Bence Jones proteins bind to a common peptide segment of Tamm-Horsfall glycoprotein to promote heterotypic aggregation.

Abstract

Bence Jones proteins (BJPs) are the major pathogenic factor causing cast nephropathy ("myeloma kidney") by coaggregation with Tamm-Horsfall glycoprotein (THP). Understanding the interaction between these proteins is therefore important in developing treatment strategies to prevent renal failure from cast formation in multiple myeloma. We developed an enzymelinked immunoassay to examine this phenomenon. Five different human BJPs (four K and one X immunoglobulin light chains) were used in this assay that demonstrated these proteins bound THP with different affinity. BJPs competed among themselves for binding to THP. The binding site was a peptide portion of THP since these proteins also bound deglycosylated THP. Also, one monoclonal antibody directed against a peptide segment of human THP prevented binding of THP to BJPs. By altering the conformation of THP, reducing agents decreased binding between these two proteins in concentration-dependent fashion. In turbidity studies, the monoclonal antibody that prevented binding and a reducing agent, dithiothreitol, decreased coaggregation. Deglycosylated THP did not coaggregate with BJPs. We concluded that ionic interaction between BJPs and a specific peptide binding site on THP promoted heterotypic coaggregation. The carbohydrate moiety of THP was also essential for coaggregation, perhaps by facilitating homotypic aggregation of THP. (J. Clin. Invest. 1993. 92:2975-2983

Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model

“…A fourth isoform that contains a 22-residue deletion within the second calcium-binding EGF-like domain has also been suggested. Prior studies identified a single FLC-binding domain (LCBD) on THP where FLCs bind (14,15). The LCBD of THP was within the D8C region just downstream of the last residue absent from isoform no.…”

“…Human THP and FLCs were purified from urine in standard fashion (6,7,(14)(15)(16)30). Purified human THP was biotinylated as described previously (36), using sulfo-N-hydroxysuccinimide biotin (ImmunoPure Sulfo-NHS-Biotin; Pierce Protein Products, Thermo Fisher Scientific), followed by dialysis against PBS at 4°C for 24 hours to remove free biotin.…”

Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4–dependent mechanism

“…Abnormal deposition of THP and ensuing inflammatory reactions have been consistently observed in cast nephropathy and urolithiasis (13,16). In acute renal transplant rejection THP deposits were found to be surrounded by mononuclear cell infiltrates (42), similar to kidneys affected by immunoglobulin light chain deposition in patients with multiple myeloma (43). Despite the apparent participation of THP in a large variety of inflammatory kidney diseases, the underlying mechanisms that would explain how THP contributes to inflammatory reactions have largely remained obscure.…”

Localization of a single binding site for immunoglobulin light chains on human Tamm-Horsfall glycoprotein.

“…Cast nephropathy, or "myeloma kidney," is a common complication of multiple myeloma. Binding and subsequent coaggregation of filtered immunoglobulin light chains (LCs) with THP obstruct flow through the renal tubule and result in renal failure (6,7). Both and LCs share a common binding site on THP, although different nephrotoxic LCs possess different affinities for THP (6).…”