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

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.

Keywords: Igκ; Igλ; free light chain; immunoglobulin; non-B cell.

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 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 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).