Immunoglobulin light chains that are circulating in serum in a free (unbound) state are called free light chains (FLCs). Measurement of the serum level of FLCs became practical as a clinical blood test in recent decades. These tests are used as an aid in the diagnosis and monitoring of multiple myeloma and related disorders. There are two types of immunoglobulin light chain produced in humans, designated by the Greek letters kappa (κ) and lambda (λ). Comparing the ratio of κ FLCs to λ FLCs in a person's serum against reference ranges indicates whether that person may have a plasma cell tumour such as multiple myeloma or AL amyloidosis.
Structure
Each immunoglobulin light-chain molecule contains approximately 220 amino acids in a single polypeptide chain that is folded to form constant and variable region domains. Each domain comprises two β-pleated sheets. The sheets are linked by a disulfide bridge and together form a roughly barrel-shaped structure known as a β-barrel. The variable (V) domain of light chains has a high degree of structural diversity, particularly the antigen-binding region. In addition, the first 23 amino acids of the 1st variable domain framework region have a number of variations known as subgroups. Four kappa (Vκ1–Vκ4) and six lambda subgroups (Vλ1–Vλ6) can be identified. The specific subgroup structures influence the potential of the free light chains to polymerise such that AL amyloidosis is associated with Vλ6 and light-chain deposition disease with Vκ1 and Vκ4.
Synthesis
Kappa light-chain molecules are constructed from approximately 40 functional Vκ gene segments (chromosome 2), five Jκ gene segments and a single Cκ gene. Lambda molecules (chromosome 22) are constructed from about 30 Vλ gene segments and four pairs of functional Jλ gene segments and a Cλ gene.
Light chains are incorporated into immunoglobulin molecules during B-cell development and are expressed initially on the surface of pre B-cells. Production of light chains occurs throughout the rest of B-cell development and in plasma cells, where secretion is highest.
Production
The production of free immunoglobulin light chains in normal individuals is approximately 500 mg/day from bone marrow and lymph node cells. There is approximately 40% excess immunoglobulin light-chain production over immunoglobulin heavy-chain synthesis. Possibly this is simply to allow proper conformation of the intact immunoglobulin molecules, but an immunological role for the free light chains has also been proposed. There are approximately twice as many kappa-producing plasma cells as lambda plasma cells. Kappa free-light chains are normally monomeric, while lambda free-light chains tend to be dimeric, joined by disulphide bonds. Polymeric forms of both types of free light chain can also occur.
Metabolism
In normal individuals, free light chains are rapidly cleared from the blood and catabolised by the kidneys. Monomeric free light chains are cleared in 2–4 hours, and dimeric light chains in 3–6 hours. Removal may be prolonged to 2–3 days in people with complete renal failure. Human kidneys are composed of approximately half a million nephrons. Each nephron contains a glomerulus with basement membrane pores that allow filtration of immunoglobulin light chains and other small molecules from the blood into the proximal tubule of the nephron.
Filtered molecules are either excreted in the urine or may be specifically re-absorbed. Protein molecules that pass through the glomerular pores are either absorbed unchanged (such as albumin), degraded in the proximal tubular cells and absorbed (such as free light chains), or excreted as fragments. This re-absorption is mediated by a receptor complex (megalin/cubulin) and prevents the loss of large amounts of protein into the urine. It is very efficient and can process 10–30 g of low-molecular-weight proteins per day, so under normal conditions no light chains pass beyond the proximal tubules.
If immunoglobulin light chains are produced in sufficient amounts to overwhelm the proximal tubules' absorption mechanisms (usually due to the presence of a plasma cell tumour) the light chains enter the distal tubules and can appear in the urine (Bence Jones protein). The passage of large amounts of immunoglobulin light chains through the kidneys may cause inflammation or blockage of the kidney tubules.