3.4. Immunoglobulin and FLC production

Chapter 3

Immunoglobulins and FLCs are produced by B-cells. During their development the earliest immunoglobulin polypeptide to be produced is the μ heavy chain, in the pre-B-cell. Immature and mature B-cells produce either κ or λ light chains, which associate with μ heavy chains to form membrane-bound IgM. Upon activation, mature B-cells differentiate into plasma cells, which secrete immunoglobulin into the serum. Activation may also stimulate plasma cells to switch the heavy chain constant domain, and hence the class of antibody produced, for example, IgM to IgG. Approximately 40% more light chains than heavy chains are synthesised [93], and this excess of FLCs is thought to favour accurate assemblty of intact immunoglobulin molecules. Light chains which remain unbound from their heavy chain partner are secreted into the blood as FLCs. Secretion of FLC is highest from plasma cells, with twice as many producing κ-chains than λ-chains. κ FLCs are normally monomeric, while λ FLCs tend to be dimeric, joined by disulphide bonds; however, higher polymeric forms of both FLCs may occur (Figure 3.7). Tumours associated with the different stages of B-cell maturation may secrete monoclonal FLCs and/or monoclonal intact immunoglobulins into the serum (Figure 3.8).

In normal individuals, approximately 500 mg of FLCs are produced each day from bone marrow and lymph node cells [91][93]. The molecules enter the blood and are rapidly partitioned between the intravascular and extravascular compartments. The normal plasma cell content of the bone marrow is about 1%, whereas in multiple myeloma (MM) this can rise to over 90%. In chronic infections and autoimmmune diseases the bone marrow may contain 5 - 10% plasma cells, and may be associated with hypergammaglobulinaemia and corresponding increases in polyclonal serum FLC (sFLC) concentrations. Identification of monoclonal plasma cells in the bone marrow by histology or flow cytometry is an essential part of MM diagnosis, and is frequently based on identifying intracellular κ and λ light chains by direct immunofluorescence techniques (Figure 3.9).