tomasson, M.H.; Camp, N.J. Elevated IgM and Abnormal Free Light Chain Ratio Are Increased in Relatives from High-Risk Chronic Lymphocytic Leukemia Pedigrees. Blood Cancer J. 2019, 9, 25. [Google Scholar] [CrossRef]
  10. Merlini, G.; Dispenzieri, A.; Sanchorawala, V.; Schönland, S.O.; Palladini, G.; Hawkins, P.N.; Gertz, M.A. Systemic Immunoglobulin Light Chain Amyloidosis. Nat. Rev. Dis. Primers 2018, 4, 38. [Google Scholar] [CrossRef]
  11. Mohan, M.; Buros, A.; Mathur, P.; Gokden, N.; Singh, M.; Susanibar, S.; Jo Kamimoto, J.; Hoque, S.; Radhakrishnan, M.; Matin, A.; et al. Clinical Characteristics and Prognostic Factors in Multiple Myeloma Patients with Light Chain Deposition Disease. Am. J. Hematol. 2017, 92, 739–745. [Google Scholar] [CrossRef] [PubMed]
  12. Napodano, C.; Pocino, K.; Rigante, D.; Stefanile, A.; Gulli, F.; Marino, M.; Basile, V.; Rapaccini, G.L.; Basile, U. Free Light Chains and Autoimmunity. Autoimmun. Rev. 2019, 18, 484–492. [Google Scholar] [CrossRef]
  13. Dekeyser, C.; De Kesel, P.; Cambron, M.; Vanopdenbosch, L.; Van Hijfte, L.; Vercammen, M.; Laureys, G. Inter-Assay Diagnostic Accuracy of Cerebrospinal Fluid Kappa Free Light Chains for the Diagnosis of Multiple Sclerosis. Front. Immunol. 2024, 15, 1385231. [Google Scholar] [CrossRef]
  14. Rosenstein, I.; Axelsson, M.; Novakova, L.; Malmeström, C.; Blennow, K.; Zetterberg, H.; Lycke, J. Intrathecal Kappa Free Light Chain Synthesis Is Associated with Worse Prognosis in Relapsing-Remitting Multiple Sclerosis. J. Neurol. 2023, 270, 4800–4811. [Google Scholar] [CrossRef] [PubMed]
  15. Levraut, M.; Laurent-Chabalier, S.; Ayrignac, X.; Bigaut, K.; Rival, M.; Squalli, S.; Zéphir, H.; Alberto, T.; Pekar, J.-D.; Ciron, J.; et al. Kappa Free Light Chain Biomarkers Are Efficient for the Diagnosis of Multiple Sclerosis: A Large Multicenter Cohort Study. Neurol. Neuroimmunol. Neuroinflamm. 2023, 10, e200049. [Google Scholar] [CrossRef]
  16. Wilf-Yarkoni, A.; Alkalay, Y.; Brenner, T.; Karni, A. High κ Free Light Chain Is a Potential Biomarker for Double Seronegative and Ocular Myasthenia Gravis. Neurol. Neuroimmunol. Neuroinflamm. 2020, 7, e831. [Google Scholar] [CrossRef]
  17. Hwang, J.K.; Alt, F.W.; Yeap, L.-S. Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination. Microbiol. Spectr. 2015, 3, 325–348. [Google Scholar] [CrossRef] [PubMed]
  18. Carmona, L.M.; Schatz, D.G. New Insights into the Evolutionary Origins of the Recombination-Activating Gene Proteins and V(D)J Recombination. FEBS J. 2017, 284, 1590–1605. [Google Scholar] [CrossRef] [PubMed]
  19. Manso, T.; Folch, G.; Giudicelli, V.; Jabado-Michaloud, J.; Kushwaha, A.; Nguefack Ngoune, V.; Georga, M.; Papadaki, A.; Debbagh, C.; Pégorier, P.; et al. IMGT® Databases, Related Tools and Web Resources through Three Main Axes of Research and Development. Nucleic Acids Res. 2022, 50, D1262–D1272. Available online: https://academic.oup.com/nar/article/50/D1/D1262/6455007?login=false (accessed on 30 July 2025). [CrossRef]
  20. Solomon, A. Light Chains of Immunoglobulins: Structural-Genetic Correlates. Blood 1986, 68, 603–610. [Google Scholar] [CrossRef]
  21. Klein, R.; Zachau, H.G. Expression and Hypermutation of Human Immunoglobulin Kappa Genes. Ann. N. Y. Acad. Sci. 1995, 764, 74–83. [Google Scholar] [CrossRef]
  22. Ignatovich, O.; Tomlinson, I.M.; Jones, P.T.; Winter, G. The Creation of Diversity in the Human Immunoglobulin Vλ Repertoire. J. Mol. Biol. 1997, 268, 69–77. [Google Scholar] [CrossRef]
  23. Farner, N.L.; Dörner, T.; Lipsky, P.E. Molecular Mechanisms and Selection Influence the Generation of the Human V Lambda J Lambda Repertoire. J. Immunol. 1999, 162, 2137–2145. [Google Scholar] [CrossRef]
  24. Cuisinier, A.M.; Fumoux, F.; Moinier, D.; Boubli, L.; Guigou, V.; Milili, M.; Schiff, C.; Fougereau, M.; Tonnelle, C. Rapid Expansion of Human Immunoglobulin Repertoire (VH, V Kappa, V Lambda) Expressed in Early Fetal Bone Marrow. New Biol. 1990, 2, 689–699. [Google Scholar]
  25. Kiyoi, H.; Naito, K.; Ohno, R.; Saito, H.; Naoe, T. Characterization of the Immunoglobulin Light Chain Variable Region Gene Expressed in Multiple Myeloma. Leukemia 1998, 12, 601–609. [Google Scholar] [CrossRef] [PubMed]
  26. Kosmas, C.; Viniou, N.; Stamato Poulos, K.; Courtenay-Luck, N.S.; Papadaki, T.; Kollia, P.; Paterakis, G.; Anagnostou, D.; Yataganas, X.; Loukopoulos, D. Analysis of the κ Light Chain Variable Region in Multiple Myeloma. Br. J. Haematol. 1996, 94, 306–317. [Google Scholar] [CrossRef] [PubMed]
  27. Sahota, S.S.; Leo, R.; Hamblin, T.J.; Stevenson, F.K. Myeloma VL and VH Gene Sequences Reveal a Complementary Imprint of Antigen Selection in Tumor Cells. Blood 1997, 89, 219–226. [Google Scholar] [CrossRef]
  28. Perfetti, V.; Palladini, G.; Casarini, S.; Navazza, V.; Rognoni, P.; Obici, L.; Invernizzi, R.; Perlini, S.; Klersy, C.; Merlini, G. The Repertoire of λ Light Chains Causing Predominant Amyloid Heart Involvement and Identification of a Preferentially Involved Germline Gene, IGLV1-44. Blood 2012, 119, 144–150. [Google Scholar] [CrossRef]
