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

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

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Activation-induced cytidine deaminase (AID) expressed by germinal center B cells is a ceptral 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 lympoid 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 hyperlasia. 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 disease by negative regulation of autoreactive B cells.

Original languageEnglish
Article numbere3033
JournalPloS one
Volume3
Issue number8
DOIs
Publication statusPublished - 2008 Aug 21

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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