Unusual Sequence of Immunoglobulin L‐Chain Rearrangements in a Gamma Heavy Chain Disease Patient

Abstract

Patients with gamma heavy chain disease (gamma-HCD) generally produce incomplete immunoglobulin (Ig) gamma-heavy chains (gamma-HCD protein) which cannot associate with light chains (IgL). In most patients Bence Jones proteins (BJP) are not observed. However, in the 61-year-old patient WIN we found gamma l-HCD proteins and lambda BJP in serum and urine. WIN gamma l-HCD protein does not carry the Ig Fd region, has a molecular weight of 33.5 kDa, and the seven N-terminal amino acid residues are not translated from any of the known immunoglobulin heavy chain (IgH) gene sequences. These residues are followed by the C gamma l-hinge region. In DNA from peripheral blood lymphocytes of patient WIN we found bands representing dominant rearrangements in one of the two alleles of the IgH, Ig kappa and Ig lambda locus. Taken together, the data from protein and DNA analysis strongly suggest, albeit do not formally prove, that one dominant B-cell clone which carries a rearranged and a non-rearranged allele of each Ig locus produces gamma-HCD protein and lambda BJP. The productive lambda-gene rearrangement in this clone thus has not been preceded by abortive rearrangements in both kappa-locus alleles. Lymphocytes with an unusual sequence of IgL-chain gene activation seem to be involved in the case of gamma-HCD described here.

Gamma Heavy-chain Disease

“…Prior reports have also included cases of gHCD with detection of clonal plasma cells by flow cytometry or immunohistochemistry, or with secretion of monoclonal light-chain (Bence Jones) proteins. 13,20,32,33 The finding of clonal plasmacytoid or plasmacytic cells by immunohistochemistry or by in situ hybridization therefore does not exclude the possibility of gHCD. Finally, PCR clonality studies may also be misleading.…”

Monoclonal free light chains can be found in heavy chain diseases

“…2 HCDs can be associated with non-Hodgkin's lymphomas (NHLs): alpha-HCD with extranodal marginal zone lymphoma of mucosa-associated lymph-node tissue, gamma-HCD with lymphoplasmacytic NHL and mu-HCD with chronic lymphocytic leukaemia. Although isolated cases with Bence-Jones proteinuria have been described, 3,4 HCD has usually been thought to lack monoclonal light chains. To investigate this possibility in depth, a new test to evaluate the presence of free light chains (FLCs) in the serum has been developed, which can be backed up by the results of immunophenotypic and molecular tests performed in samples containing the neoplastic cells responsible for M-component production.…”