Accelerated Systemic Autoimmunity in the Absence of Somatic Hypermutation in 564Igi: A Mouse Model of Systemic Lupus with Knocked-In Heavy and Light Chain Genes

Abstract

564Igi mice have knocked-in immunoglobulin (Ig) heavy (H) and light (L) chain genes that encode an autoantibody recognizing RNA. Previously, we showed that these mice produce pathogenic IgG autoantibodies when activation-induced deaminase (AID) is expressed in pre-B and immature B cells but not when it is expressed only in mature B cells. AID has two functions; it is necessary for somatic hypermutation (SHM) and class switch recombination (CSR). To determine the role of each of these functions in the generation of pathogenic autoantibodies, we generated 564Igi mice that carry a mutant AID-encoding gene, Aicda (AicdaG23S), which is capable of promoting CSR but not SHM. We found that 564Igi AicdaG23S mice secreted class-switched antibodies (Abs) at levels approximately equal to 564Igi mice. However, compared to 564Igi mice, 564Igi AicdaG23S mice had increased pathogenic IgG Abs and severe systemic lupus erythematosus-like disease, including, glomerulonephritis, and early death. We suggest that in 564Igi mice SHM by AID changes Ig receptors away from self reactivity, thereby mitigating the production of autoantibody, providing a novel mechanism of tolerance.

Abrogation of Lupus Nephritis in Somatic Hypermutation–Deficient B6.MRL-Faslpr/J Mice

“…In contrast to the prevailing view supported by others and us, which illustrates an essential role of SHM deficiency in SLE alleviation (8,25,26,37), a more recent work based on 564Igi mice reported that SHM deficiency caused by AID G23S accelerated lupus nephritis (39). Clearly, a major difference between these studies lies in distinct SLE mouse models.…”

“…In bone marrow B cells, SHM controlled by AID participates in the regulation of central B cell tolerance through removing developing autoreactive B cells via receptor editing in autoreactive BCR (42)(43)(44). Owing to the lack of SHM in AID G23S 564Igi mice, inefficient removal of the developing autoreactive B cells led to the accumulation of pathogenic autoantibodies and thereby accelerated lupus nephritis (39). In the alternative MRL/lpr mouse model, created in a different manner and widely used in numerous studies, impaired fas gene expression blocks the Fas-FasL apoptotic pathway and thereby causes the persistence of activated B cells in periphery (29,30,45,46).…”

Transforming mutations in the development of pathogenic B cell clones and autoantibodies*

“…It has been proposed that clones that continue to mutate at high rates could acquire mutations that are detrimental to immunoglobulin structure 129 . Another explanation is that RF clones could acquire “redeeming” mutations that remove their IgG‐binding activity similar to that proposed for other autoreactive B cells 91,130 …”

Immune System Sex Differences May Bridge the Gap Between Sex and Gender in Fibromyalgia

“…In a 564Igi mouse model of SLE, a dosage difference in TLR8 determined the sex bias in anti-RNA IgG antibodies, which were higher in female than male mice (Umiker et al, 2014). 564Igi mice are especially susceptible to autoimmunity because of diminished somatic hypermutation (McDonald et al, 2017). The release of miR-21 due to neuropathy stimulates TLR8 signaling in the dorsal root ganglia, which leads to hyperexcitability and pain (Zhang et al, 2018).…”