  29. Kourelis, T.V.; Dasari, S.; Theis, J.D.; Ramirez-Alvarado, M.; Kurtin, P.J.; Gertz, M.A.; Zeldenrust, S.R.; Zenka, R.M.; Dogan, A.; Dispenzieri, A. Clarifying Immunoglobulin Gene Usage in Systemic and Localized Immunoglobulin Light-Chain Amyloidosis by Mass Spectrometry. Blood 2017, 129, 299–306. [Google Scholar] [CrossRef]
  30. Comenzo, R.L.; Zhang, Y.; Martinez, C.; Osman, K.; Herrera, G.A. The Tropism of Organ Involvement in Primary Systemic Amyloidosis: Contributions of Ig VL Germ Line Gene Use and Clonal Plasma Cell Burden. Blood 2001, 98, 714–720. [Google Scholar] [CrossRef]
  31. Nevone, A.; Girelli, M.; Mangiacavalli, S.; Paiva, B.; Milani, P.; Cascino, P.; Piscitelli, M.; Speranzini, V.; Cartia, C.S.; Benvenuti, P.; et al. An N-Glycosylation Hotspot in Immunoglobulin κ Light Chains Is Associated with AL Amyloidosis. Leukemia 2022, 36, 2076–2085. [Google Scholar] [CrossRef]
  32. Sletten, K.; Natvig, J.B.; Husby, G.; Juul, J. The Complete Amino Acid Sequence of a Prototype Immunoglobulin-Lambda Light-Chain-Type Amyloid-Fibril Protein AR. Biochem. J. 1981, 195, 561–572. [Google Scholar] [CrossRef]
  33. Rocca, A.; Khamlichi, A.A.; Aucouturier, P.; Noël, L.H.; Denoroy, L.; Preud’homme, J.L.; Cogné, M. Primary Structure of a Variable Region of the V Kappa I Subgroup (ISE) in Light Chain Deposition Disease. Clin. Exp. Immunol. 1993, 91, 506–509. [Google Scholar] [CrossRef]
  34. Bellotti, V.; Stoppini, M.; Merlini, G.; Zapponi, M.C.; Meloni, M.L.; Banfi, G.; Ferri, G. Amino Acid Sequence of k Sci, the Bence Jones Protein Isolated from a Patient with Light Chain Deposition Disease. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 1991, 1097, 177–182. [Google Scholar] [CrossRef]
  35. Structure of a Monoclonal Kappa Chain of the V Kappa IV Subgroup in the Kidney and Plasma Cells in Light Chain Deposition Disease. Available online: https://pubmed.ncbi.nlm.nih.gov/1904072/ (accessed on 21 March 2025).
  36. Morbach, H.; Richl, P.; Faber, C.; Singh, S.K.; Girschick, H.J. The Kappa Immunoglobulin Light Chain Repertoire of Peripheral Blood B Cells in Patients with Juvenile Rheumatoid Arthritis. Mol. Immunol. 2008, 45, 3840–3846. [Google Scholar] [CrossRef]
  37. Girschick, H.J.; Grammer, A.C.; Nanki, T.; Vazquez, E.; Lipsky, P.E. Expression of Recombination Activating Genes 1 and 2 in Peripheral B Cells of Patients with Systemic Lupus Erythematosus. Arthritis Rheum. 2002, 46, 1255–1263. [Google Scholar] [CrossRef] [PubMed]
  38. Yurasov, S.; Tiller, T.; Tsuiji, M.; Velinzon, K.; Pascual, V.; Wardemann, H.; Nussenzweig, M.C. Persistent Expression of Autoantibodies in SLE Patients in Remission. J. Exp. Med. 2006, 203, 2255–2261. [Google Scholar] [CrossRef] [PubMed]
  39. Huang, J.; Zhang, L.; Ma, T.; Zhang, P.; Qiu, X. Expression of Immunoglobulin Gene with Classical V-(D)-J Rearrangement in Mouse Testis and Epididymis. J. Histochem. Cytochem. 2009, 57, 339–349. [Google Scholar] [CrossRef]
  40. Zhu, Z.; Zhang, M.; Shao, W.; Wang, P.; Gong, X.; Ma, J.; Qiu, X.; Wang, B. Immunoglobulin M, a Novel Molecule of Myocardial Cells of Mice. Int. J. Biochem. Cell Biol. 2017, 88, 172–180. [Google Scholar] [CrossRef] [PubMed]
  41. Yin, S.; Shi, Q.; Shao, W.; Zhang, C.; Zhang, Y.; Qiu, X.; Huang, J. Hepatocyte-Derived Igκ Exerts a Protective Effect against ConA-Induced Acute Liver Injury. Int. J. Mol. Sci. 2020, 21, 9379. [Google Scholar] [CrossRef]
  42. Wang, C.; Xia, M.; Sun, X.; He, Z.; Hu, F.; Chen, L.; Bueso-Ramos, C.; Qiu, X.; Yin, C. IGK with Conserved IGKappaV/IGKappaJ Repertoire Is Expressed in Acute Myeloid Leukemia and Promotes Leukemic Cell Migration. Oncotarget 2015, 6, 39062–39072. [Google Scholar] [CrossRef]
  43. Wang, Q.; Jiang, D.; Ye, Q.; Zhou, W.; Ma, J.; Wang, C.; Geng, Z.; Chu, M.; Zheng, J.; Chen, H.; et al. A Widely Expressed Free Immunoglobulin κ Chain with a Unique Vκ4-1/Jκ3 Pattern Promotes Colon Cancer Invasion and Metastasis by Activating the Integrin Β1/FAK Pathway. Cancer Lett. 2022, 540, 215720. [Google Scholar] [CrossRef] [PubMed]
  44. Guo, J.; Gu, H.; Yin, S.; Yang, J.; Wang, Q.; Xu, W.; Wang, Y.; Zhang, S.; Liu, X.; Xian, X.; et al. Hepatocyte-Derived Igκ Promotes HCC Progression by Stabilizing Electron Transfer Flavoprotein Subunit α to Facilitate Fatty Acid β-Oxidation. J. Exp. Clin. Cancer Res. CR 2024, 43, 280. [Google Scholar] [CrossRef]
  45. Chen, Z.; Huang, X.; Ye, J.; Pan, P.; Cao, Q.; Yang, B.; Li, Z.; Su, M.; Huang, C.; Gu, J. Immunoglobulin G Is Present in a Wide Variety of Soft Tissue Tumors and Correlates Well with Proliferation Markers and Tumor Grades. Cancer 2010, 116, 1953–1963. Available online: https://acsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cncr.24892 (accessed on 6 April 2025). [CrossRef]
  46. Leboulleux, M.; Lelongt, B.; Mougenot, B.; Touchard, G.; Makdassi, R.; Rocca, A.; Noel, L.-H.; Ronco, P.M.; Aucouturier, P. Protease Resistance and Binding of Ig Light Chains in Myeloma-Associated Tubulopathies. Kidney Int. 1995, 48, 72–79. [Google Scholar] [CrossRef]
