Production of IgG autoantibody requires expression of activation‐induced deaminase in early‐developing B cells in a mouse model of SLE

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of pathogenic IgG anti-nuclear antibodies. Pathogenic IgG autoantibody production requires B-cell activation, leading to the production of activation-induced deaminase (AID) and class switching of IgM genes to IgG. To understand how and when B cells are activated to produce these IgG autoantibodies, we studied cells from 564Igi, a mouse model of SLE. 564Igi mice develop a disease profile closely resembling that found in human SLE patients, including the presence of IgG anti-nucleic acid antibodies. We have generated 564Igi mice that conditionally express an activation-induced cytidine deaminase transgene (Aicdatg), either in all B cells or only in mature B cells. Here we show that class-switched pathogenic IgG autoantibodies were produced only in 564Igi mice in which AID was functional in early developing B cells, resulting in loss of tolerance. Furthermore, we show that the absence of AID in early developing B cells also results in increased production of self-reactive IgM, indicating that AID, through somatic hypermutation (SHM), contributes to tolerance. Our results suggest that the pathophysiology of clinical SLE might also be dependent on AID expression in early developing B cells.

Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance

“…These findings, together with the identification of AID transcripts in B-cell precursors in both mice and humans support the idea that AID expression in immature B cells is relevant to tolerance induction (Han et al, 2007; Kuraoka et al, 2009; Mao et al, 2004; Meyers et al, 2011; Ueda et al, 2007; Umiker et al, 2014). However, it remains to be determined if the AID enzyme is in fact expressed in some B-cell precursors or if central B-cell tolerance defects in AID-deficient patients or mice might be related to their susceptibility to infections in the absence of isotype switched, affinity matured antibodies.…”

IgH Chain Class Switch Recombination: Mechanism and Regulation

“…In a different study, pro-B cells from Rag1-deficient mice could be induced in culture to switch at the DNA level from μ>γ2b and from μ>ε, although these cells do not express either μ chains or light chains (67). The physiological role of this H chain switching is unknown, although it might contribute to autoimmunity (68). …”

BCR and Endosomal TLR Signals Synergize to Increase AID Expression and Establish Central B Cell Tolerance

“…We and others have shown that expression of activation-induced cytidine deaminase (AID) in immature/transitional-1 (T1) B cells is required for the first tolerance checkpoint (Cantaert et al, 2015; Kuraoka et al, 2011; Meyers et al, 2011; Umiker et al, 2014). In the absence of AID, autoreactive immature/T1 B cells are inefficiently purged and exhibit increased resistance to receptor-induced apoptosis (Kuraoka et al, 2011).…”

“…Aicda −/− mice (Umiker et al, 2014). These results are consistent with a significant role for AID in the tolerization of developing B cells, but peak levels of AID expression by immature/T1 B cells reach only about 3% of that present in germinal center (GC) B cells (Kuraoka et al, 2011).…”