Human anti-IgG1 hinge autoantibodies reconstitute the effector functions of proteolytically inactivated IgGs

The Journal of Immunology : Official Journal of the American Association of Immunologists
Randall J BrezskiRobert E Jordan

Abstract

A number of proteases of potential importance to human physiology possess the ability to selectively degrade and inactivate Igs. Proteolytic cleavage within and near the hinge domain of human IgG1 yielded products including Fab and F(ab')(2) possessing full Ag binding capability but absent several functions needed for immune destruction of cellular pathogens. In parallel experiments, we showed that the same proteolytically generated Fabs and F(ab')(2)s become self-Ags that were widely recognized by autoantibodies in the human population. Binding analyses using various Fab and F(ab')(2), as well as single-chain peptide analogues, indicated that the autoantibodies targeted the newly exposed sequences where proteases cleave the hinge. The point of cleavage may be less of a determinant for autoantibody binding than the exposure of an otherwise cryptic stretch of hinge sequence. It was noted that the autoantibodies possessed an unusually high proportion of the IgG3 isotype in contrast to Abs induced against foreign immunogens in the same human subjects. In light of the recognized potency of IgG3 effector mechanisms, we adopted a functional approach to determine whether human anti-hinge (HAH) autoantibodies could reconstitute the (mi...Continue Reading

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Citations

Jan 7, 2020·Médecine sciences : M/S·Quentin DeveuveLaurie Lajoie
Aug 30, 2013·The Journal of Biological Chemistry·Michelle KinderRandall J Brezski
Jul 15, 2016·Journal of Immunology Research·Jane RuppelEric Wakshull
Nov 20, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Willem J J FalkenburgTheo Rispens
Sep 20, 2018·Oncoimmunology·Robert E JordanZhiqiang An
Oct 10, 2009·Proceedings of the National Academy of Sciences of the United States of America·Randall J BrezskiRobert E Jordan
May 17, 2014·Bioanalysis·Boris GorovitsSheldon Leung
Dec 2, 2017·The Journal of Biological Chemistry·Tao HuangRandall J Brezski
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Oct 30, 2016·MAbs·Hok Seon KimChristoph Spiess
Jun 30, 2018·Expert Review of Gastroenterology & Hepatology·Samuele NaviglioAntonio Di Sabatino
Oct 4, 2020·The Journal of Pharmacology and Experimental Therapeutics·Keito HoshitsukiChristian A Fernandez
Aug 1, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ningyan ZhangZhiqiang An

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