  47. Messiaen, T.; Deret, S.; Mougenot, B.; Bridoux, F.; Dequiedt, P.; Dion, J.J.; Makdassi, R.; Meeus, F.; Pourrat, J.; Touchard, G.; et al. Adult Fanconi Syndrome Secondary to Light Chain Gammopathy: Clinicopathologic Heterogeneity and Unusual Features in 11 Patients. Medicine 2000, 79, 135–154. [Google Scholar] [CrossRef]
  48. Luciani, A.; Sirac, C.; Terryn, S.; Javaugue, V.; Prange, J.A.; Bender, S.; Bonaud, A.; Cogné, M.; Aucouturier, P.; Ronco, P.; et al. Impaired Lysosomal Function Underlies Monoclonal Light Chain-Associated Renal Fanconi Syndrome. J. Am. Soc. Nephrol. 2016, 27, 2049–2061. [Google Scholar] [CrossRef]
  49. Basnayake, K.; Stringer, S.J.; Hutchison, C.A.; Cockwell, P. The Biology of Immunoglobulin Free Light Chains and Kidney Injury. Kidney Int. 2011, 79, 1289–1301. [Google Scholar] [CrossRef]
  50. Bruccoleri, R.E.; Haber, E.; Novotný, J. Structure of Antibody Hypervariable Loops Reproduced by a Conformational Search Algorithm. Nature 1988, 335, 564–568. [Google Scholar] [CrossRef] [PubMed]
  51. Mian, I.S.; Bradwell, A.R.; Olson, A.J. Structure, Function and Properties of Antibody Binding Sites. J. Mol. Biol. 1991, 217, 133–151. [Google Scholar] [CrossRef] [PubMed]
  52. Chothia, C.; Lesk, A.M. Canonical Structures for the Hypervariable Regions of Immunoglobulins. J. Mol. Biol. 1987, 196, 901–917. [Google Scholar] [CrossRef] [PubMed]
  53. Kaplan, B.; Livneh, A.; Sela, B.-A. Immunoglobulin Free Light Chain Dimers in Human Diseases. Sci. World J. 2011, 11, 901843. [Google Scholar] [CrossRef]
  54. Katzmann, J.A.; Clark, R.J.; Abraham, R.S.; Bryant, S.; Lymp, J.F.; Bradwell, A.R.; Kyle, R.A. Serum Reference Intervals and Diagnostic Ranges for Free Kappa and Free Lambda Immunoglobulin Light Chains: Relative Sensitivity for Detection of Monoclonal Light Chains. Clin. Chem. 2002, 48, 1437–1444. [Google Scholar] [CrossRef]
  55. Kaplan, B.; Golderman, S.; Yahalom, G.; Yeskaraev, R.; Ziv, T.; Aizenbud, B.M.; Sela, B.-A.; Livneh, A. Free Light Chain Monomer-Dimer Patterns in the Diagnosis of Multiple Sclerosis. J. Immunol. Methods 2013, 390, 74–80. [Google Scholar] [CrossRef] [PubMed]
  56. Kaplan, B.; Ramirez-Alvarado, M.; Sikkink, L.; Golderman, S.; Dispenzieri, A.; Livneh, A.; Gallo, G. Free Light Chains in Plasma of Patients with Light Chain Amyloidosis and Non-Amyloid Light Chain Deposition Disease. High Proportion and Heterogeneity of Disulfide-Linked Monoclonal Free Light Chains as Pathogenic Features of Amyloid Disease. Br. J. Haematol. 2009, 144, 705–715. [Google Scholar] [CrossRef] [PubMed]
  57. Sølling, K.; Sølling, J.; Lanng Nielsen, J. Polymeric Bence Jones Proteins in Serum in Myeloma Patients with Renal Insufficiency. Acta Med. Scand. 1984, 216, 495–502. [Google Scholar] [CrossRef]
  58. Kim, Y.; Wall, J.S.; Meyer, J.; Murphy, C.; Randolph, T.W.; Manning, M.C.; Solomon, A.; Carpenter, J.F. Thermodynamic Modulation of Light Chain Amyloid Fibril Formation. J. Biol. Chem. 2000, 275, 1570–1574. [Google Scholar] [CrossRef]
  59. Klimtchuk, E.S.; Gursky, O.; Patel, R.S.; Laporte, K.L.; Connors, L.H.; Skinner, M.; Seldin, D.C. The Critical Role of the Constant Region in Thermal Stability and Aggregation of Amyloidogenic Immunoglobulin Light Chain. Biochemistry 2010, 49, 9848–9857. [Google Scholar] [CrossRef]
  60. Oberti, L.; Rognoni, P.; Barbiroli, A.; Lavatelli, F.; Russo, R.; Maritan, M.; Palladini, G.; Bolognesi, M.; Merlini, G.; Ricagno, S. Concurrent Structural and Biophysical Traits Link with Immunoglobulin Light Chains Amyloid Propensity. Sci. Rep. 2017, 7, 16809. [Google Scholar] [CrossRef]
  61. Deret, S.; Chomilier, J.; Huang, D.B.; Preud’homme, J.L.; Stevens, F.J.; Aucouturier, P. Molecular Modeling of Immunoglobulin Light Chains Implicates Hydrophobic Residues in Non-Amyloid Light Chain Deposition Disease. Protein Eng. Des. Sel. 1997, 10, 1191–1197. [Google Scholar] [CrossRef]
  62. Weichman, K.; Dember, L.M.; Prokaeva, T.; Wright, D.G.; Quillen, K.; Rosenzweig, M.; Skinner, M.; Seldin, D.C.; Sanchorawala, V. Clinical and Molecular Characteristics of Patients with Non-Amyloid Light Chain Deposition Disorders, and Outcome Following Treatment with High-Dose Melphalan and Autologous Stem Cell Transplantation. Bone Marrow Transpl. 2006, 38, 339–343. [Google Scholar] [CrossRef]
  63. Preud’homme, J.-L.; Aucouturier, P.; Touchard, G.; Striker, L.; Khamlichi, A.A.; Rocca, A.; Denoroy, L.; Cogné, M. Monoclonal Immunoglobulin Deposition Disease (Randall Type). Relationship with Structural Abnormalities of Immunoglobulin Chains. Kidney Int. 1994, 46, 965–972. [Google Scholar] [CrossRef]
  64. Polymenis, M.; Stollar, B.D. Domain Interactions and Antigen Binding of Recombinant Anti-Z-DNA Antibody Variable Domains. The Role of Heavy and Light Chains Measured by Surface Plasmon Resonance. J. Immunol. 1995, 154, 2198–2208. [Google Scholar] [CrossRef]
  65. Franek, F.; Nezlin, R.S. Recovery of Antibody Combining Activity by Interaction of Different Peptide Chains Isolated from Purified Horse Antitoxins. Folia Microbiol. 1963, 8, 128–130. [Google Scholar] [CrossRef]
  66. Porter, R.R.; Weir, R.C. Subunits of Immunoglobulins and Their Relationship to Antibody Specificity. J. Cell Physiol. 1966, 67 (Suppl. S1), 51–64. [Google Scholar] [CrossRef]
