Activation-induced cytidine deaminase deficiency causes organ-specific autoimmune disease.

Koji Hase,Sayaka Kawano,Masashi Ebisawa,Daisuke Takahashi,Hiroshi Ohno,Kikuji Itoh,Lena Alexopoulou

doi:10.1371/journal.pone.0003033

Koji Hase, Sayaka Kawano + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0003033

Copy DOI

Abstract

Activation-induced cytidine deaminase (AID) expressed by germinal center B cells is a central regulator of somatic hypermutation (SHM) and class switch recombination (CSR). Humans with AID mutations develop not only the autosomal recessive form of hyper-IgM syndrome (HIGM2) associated with B cell hyperplasia, but also autoimmune disorders by unknown mechanisms. We report here that AID−/− mice spontaneously develop tertiary lymphoid organs (TLOs) in non-lymphoid tissues including the stomach at around 6 months of age. At a later stage, AID−/− mice develop a severe gastritis characterized by loss of gastric glands and epithelial hyperplasia. The disease development was not attenuated even under germ-free (GF) conditions. Gastric autoantigen -specific serum IgM was elevated in AID−/− mice, and the serum levels correlated with the gastritis pathological score. Adoptive transfer experiments suggest that autoimmune CD4+ T cells mediate gastritis development as terminal effector cells. These results suggest that abnormal B-cell expansion due to AID deficiency can drive B-cell autoimmunity, and in turn promote TLO formation, which ultimately leads to the propagation of organ-specific autoimmune effector CD4+ T cells. Thus, AID plays an important role in the containment of autoimmune diseases by negative regulation of autoreactive B cells.

Highlights

The targeted deamination of Ig genes by Activation-induced cytidine deaminase (AID) is a prerequisite for Ab affinity maturation through somatic hypermutation (SHM) and class switch recombination (CSR) [1]
We observed that AID2/2 mice housed under specific pathogen-free (SPF) conditions developed a number of polyp-like lesions in the gastric mucosa (Figure 1A, see arrows)
In the present study we have shown that as they age, AID2/2 mice sequentially develop lymphoid neogenesis followed by severe gastritis

Summary

Introduction

The targeted deamination of Ig genes by AID is a prerequisite for Ab affinity maturation through somatic hypermutation (SHM) and class switch recombination (CSR) [1]. Enhanced proliferation of B cells and increased repertoire diversity were observed in aged AID2/2 mice, suggesting a critical role of AID in B-cell growth regulation [3]. AID2/2 mice display abnormal expansion of anaerobic commensal bacteria in the small intestine, which induces hypertrophic enlargement of Peyer’s patches and protrusion of isolated lymphoid follicles (ILFs). The abnormality of intestinal flora is due to the lack of hypermutated IgA, because reconstitution of intestinal IgA production recovered the normal composition of gut flora[4]. These results suggest that AID plays a key role in homeostasis of intestinal flora. A fraction of patients carrying AID mutations suffer from various organ-specific autoimmune diseases, including diabetes mellitus, autoimmune hepatitis and Crohn’s disease, via unknown mechanisms [5]

Methods

Results

Conclusion