Activation-Induced Cytidine Deaminase Deficiency Causes Organ-Specific Autoimmune Disease

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.

Activation-induced cytidine deaminase mediates central tolerance in B cells

“…2); spontaneous GC responses were also abrogated in Aicda −/− Cd154 −/− mice (Fig. S3), lending support to the notion that self-reactivity is a significant factor in the follicular hypertrophy of AID-deficient mice and humans (19).…”

“…AID deficiency in aging mice (19,20) and humans (21) has been linked to organ-specific autoAb and autoimmune disease. To determine whether autoAb levels are increased in young Aicda −/− mice, we quantified their serum Ab bearing κ-light chains (Igκ) reactive with DNA or NIH 3T3 cells; serum Igκ Ab titers in congenic B6, autoimmune C4 −/− (22), and Ab deficient Rag1 −/− mice were also determined as controls ( Fig.…”

“…Others have shown that AID deficiency can enhance autoimmunity in B6.lpr mice (20) and promote organ-specific responses in germ-free BALB/c mice (19); in both cases, the onset of autoAb and disease became obvious in 6-to 12-mo-old animals. Here, we have demonstrated that AID deficiency leads to impaired central B-cell tolerance in young animals (Figs.…”

AID constrains germinal center size by rendering B cells susceptible to apoptosis

“…44 Furthermore, aged AID Ϫ/Ϫ mice were recently reported to develop a fatal autoimmune gastritis linked to activation of peripheral B cells and the development of tertiary lymphoid organs. 42 We suggest that the development of autoimmune diseases in AID Ϫ/Ϫ mice may be linked to improper maintenance of the GC and potential escape of hazardous B-cell clones. These data emphasize the necessity for a fine-tuned balance of AID expression under physiologic conditions that is required for protection against B-cell disease.…”

“…These data are also corroborated by previous studies in which AID Ϫ/Ϫ mice were shown to produce tertiary lymphoid organs even when raised in a germ-free facility. 42 The GC is often linked to the development of autoimmune B cells, a process associated with abnormal persistence of B cells within this structure. Spontaneous GC formation, such as that found in AID Ϫ/Ϫ GCs, has also been linked to progression of humoral autoimmunity.…”