  67. Thio, M.; Groot Kormelink, T.; Fischer, M.J.; Blokhuis, B.R.; Nijkamp, F.P.; Redegeld, F.A. Antigen Binding Characteristics of Immunoglobulin Free Light Chains: Crosslinking by Antigen Is Essential to Induce Allergic Inflammation. PLoS ONE 2012, 7, e40986. [Google Scholar] [CrossRef]
  68. Redegeld, F.A.; Van Der Heijden, M.W.; Kool, M.; Heijdra, B.M.; Garssen, J.; Kraneveld, A.D.; Loveren, H.V.; Roholl, P.; Saito, T.; Verbeek, J.S.; et al. Immunoglobulin-Free Light Chains Elicit Immediate Hypersensitivity-like Responses. Nat. Med. 2002, 8, 694–701. [Google Scholar] [CrossRef]
  69. Cohen, G.; Haag-Weber, M.; Mai, B.; Deicher, R.; Hörl, W.H. Effect of Immunoglobulin Light Chains from Hemodialysis and Continuous Ambulatory Peritoneal Dialysis Patients on Polymorphonuclear Leukocyte Functions. J. Am. Soc. Nephrol. 1995, 6, 1592–1599. [Google Scholar] [CrossRef]
  70. Cohen, G.; Rudnicki, M.; Deicher, R.; Hörl, W.H. Immunoglobulin Light Chains Modulate Polymorphonuclear Leucocyte Apoptosis. Eur. J. Clin. Investig. 2003, 33, 669–676. [Google Scholar] [CrossRef]
  71. Cohen, G.; Rudnicki, M.; Hörl, W.H. Uremic Toxins Modulate the Spontaneous Apoptotic Cell Death and Essential Functions of Neutrophils. Kidney Int. 2001, 59, S48–S52. [Google Scholar] [CrossRef]
  72. Ikura, H.; Endo, J.; Kitakata, H.; Moriyama, H.; Sano, M.; Fukuda, K. Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis. Int. J. Mol. Sci. 2022, 23, 6336. [Google Scholar] [CrossRef]
  73. Bianchi, G.; Kumar, S. Systemic Amyloidosis Due to Clonal Plasma Cell Diseases. Hematol./Oncol. Clin. N. Am. 2020, 34, 1009–1026. [Google Scholar] [CrossRef] [PubMed]
  74. Diomede, L.; Romeo, M.; Rognoni, P.; Beeg, M.; Foray, C.; Ghibaudi, E.; Palladini, G.; Cherny, R.A.; Verga, L.; Capello, G.L.; et al. Cardiac Light Chain Amyloidosis: The Role of Metal Ions in Oxidative Stress and Mitochondrial Damage. Antioxid. Redox Signal. 2017, 27, 567–582. [Google Scholar] [CrossRef]
  75. Shi, J.; Guan, J.; Jiang, B.; Brenner, D.A.; del Monte, F.; Ward, J.E.; Connors, L.H.; Sawyer, D.B.; Semigran, M.J.; Macgillivray, T.E.; et al. Amyloidogenic Light Chains Induce Cardiomyocyte Contractile Dysfunction and Apoptosis via a Non-Canonical P38α MAPK Pathway. Proc. Natl. Acad. Sci. USA 2010, 107, 4188–4193. [Google Scholar] [CrossRef] [PubMed]
  76. Guan, J.; Mishra, S.; Qiu, Y.; Shi, J.; Trudeau, K.; Las, G.; Liesa, M.; Shirihai, O.S.; Connors, L.H.; Seldin, D.C.; et al. Lysosomal Dysfunction and Impaired Autophagy Underlie the Pathogenesis of Amyloidogenic Light Chain-Mediated Cardiotoxicity. EMBO Mol. Med. 2014, 6, 1493–1507. [Google Scholar] [CrossRef] [PubMed]
  77. Sanders, P.W.; Booker, B.B. Pathobiology of Cast Nephropathy from Human Bence Jones Proteins. J. Clin. Investig. 1992, 89, 630–639. [Google Scholar] [CrossRef]
  78. Keeling, J.; Teng, J.; Herrera, G.A. AL-Amyloidosis and Light-Chain Deposition Disease Light Chains Induce Divergent Phenotypic Transformations of Human Mesangial Cells. Lab. Investig. 2004, 84, 1322–1338. [Google Scholar] [CrossRef]
  79. Teng, J.; Russell, W.J.; Gu, X.; Cardelli, J.; Jones, M.L.; Herrera, G.A. Different Types of Glomerulopathic Light Chains Interact with Mesangial Cells Using a Common Receptor but Exhibit Different Intracellular Trafficking Patterns. Lab. Investig. 2004, 84, 440–451. [Google Scholar] [CrossRef]
  80. Russell, W.J.; Cardelli, J.; Harris, E.; Baier, R.J.; Herrera, G.A. Monoclonal Light Chain–Mesangial Cell Interactions: Early Signaling Events and Subsequent Pathologic Effects. Lab. Investig. 2001, 81, 689–703. [Google Scholar] [CrossRef]
  81. Sanders, P.W. Mechanisms of Light Chain Injury along the Tubular Nephron. J. Am. Soc. Nephrol. 2012, 23, 1777–1781. [Google Scholar] [CrossRef]
  82. Ying, W.-Z.; Li, X.; Rangarajan, S.; Feng, W.; Curtis, L.M.; Sanders, P.W. Immunoglobulin Light Chains Generate Proinflammatory and Profibrotic Kidney Injury. J. Clin. Investig. 2019, 129, 2792–2806. [Google Scholar] [CrossRef]
  83. Ying, W.-Z.; Wang, P.-X.; Aaron, K.J.; Basnayake, K.; Sanders, P.W. Immunoglobulin Light Chains Activate Nuclear Factor-κB in Renal Epithelial Cells through a Src-Dependent Mechanism. Blood 2011, 117, 1301–1307. [Google Scholar] [CrossRef]
  84. Thiagarajan, P.; Dannenbring, R.; Matsuura, K.; Tramontano, A.; Gololobov, G.; Paul, S. Monoclonal Antibody Light Chain with Prothrombinase Activity. Biochemistry 2000, 39, 6459–6465. [Google Scholar] [CrossRef]
  85. Sun, M.; Gao, Q.S.; Li, L.; Paul, S. Proteolytic Activity of an Antibody Light Chain. J. Immunol. 1994, 153, 5121–5126. [Google Scholar] [CrossRef]
  86. Paul, S.; Li, L.; Kalaga, R.; Wilkins-Stevens, P.; Stevens, F.J.; Solomon, A. Natural Catalytic Antibodies: Peptide-Hydrolyzing Activities of Bence Jones Proteins and VL Fragment. J. Biol. Chem. 1995, 270, 15257–15261. [Google Scholar] [CrossRef]
  87. Immunoglobulin Free Light Chains and Mast Cells: Pivotal Role in T-Cell-Mediated Immune Reactions? Available online: https://pubmed.ncbi.nlm.nih.gov/12697449/ (accessed on 21 February 2025).
