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

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

Research output: Contribution to journalArticle

48 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
Externally publishedYes

Fingerprint

autoimmune diseases
Autoimmune Diseases
B-lymphocytes
B-Lymphocytes
Cells
gastritis
Gastritis
T-cells
Immunoglobulin M
Hyper-IgM Immunodeficiency Syndrome
Stomach
mice
stomach
T-lymphocytes
autoantigens
T-Lymphocytes
autoimmunity
Germinal Center
Adoptive Transfer
gastric mucosa

ASJC Scopus subject areas

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

Cite this

Activation-induced cytidine deaminase deficiency causes organ-specific autoimmune disease. / Hase, Kouji; Takahashi, Daisuke; Ebisawa, Masashi; Kawano, Sayaka; Itoh, Kikuji; Ohno, Hiroshi.

In: PLoS One, Vol. 3, No. 8, e3033, 21.08.2008.

Research output: Contribution to journalArticle

Hase, Kouji ; Takahashi, Daisuke ; Ebisawa, Masashi ; Kawano, Sayaka ; Itoh, Kikuji ; Ohno, Hiroshi. / Activation-induced cytidine deaminase deficiency causes organ-specific autoimmune disease. In: PLoS One. 2008 ; Vol. 3, No. 8.
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