Detailed Structure and Pathophysiological Roles of the IgA-Albumin Complex in Multiple Myeloma

Abstract

Immunoglobulin A (IgA)-albumin complexes may be associated with pathophysiology of multiple myeloma, although the etiology is not clear. Detailed structural analyses of these protein–protein complexes may contribute to our understanding of the pathophysiology of this disease. We analyzed the structure of the IgA-albumin complex using various electrophoresis, mass spectrometry, and in silico techniques. The data based on the electrophoresis and mass spectrometry showed that IgA in the sera of patients was dimeric, linked via the J chain. Only dimeric IgA can bind to albumin molecules leading to IgA-albumin complexes, although both monomeric and dimeric forms of IgA were present in the sera. Molecular interaction analyses in silico implied that dimeric IgA and albumin interacted not only via disulfide bond formation, but also via noncovalent bonds. Disulfide bonds were predicted between Cys34 of albumin and Cys311 of IgA, resulting in an oxidized form of albumin. Furthermore, complex formation prolongs the half-life of IgA molecules in the IgA-albumin complex, leading to excessive glycation of IgA molecules and affects the accumulation of IgA in serum. These findings may demonstrate why complications such as hyperviscosity syndrome occur more often in patients with IgA dimer producing multiple myeloma.

Proteins in human body fluids contain in vivo antigen analog of the melibiose-derived glycation product: MAGE

“…AGEs increase immunogenicity of immunoglobulins and cause production of antibodies against this modified protein 77 , as reported in type 2 diabetes 78 , atherosclerosis 79 , and rheumatoid arthritis (RA) 80 – 82 . Glycation is also a suspected cause of decreased elimination of IgA by the liver and the protein accumulation in blood 83 . Serum IgA levels are significantly higher in diabetic patients than in healthy subjects 84 – 86 .…”