  88. Gao, E.; Shao, W.; Zhang, C.; Yu, M.; Dai, H.; Fan, T.; Zhu, Z.; Xu, W.; Huang, J.; Zhang, Y.; et al. Lung Epithelial Cells Can Produce Antibodies Participating In Adaptive Humoral Immune Responses. bioRxiv 2021. [Google Scholar] [CrossRef]
  89. Ma, J.; Jiang, D.; Gong, X.; Shao, W.; Zhu, Z.; Xu, W.; Qiu, X. Free Immunoglobulin Light Chain (FLC) Promotes Murine Colitis and Colitis-Associated Colon Carcinogenesis by Activating the Inflammasome. Sci. Rep. 2017, 7, 5165. [Google Scholar] [CrossRef]
  90. Wang, J.; Huang, J.; Ding, H.; Ma, J.; Zhong, H.; Wang, F.; Chen, Y.; Peng, H. Functional Analysis of Tumor-Derived Immunoglobulin Lambda and Its Interacting Proteins in Cervical Cancer. BMC Cancer 2023, 23, 929. [Google Scholar] [CrossRef]
  91. Sun, M.; Li, L.; Gao, Q.S.; Paul, S. Antigen Recognition by an Antibody Light Chain. J. Biol. Chem. 1994, 269, 734–738. [Google Scholar] [CrossRef]
  92. Nakano, T.; Takahashi, H.; Miyazaki, S.; Kawai, S.; Shinozaki, R.; Komoda, T.; Nagata, A. Antigen-Specific Free Immunoglobulin Light-Chain Antibodies: Could It Be a New Diagnostic Marker for Patients with Allergy? Clin. Biochem. 2006, 39, 955–959. [Google Scholar] [CrossRef]
  93. Painter, R.G.; Sage, H.J.; Tanford, C. Contributions of Heavy and Light Chains of Rabbit Immunoglobulin G to Antibody Activity. I. Binding Studies on Isolated Heavy and Light Chains. Biochemistry 1972, 11, 1327–1337. [Google Scholar] [CrossRef]
  94. Mahana, W.; Jacquemart, F.; Ermonval, M. A Murine Monoclonal Multireactive Immunoglobulin Kappa Light Chain. Scand. J. Immunol. 1994, 39, 107–110. [Google Scholar] [CrossRef] [PubMed]
  95. A Simpler Sort of Antibody. Available online: https://www.pnas.org/doi/epdf/10.1073/pnas.91.3.893 (accessed on 5 July 2025).
  96. Schechter, I.; Ziv, E. Binding of 2,4-Dinitrophenyl Derivatives by the Light Chain Dimer Obtained from Immunoglobulin A Produced by MOPC-315 Mouse Myeloma. Biochemistry 1976, 15, 2785–2790. [Google Scholar] [CrossRef]
  97. Galli, S.J.; Tsai, M. IgE and Mast Cells in Allergic Disease. Nat. Med. 2012, 18, 693–704. [Google Scholar] [CrossRef]
  98. An Association between Neutrophils and Immunoglobulin Free Light Chains in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Available online: https://www.atsjournals.org/doi/epdf/10.1164/rccm.201104-0761OC?role=tab (accessed on 4 April 2025).
  99. Judde, J.G.; Max, E.E. Characterization of the Human Immunoglobulin Kappa Gene 3′ Enhancer: Functional Importance of Three Motifs That Demonstrate B-Cell-Specific in Vivo Footprints. Mol. Cell Biol. 1992, 12, 5206–5216. [Google Scholar] [CrossRef]
  100. Liu, H.; Duan, Z.; Zheng, H.; Hu, D.; Li, M.; Tao, Y.; Bode, A.M.; Dong, Z.; Cao, Y. EBV-Encoded LMP1 Upregulates Igκ 3′enhancer Activity and Igκ Expression in Nasopharyngeal Cancer Cells by Activating the Ets-1 through ERKs Signaling. PLoS ONE 2012, 7, e32624. [Google Scholar] [CrossRef] [PubMed]
  101. Liu, H.; Zheng, H.; Duan, Z.; Hu, D.; Li, M.; Liu, S.; Li, Z.; Deng, X.; Wang, Z.; Tang, M.; et al. LMP1-Augmented Kappa Intron Enhancer Activity Contributes to Upregulation Expression of Ig Kappa Light Chain via NF-kappaB and AP-1 Pathways in Nasopharyngeal Carcinoma Cells. Mol. Cancer 2009, 8, 92. [Google Scholar] [CrossRef]
  102. Liu, H.; Zheng, H.; Li, M.; Hu, D.; Tang, M.; Cao, Y. Upregulated Expression of Kappa Light Chain by Epstein-Barr Virus Encoded Latent Membrane Protein 1 in Nasopharyngeal Carcinoma Cells via NF-kappaB and AP-1 Pathways. Cell Signal 2007, 19, 419–427. [Google Scholar] [CrossRef]
  103. Kang, B.-Y.; Hu, C.; Prayaga, S.; Khaidakov, M.; Sawamura, T.; Seung, K.-B.; Mehta, J.L. LOX-1 Dependent Overexpression of Immunoglobulins in Cardiomyocytes in Response to Angiotensin II. Biochem. Biophys. Res. Commun. 2009, 379, 395–399. [Google Scholar] [CrossRef] [PubMed]
  104. Liu, B.; Min, M.; Bao, J.-K. Induction of Apoptosis by Concanavalin A and Its Molecular Mechanisms in Cancer Cells. Autophagy 2009, 5, 432–433. [Google Scholar] [CrossRef]
  105. Gantner, F.; Leist, M.; Lohse, A.W.; Germann, P.G.; Tiegs, G. Concanavalin A-Induced T-Cell-Mediated Hepatic Injury in Mice: The Role of Tumor Necrosis Factor. Hepatology 1995, 21, 190–198. [Google Scholar] [CrossRef] [PubMed]
  106. Eifan, A.O.; Durham, S.R. Pathogenesis of Rhinitis. Clin. Exp. Allergy 2016, 46, 1139–1151. [Google Scholar] [CrossRef]
  107. Powe, D.G.; Groot Kormelink, T.; Sisson, M.; Blokhuis, B.J.; Kramer, M.F.; Jones, N.S.; Redegeld, F.A. Evidence for the Involvement of Free Light Chain Immunoglobulins in Allergic and Nonallergic Rhinitis. J. Allergy Clin. Immunol. 2010, 125, 139–145.e1-3. [Google Scholar] [CrossRef]
