Primary Localized Orbital Amyloidosis Composed of the Immunoglobulin γ Heavy Chain CH3 Domain

Abstract

1. Primary orbital amyloidosis is a rare form of localized amyloidosis in which the precursor protein has not previously been identified. We report here the first extraction of amyloid fibrils from a tissue biopsy containing orbital amyloid, and characterization of the fibril protein. 2. The N-terminal nine residues were identical with residues 278–286 and 275–283 of the third constant (CH3) domains of IgG1 and IgG4 γ heavy chains, respectively. The mass of the fibril subunit protein was 6125 Da by time-of-flight mass spectrometry, compared with the expected masses of 6169.9 Da and 6214.9 Da for the CH3 domains of γ1 from residue 278 and γ4 from residue 275, respectively. The fibril protein thus appeared to consist exclusively of an immunoglobulin heavy chain constant domain. 3. Only two examples of immunoglobulin heavy chain derived amyloid have been reported previously and both of these, as well as all published cases of the usual immunoglobulin light chain derived amyloid, contained variable domain sequence. The present case therefore represents a form of local, presumably clonal, B-cell/plasma-cell disorder characterized uniquely by deposition of an amyloidogenic immunoglobulin heavy chain constant domain fragment.