Physiological IgM class catalytic antibodies selective for transthyretin amyloid

J Biol Chem. 2014 May 9;289(19):13243-58. doi: 10.1074/jbc.M114.557231. Epub 2014 Mar 19.


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.

Keywords: Aging; Amyloid; Amyloidosis; Antibodies; Catalytic Antibody; Innate Immunity; Protein Evolution; Superantigen; Transthyretin.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amyloid / immunology
  • Amyloid / metabolism*
  • Antibodies, Catalytic / immunology
  • Antibodies, Catalytic / metabolism*
  • Antibody Specificity / immunology
  • Female
  • Humans
  • Immunoglobulin M / immunology
  • Immunoglobulin M / metabolism*
  • Male
  • Prealbumin / immunology
  • Prealbumin / metabolism*
  • Proteolysis*


  • Amyloid
  • Antibodies, Catalytic
  • Immunoglobulin M
  • Prealbumin