  108. Meng, C.; Sha, J.; Li, L.; An, L.; Zhu, X.; Meng, X.; Zhu, D.; Dong, Z. The Expression and Significance of Immunoglobulin Free Light Chain in the Patients with Allergic Rhinitis and Nonallergic Rhinitis. Am. J. Rhinol. Allergy 2014, 28, 302–307. [Google Scholar] [CrossRef]
  109. Li, M.; Feng, D.-Y.; Ren, W.; Zheng, L.; Zheng, H.; Tang, M.; Cao, Y. Expression of Immunoglobulin Kappa Light Chain Constant Region in Abnormal Human Cervical Epithelial Cells. Int. J. Biochem. Cell Biol. 2004, 36, 2250–2257. [Google Scholar] [CrossRef]
  110. Groot Kormelink, T.; Powe, D.G.; Kuijpers, S.A.; Abudukelimu, A.; Fens, M.H.A.M.; Pieters, E.H.E.; Kassing van der Ven, W.W.; Habashy, H.O.; Ellis, I.O.; Blokhuis, B.R.; et al. Immunoglobulin Free Light Chains Are Biomarkers of Poor Prognosis in Basal-like Breast Cancer and Are Potential Targets in Tumor-Associated Inflammation. Oncotarget 2014, 5, 3159–3167. [Google Scholar] [CrossRef]
  111. Schiffelers, R.M.; Metselaar, J.M.; Fens, M.H.A.M.; Janssen, A.P.C.A.; Molema, G.; Storm, G. Liposome-Encapsulated Prednisolone Phosphate Inhibits Growth of Established Tumors in Mice. Neoplasia 2005, 7, 118–127. [Google Scholar] [CrossRef]
  112. Samoszuk, M.; Corwin, M.; Yu, H.; Wang, J.; Nalcioglu, O.; Su, M.-Y. Inhibition of Thrombosis in Melanoma Allografts in Mice by Endogenous Mast Cell Heparin. Thromb. Haemost. 2003, 90, 351–360. [Google Scholar] [CrossRef]
  113. Maltby, S.; Freeman, S.; Gold, M.J.; Baker, J.H.E.; Minchinton, A.I.; Gold, M.R.; Roskelley, C.D.; McNagny, K.M. Opposing Roles for CD34 in B16 Melanoma Tumor Growth Alter Early Stage Vasculature and Late Stage Immune Cell Infiltration. PLoS ONE 2011, 6, e18160. [Google Scholar] [CrossRef]
  114. Yang, S.-B.; Chen, X.; Wu, B.-Y.; Wang, M.-W.; Cai, C.-H.; Cho, D.-B.; Chong, J.; Li, P.; Tang, S.-G.; Yang, P.-C. Immunoglobulin Kappa and Immunoglobulin Lambda Are Required for Expression of the Anti-Apoptotic Molecule Bcl-xL in Human Colorectal Cancer Tissue. Scand. J. Gastroenterol. 2009, 44, 1443–1451. [Google Scholar] [CrossRef]
  115. Lee, S.B.; Kwon, I.-S.; Park, J.; Lee, K.-H.; Ahn, Y.; Lee, C.; Kim, J.; Choi, S.Y.; Cho, S.-W.; Ahn, J.-Y. Ribosomal Protein S3, a New Substrate of Akt, Serves as a Signal Mediator between Neuronal Apoptosis and DNA Repair. J. Biol. Chem. 2010, 285, 29457–29468. [Google Scholar] [CrossRef]
  116. Gao, X.; Hardwidge, P.R. Ribosomal Protein S3: A Multifunctional Target of Attaching/Effacing Bacterial Pathogens. Front. Microbiol. 2011, 2, 137. [Google Scholar] [CrossRef] [PubMed]
  117. Alam, E.; Maaliki, L.; Nasr, Z. Ribosomal Protein S3 Selectively Affects Colon Cancer Growth by Modulating the Levels of P53 and Lactate Dehydrogenase. Mol. Biol. Rep. 2020, 47, 6083–6090. [Google Scholar] [CrossRef]
  118. Brockers, K.; Schneider, R. Histone H1, the Forgotten Histone. Epigenomics 2019, 11, 363–366. [Google Scholar] [CrossRef]
  119. Khachaturov, V.; Xiao, G.-Q.; Kinoshita, Y.; Unger, P.D.; Burstein, D.E. Histone H1.5, a Novel Prostatic Cancer Marker: An Immunohistochemical Study. Hum. Pathol. 2014, 45, 2115–2119. [Google Scholar] [CrossRef]
  120. Behrends, M.; Engmann, O. Linker Histone H1.5 Is an Underestimated Factor in Differentiation and Carcinogenesis. Environ. Epigenet. 2020, 6, dvaa013. [Google Scholar] [CrossRef]
  121. Hayakawa, K.; Tani, R.; Nishitani, K.; Tanaka, S. Linker Histone Variant H1T Functions as a Chromatin De-Condenser on Genic Regions. Biochem. Biophys. Res. Commun. 2020, 528, 685–690. [Google Scholar] [CrossRef] [PubMed]
  122. Merlini, G. AL Amyloidosis: From Molecular Mechanisms to Targeted Therapies. Hematol. Am. Soc. Hematol. Educ. Program 2017, 2017, 1–12. [Google Scholar] [CrossRef] [PubMed]
  123. Herrera, G.A.; Teng, J.; Turbat-Herrera, E.A.; Zeng, C.; del Pozo-Yauner, L. Understanding Mesangial Pathobiology in AL-Amyloidosis and Monoclonal Ig Light Chain Deposition Disease. Kidney Int. Rep. 2020, 5, 1870–1893. [Google Scholar] [CrossRef]
  124. Esparvarinha, M.; Nickho, H.; Mohammadi, H.; Aghebati-Maleki, L.; Abdolalizadeh, J.; Majidi, J. The Role of Free Kappa and Lambda Light Chains in the Pathogenesis and Treatment of Inflammatory Diseases. Biomed. Pharmacother. 2017, 91, 632–644. [Google Scholar] [CrossRef]
  125. Katzmann, J.A.; Abraham, R.S.; Dispenzieri, A.; Lust, J.A.; Kyle, R.A. Diagnostic Performance of Quantitative κ and λ Free Light Chain Assays in Clinical Practice. Clin. Chem. 2005, 51, 878–881. [Google Scholar] [CrossRef]
  126. Chen, B.; Wang, W.; Xu, W.; Ying, L.; Zhou, C.; Zheng, M. Serum Free Light Chain Is Associated with Histological Activity and Cirrhosis in Patients with Chronic Hepatitis B. Int. Immunopharmacol. 2021, 99, 107881. [Google Scholar] [CrossRef]
  127. Novel Biomarkers of Inflammation for the Management of Diabetes: Immunoglobulin-Free Light Chains. Available online: https://www.mdpi.com/2227-9059/10/3/666 (accessed on 28 April 2025).
