Molecular Basis of 9G4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus

• Type of Material: Article
• Authors: Christopher Richardson, University of Rochester; Asida Seema Chida, Emory University; Diana Adlowitz, University of Rochester; Lin Silver, University of Rochester; Erin Fox, University of Rochester; Scott A. Jenks, Emory University; Elise Palmer, University of Rochester; Youliang Wang, Emory University; Jamie Heimburg-Molinaro, Emory University; Quan-Zhen Li, University of Texas; Chandra Mohan, University of Texas; Richard Cummings, Emory University; Christopher Tipton, Emory University; Ignacio Sanz, Emory University
• Language: English
• Date: 2013-11
• Publisher: American Association of Immunologists
• Publication Version: Final Published Version
• Copyright Statement: © 2013 by The American Association of Immunologists, Inc. This article is distributed under The American Association of Immunologists, Inc., Reuse Terms and Conditions for Author Choice articles.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://www.jimmunol.org/content/191/10/4926
• Title of Journal or Parent Work: Journal of Immunology
• ISSN: 0022-1767
• Volume: 191
• Issue: 10
• Start Page: 4926
• End Page: 4939
• Grant/Funding Information: A.S.C. was also supported by Training Grants NIH-T32 DE 007202 and NIH-T90 DE 21985.; The Consortium for Functional Glycomics was funded by NIH-National Institute of General Medical Sciences Grants GM62116 and GM98791.; This work was supported in part by the following grants from the National Institutes of Health (NIH): NIH-National Institute of Allergy and Infectious Diseases (NIAID) R37AI049660 (to I.S.), NIH-NIAID ACE U19 AI56390 (Autoimmunity Centers of Excellence), and NIH-NIAID P01 AI078907.
• Research Categories: Health Sciences, Immunology

Abstract

9G4+ IgG Abs expand in systemic lupus erythematosus (SLE) in a disease-specific fashion and react with different lupus Ags including B cell Ags and apoptotic cells. Their shared use of VH4-34 represents a unique system to understand the molecular basis of lupus autoreactivity. In this study, a large panel of recombinant 9G4+ mAbs from single naive and memory cells was generated and tested against B cells, apoptotic cells, and other Ags. Mutagenesis eliminated the framework-1 hydrophobic patch (HP) responsible for the 9G4 idiotype. The expression of the HP in unselected VH4-34 cells was assessed by deep sequencing. We found that 9G4 Abs recognize several Ags following two distinct structural patterns. B cell binding is dependent on the HP, whereas anti-nuclear Abs, apoptotic cells, and dsDNA binding are HP independent and correlate with positively charged H chain third CDR. The majority of mutated VH4-34 memory cells retain the HP, thereby suggesting selection by Ags that require this germline structure. Our findings show that the germline-encoded HP is compulsory for the anti–B cell reactivity largely associated with 9G4 Abs in SLE but is not required for reactivity against apoptotic cells, dsDNA, chromatin, anti-nuclear Abs, or cardiolipin. Given that the lupus memory compartment contains a majority of HP+ VH4-34 cells but decreased B cell reactivity, additional HP-dependent Ags must participate in the selection of this compartment. This study represents the first analysis, to our knowledge, of VH-restricted autoreactive B cells specifically expanded in SLE and provides the foundation to understand the antigenic forces at play in this disease.