Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus

Christopher Richardson, Asiya Seema Chida, Diana Adlowitz, Lin Silver, Erin Fox, Scott A. Jenks, Elise Palmer, Youliang Wang, Jamie Heimburg-Molinaro, Quan Zhen Li, Chandra Mohan, Richard Cummings, Christopher Tipton, Ignacio Sanz

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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.

Original languageEnglish (US)
Pages (from-to)4926-4939
Number of pages14
JournalJournal of Immunology
Volume191
Issue number10
DOIs
StatePublished - Nov 15 2013

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Systemic Lupus Erythematosus
B-Lymphocytes
High-Throughput Nucleotide Sequencing
Cardiolipins
Mutagenesis
Chromatin
Immunoglobulin G

ASJC Scopus subject areas

  • Immunology

Cite this

Richardson, C., Chida, A. S., Adlowitz, D., Silver, L., Fox, E., Jenks, S. A., ... Sanz, I. (2013). Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus. Journal of Immunology, 191(10), 4926-4939. https://doi.org/10.4049/jimmunol.1202263

Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus. / Richardson, Christopher; Chida, Asiya Seema; Adlowitz, Diana; Silver, Lin; Fox, Erin; Jenks, Scott A.; Palmer, Elise; Wang, Youliang; Heimburg-Molinaro, Jamie; Li, Quan Zhen; Mohan, Chandra; Cummings, Richard; Tipton, Christopher; Sanz, Ignacio.

In: Journal of Immunology, Vol. 191, No. 10, 15.11.2013, p. 4926-4939.

Research output: Contribution to journalArticle

Richardson, C, Chida, AS, Adlowitz, D, Silver, L, Fox, E, Jenks, SA, Palmer, E, Wang, Y, Heimburg-Molinaro, J, Li, QZ, Mohan, C, Cummings, R, Tipton, C & Sanz, I 2013, 'Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus', Journal of Immunology, vol. 191, no. 10, pp. 4926-4939. https://doi.org/10.4049/jimmunol.1202263
Richardson C, Chida AS, Adlowitz D, Silver L, Fox E, Jenks SA et al. Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus. Journal of Immunology. 2013 Nov 15;191(10):4926-4939. https://doi.org/10.4049/jimmunol.1202263
Richardson, Christopher ; Chida, Asiya Seema ; Adlowitz, Diana ; Silver, Lin ; Fox, Erin ; Jenks, Scott A. ; Palmer, Elise ; Wang, Youliang ; Heimburg-Molinaro, Jamie ; Li, Quan Zhen ; Mohan, Chandra ; Cummings, Richard ; Tipton, Christopher ; Sanz, Ignacio. / Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus. In: Journal of Immunology. 2013 ; Vol. 191, No. 10. pp. 4926-4939.
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