  128. Gottenberg, J.-E.; Aucouturier, F.; Goetz, J.; Sordet, C.; Jahn, I.; Busson, M.; Cayuela, J.-M.; Sibilia, J.; Mariette, X. Serum Immunoglobulin Free Light Chain Assessment in Rheumatoid Arthritis and Primary Sjogren’s Syndrome. Ann. Rheum. Dis. 2007, 66, 23–27. [Google Scholar] [CrossRef] [PubMed]
  129. Sarto, C.; Intra, J.; Fania, C.; Brivio, R.; Brambilla, P.; Leoni, V. Monoclonal Free Light Chain Detection and Quantification: Performances and Limits of Available Laboratory Assays. Clin. Biochem. 2021, 95, 28–33. [Google Scholar] [CrossRef]
  130. Bradwell, A.R.; Carr-Smith, H.D.; Mead, G.P.; Tang, L.X.; Showell, P.J.; Drayson, M.T.; Drew, R. Highly Sensitive, Automated Immunoassay for Immunoglobulin Free Light Chains in Serum and Urine. Clin. Chem. 2001, 47, 673–680. [Google Scholar] [CrossRef]
  131. Caponi, L.; Romiti, N.; Koni, E.; Fiore, A.D.; Paolicchi, A.; Franzini, M. Inter-Assay Variability in Automated Serum Free Light Chain Assays and Their Use in the Clinical Laboratory. Crit. Rev. Clin. Lab. Sci. 2020, 57, 73–85. [Google Scholar] [CrossRef]
  132. Velthuis, H.T.; Drayson, M.; Campbell, J.P. Measurement of Free Light Chains with Assays Based on Monoclonal Antibodies. Clin. Chem. Lab. Med. (CCLM) 2016, 54, 1005–1014. [Google Scholar] [CrossRef] [PubMed]
  133. Giles, H.V.; Wechalekar, A.; Pratt, G. The Potential Role of Mass Spectrometry for the Identification and Monitoring of Patients with Plasma Cell Disorders: Where Are We Now and Which Questions Remain Unanswered? Br. J. Haematol. 2022, 198, 641–653. [Google Scholar] [CrossRef] [PubMed]
  134. Edwards, C.V.; Rao, N.; Bhutani, D.; Mapara, M.; Radhakrishnan, J.; Shames, S.; Maurer, M.S.; Leng, S.; Solomon, A.; Lentzsch, S.; et al. Phase 1a/b Study of Monoclonal Antibody CAEL-101 (11-1F4) in Patients with AL Amyloidosis. Blood 2021, 138, 2632–2641. [Google Scholar] [CrossRef]
  135. Dispenzieri, A.; Gertz, M.A.; Kyle, R.A.; Lacy, M.Q.; Burritt, M.F.; Therneau, T.M.; Greipp, P.R.; Witzig, T.E.; Lust, J.A.; Rajkumar, S.V.; et al. Serum Cardiac Troponins and N-Terminal pro-Brain Natriuretic Peptide: A Staging System for Primary Systemic Amyloidosis. J. Clin. Oncol. 2004, 22, 3751–3757. [Google Scholar] [CrossRef]
  136. Thio, M.; Blokhuis, B.R.; Nijkamp, F.P.; Redegeld, F.A. Free Immunoglobulin Light Chains: A Novel Target in the Therapy of Inflammatory Diseases. Trends Pharmacol. Sci. 2008, 29, 170–174. [Google Scholar] [CrossRef]
Ijms 26 07607 g001
Figure 1. Schematic Diagram of κ-LC and λ-LC Locus Structures and V–J Recombination Mechanism. This diagram illustrates the genomic organization of variable (V), joining (J), and constant (C) gene segments in immunoglobulin light chains, along with recombination signal sequences (RSS) flanking V and J segments. The complex V gene clusters are depicted in simplified form. Within the IGK locus (κ-LC), the physical arrangements of 5 IGKJ segments and the single IGKC gene is shown. Within the IGL locus (λ-LC), the arrangement of the tandem array of IGLJ-IGLC units is shown. A simplified V–J recombination process, involving RSS (12-RSS flanking V segments and 23-RSS flanking J segments), is also schematized. Created in BioRender (BioRender.com). Li, L. (2025).
Figure 1. Schematic Diagram of κ-LC and λ-LC Locus Structures and V–J Recombination Mechanism. This diagram illustrates the genomic organization of variable (V), joining (J), and constant (C) gene segments in immunoglobulin light chains, along with recombination signal sequences (RSS) flanking V and J segments. The complex V gene clusters are depicted in simplified form. Within the IGK locus (κ-LC), the physical arrangements of 5 IGKJ segments and the single IGKC gene is shown. Within the IGL locus (λ-LC), the arrangement of the tandem array of IGLJ-IGLC units is shown. A simplified V–J recombination process, involving RSS (12-RSS flanking V segments and 23-RSS flanking J segments), is also schematized. Created in BioRender (BioRender.com). Li, L. (2025).
Ijms 26 07607 g001
Ijms 26 07607 g002
Figure 2. Morphology and Distribution of B Cell-derived and Non-B Cell-Derived Free Light Chains. This figure illustrates the typical morphological forms and tissue distributions of B cell-derived free light chains (B-FLCs) and non-B cell-derived free light chains (Non-B-FLCs). (A) B-FLCs predominantly deposit in the renal and cardiovascular systems, manifesting as crystalline inclusions in proximal tubule epithelial cells (light-chain proximal tubulopathy, LCPT), granular deposits in the glomerular basement membrane (light-chain deposition disease, LCDD), misfolded fibrils in the basement membrane, podocyte slit diaphragm, and cardiomyocyte extracellular matrix (AL amyloidosis), or uromodulin-bound casts in the distal tubule (light-chain cast nephropathy, LCCN). (B) Cancer-cell-derived or epithelial-cell-derived non-B-FLCs exist as extracellular amorphous monomers, dimers, polymers, and fibrils or are intracellularly located around the nucleus to display a filamentous network. Created in BioRender (BioRender.com). Li, L. (2025).
Figure 2. Morphology and Distribution of B Cell-derived and Non-B Cell-Derived Free Light Chains. This figure illustrates the typical morphological forms and tissue distributions of B cell-derived free light chains (B-FLCs) and non-B cell-derived free light chains (Non-B-FLCs). (A) B-FLCs predominantly deposit in the renal and cardiovascular systems, manifesting as crystalline inclusions in proximal tubule epithelial cells (light-chain proximal tubulopathy, LCPT), granular deposits in the glomerular basement membrane (light-chain deposition disease, LCDD), misfolded fibrils in the basement membrane, podocyte slit diaphragm, and cardiomyocyte extracellular matrix (AL amyloidosis), or uromodulin-bound casts in the distal tubule (light-chain cast nephropathy, LCCN). (B) Cancer-cell-derived or epithelial-cell-derived non-B-FLCs exist as extracellular amorphous monomers, dimers, polymers, and fibrils or are intracellularly located around the nucleus to display a filamentous network. Created in BioRender (BioRender.com). Li, L. (2025).
