Physiological IgM Class Catalytic Antibodies Selective for Transthyretin Amyloid

• Published in: The Journal of biological chemistry 2014-05, Vol.289 (19), p.13243-13258
• Main Authors: Planque, Stephanie A., Nishiyama, Yasuhiro, Hara, Mariko, Sonoda, Sari, Murphy, Sarah K., Watanabe, Kenji, Mitsuda, Yukie, Brown, Eric L., Massey, Richard J., Primmer, Stanley R., O'Nuallain, Brian, Paul, Sudhir
• Format: Article
• Language: English
• Subjects: Adult; Aging; Amyloid; Amyloid - immunology; Amyloid - metabolism; Amyloidosis; Antibodies; Antibodies, Catalytic - immunology; Antibodies, Catalytic - metabolism; Antibody Specificity - immunology; Catalytic Antibody; Female; Humans; Immunoglobulin M - immunology; Immunoglobulin M - metabolism; Immunology; Innate Immunity; Male; Prealbumin - immunology; Prealbumin - metabolism; Protein Evolution; Proteolysis; Superantigen; Transthyretin
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M114.557231

Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded β-sheet aggregates responsible for age-associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the physiological tetrameric TTR (phyTTR). IgM class B cell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-amyloidogenic, non-superantigenic proteins. Individual monoclonal IgMs (mIgMs) expressed variable misTTR hydrolytic rates and differing oligoreactivity directed to amyloid β peptide and microbial superantigen proteins. A subset of the mIgMs was monoreactive for misTTR. Excess misTTR was dissolved by a hydrolytic mIgM. The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function. Some antibodies express serine protease activity. Transthyretin misfolding causes accumulation of pathogenic amyloid. Constitutively produced IgM but not IgG class antibodies selectively hydrolyzed and dissolved misfolded transthyretin without hydrolyzing physiologically folded transthyretin. Some IgMs were oligoreactive with amyloids and superantigens. Catalytic IgMs may clear misfolded TTR and delay amyloidosis. The innate antibody repertoire is a source of selective catabodies to toxic proteins.