Ijms 26 07607 g002
Ijms 26 07607 g003
Figure 3. Diverse Biological Functions of B Cell-Derived and Non-B Cell-Derived Free Light Chains. This figure illustrates B-FLCs/Non-B-FLCs’ diverse biological functions with currently elucidated molecular mechanisms, both physiologically and pathologically. (A) Classical B-FLCs participate in the formation of the antigen-binding region of intact immunoglobulins, interact with innate immune cells, e.g., mast cells and neutrophils in inflammation, perform enzymatic activity, e.g., anti-angiogenic, prothrombinase, and proteolytic activity, as well as function in damage to the cardiovascular system and renal system. (B) Non-B-FLCs exhibit distinct mechanistic roles: inflammasome activation in colitis, integrin-mediated FAK/SRC pathway activation in colon cancer progression, hepatoprotection via apoptosis inhibition during liver injury and promotion of hepatocellular carcinoma through ETFA binding and stabilization to enhance β-oxidation. Created in BioRender (BioRender.com). Li, L. (2025).
Figure 3. Diverse Biological Functions of B Cell-Derived and Non-B Cell-Derived Free Light Chains. This figure illustrates B-FLCs/Non-B-FLCs’ diverse biological functions with currently elucidated molecular mechanisms, both physiologically and pathologically. (A) Classical B-FLCs participate in the formation of the antigen-binding region of intact immunoglobulins, interact with innate immune cells, e.g., mast cells and neutrophils in inflammation, perform enzymatic activity, e.g., anti-angiogenic, prothrombinase, and proteolytic activity, as well as function in damage to the cardiovascular system and renal system. (B) Non-B-FLCs exhibit distinct mechanistic roles: inflammasome activation in colitis, integrin-mediated FAK/SRC pathway activation in colon cancer progression, hepatoprotection via apoptosis inhibition during liver injury and promotion of hepatocellular carcinoma through ETFA binding and stabilization to enhance β-oxidation. Created in BioRender (BioRender.com). Li, L. (2025).
Ijms 26 07607 g003
Table 1. Biased Gene Segment Usage by B-FLCs and Non-B-FLCs in Health and Disease.
Table 1. Biased Gene Segment Usage by B-FLCs and Non-B-FLCs in Health and Disease.
FLC OriginConditionGene Segment UsageRefs.
B-FLCsPlasma cellsPhysiologicalIGKV1, IGKV2, IGKV3, IGKV4;IGKJ1, IGKJ2, IGKJ4;IGLV1, IGLV2, IGLV3;IGLJ7[20,21,22,23]
Multiple MyelomaIGKV1, IGKV2, IGKV3[24,25,26,27]
Systemic AmyloidosisIGLV3 (IGVL3-1), IGLV6 (IGLV6-57), IGLV1(IGLV1-44)[28,29,30,31]
Light-Chain Deposition DiseaseIGKV4 (IGKV4-1), IGKV1(IGKV1-5), IGKV3(IGKV3-11 and IGKV3-15), IGLV2(IGLV2-23 and DPL12)[32,33,34,35]
Light-Chain Fanconi SyndromeIGKV1[32,33,34,35]
Juvenile Rheumatoid ArthritisIGKJ1, IGKJ2[36,37,38]
Systemic Lupus ErythematosusIGKJ1, IGKJ2[36,37,38]
Non-B-FLCsPrimary spermatocytes(mouse)PhysiologicalIgkvbv9/Igkj1, Igkv21-10/Igkj2[39]
Epididymal epithelial cells(mouse)PhysiologicalIgkvbw20/Igkj5[39]
Cardiomyocytes(mouse)PhysiologicalIgkv17-121, Igkv9-120, Igkv14-100[40]
Hepatocytes(mouse)PhysiologicalIgkv1-135*01/Igkj1, Igkv12–44*01/Igkj5[41]
MyeloblastsAcute Myeloid LeukemiaIGKV15*03/IGKJ1*01, IGKV1-5*03/IGKJ3*01, IGKV1-NL1*01/IGKJ5*01[42]
Carcinoma cellsLung Cancer, Hepatocellular Carcinoma, Cervical CancerIGKV4-1/IGKJ3[43,44]
Sarcoma cellsFibrosarcoma, Leiomyoma, Rhabdomyosarcoma, LeiomyosarcomaIGKV3D-20*01; IGKJ1[45]
Table 2. Biological Functions of B-FLCs and Non-B-FLCs.
Table 2. Biological Functions of B-FLCs and Non-B-FLCs.
FLC OriginBiological FunctionRefs.
B-FLCPlasma cellsContributing to the formation of the antigen-binding region[64,65,66]
Activating mast cells[67,68]
Promoting activation and inhibiting the apoptosis of neutrophils[69,70,71]
Cardiotoxicity[10,72,73,74,75,76]
Renal toxicity[77,78,79,80,81,82,83]
Enzymatic activity[5,84,85,86]
Non-B-FLCNasal mucosal cells (not assured)Potential interaction with mast cells[87]
HepatocytesProtecting hepatocytes[41]
Lung epithelial cellsFacilitating the secretion of TD-Ag-specific antibodies of lung epithelial cells[88]
Colon cancer cellsPromoting colon cancer[43]
Colon cancer cellsPromoting colitis-associated colon carcinogenesis[89]
Hepatocyte carcinoma cellsPromoting hepatocyte carcinoma[44]
Cervical cancer cellsPromoting cervical cancer[90]
Myeloblasts of AMLPromoting acute myelocytic leukemia[42]
Mesenchymal tumor cellsCorrelating with hyperproliferative phenotypes in mesenchymal tumors[45]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Li, L.; Gu, H.; Qiu, X.; Huang, J. B Cell-Derived and Non-B Cell-Derived Free Light Chains: From Generation to Biological and Pathophysiological Roles. Int. J. Mol. Sci. 2025, 26, 7607. https://doi.org/10.3390/ijms26157607

AMA Style

Li L, Gu H, Qiu X, Huang J. B Cell-Derived and Non-B Cell-Derived Free Light Chains: From Generation to Biological and Pathophysiological Roles. International Journal of Molecular Sciences. 2025; 26(15):7607. https://doi.org/10.3390/ijms26157607

Chicago/Turabian Style

Li, Linyang, Huining Gu, Xiaoyan Qiu, and Jing Huang. 2025. "B Cell-Derived and Non-B Cell-Derived Free Light Chains: From Generation to Biological and Pathophysiological Roles" International Journal of Molecular Sciences 26, no. 15: 7607. https://doi.org/10.3390/ijms26157607

APA Style

Li, L., Gu, H., Qiu, X., & Huang, J. (2025). B Cell-Derived and Non-B Cell-Derived Free Light Chains: From Generation to Biological and Pathophysiological Roles. International Journal of Molecular Sciences, 26(15), 7607. https://doi.org/10.3390/ijms26157607

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Article metric data becomes available approximately 24 hours after publication online.
Back to TopTop