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. 2020 Sep 17;15(9):e0239295.
doi: 10.1371/journal.pone.0239295. eCollection 2020.

Deficiency of activation-induced cytidine deaminase in a murine model of ulcerative colitis

Laura P Hale  1
Affiliations

Deficiency of activation-induced cytidine deaminase in a murine model of ulcerative colitis

Laura P Hale. PLoS One. .

Abstract

Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal cancer, particularly in ulcerative colitis (UC) when the majority of colon epithelial cells may be exposed to inflammation-associated mutagenesis. In addition to mutagenesis generated by oxidative stress, inflammation can induce activation-induced cytidine deaminase (Aicda), a mutator enzyme in the APOBEC family, within colon epithelial cells. This study tested the hypothesis that deletion of the Aicda gene could protect against the development of inflammation-associated colorectal cancers, using a model of UC-like colitis in "T/I" mice deficient in TNF and IL10. Results showed that T/I mice that were additionally Aicda-deficient ("TIA" mice) spontaneously developed moderate to severe UC-like colitis soon after weaning, with histologic features and colon inflammation severity scores similar those in T/I mice. Although the mean survival of TIA mice was decreased compared to T/I mice, multivariable analysis that adjusted for age when neoplasia was ascertained showed a decreased numbers of neoplastic colorectal lesions in TIA mice, with a trend toward decreased incidence of neoplasia. Aicda deficiency increased serum IL1α and slightly decreased IL12p40 and M-CSF, as compared with T/I mice, and led to undetectable levels of IgA, IgG1, IgG2a, IgG2b, and IgG3. Taken together, these studies show that Aicda deficiency can decrease the number of neoplastic lesions but is not sufficient to prevent the risk of inflammation-associated colorectal neoplasia in the setting of severe UC-like inflammation. The TIA model may also be useful for assessing the roles of antibody class-switch recombination deficiency and somatic hypermutation on regulation of microbiota and inflammation in the small intestine and colon, as well as the pathogenesis of colitis associated with hyper-IgM syndrome in humans. Further studies will be required to determine the mechanisms that drive early mortality in TIA mice.

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Conflict of interest statement

The author has declared that no competing interests exist.

Figures

Fig 1
Fig 1. Histology of colitis in TIA mice.
TIA mice generally presented with moderate to severe pan-colitis, primarily involving the mucosa, as shown in these representative fields derived from the terminal colon/rectum (A), distal colon (B), and mid-colon (C). The lamina propria is packed with inflammatory cells. Representative crypt abscesses are indicated by arrows. “e” in panel B denotes areas of edema in the submucosa. Scale bar represents 500 μm in A and 250 μm in B and C.
Fig 2
Fig 2. Squamous metaplasia and neoplasia in TIA mice.
A. Squamous metaplasia (arrowheads) was common in the rectum of TIA mice, shown here in a 9 week old. B. The dotted lines highlight a focus of invasive mucinous adenocarcinoma identified in the proximal colon of a 15 week old TIA mouse with severe pan-colitis (histologic score = 55). “Mu” indicates mucin lakes associated with invasive carcinoma. Scale bar in A and B represents 500 μm.
Fig 3
Fig 3. Serum immunoglobulin concentrations in TIA, T/I, and control T/Ihet mice.
The serum concentration of various immunoglobulin isotypes are shown for 8–10 week old TIA (n = 17), T/I (n = 28), and control T/Ihet mice (n = 13). Values shown represent the mean ± standard error of the mean (SEM). Values obtained for TIA mice were statistically different than for T/I mice for all isotypes tested, with p values ranging from p = 0.006 for IgM to 7 x 10−12 for IgG3 (Student’s t-test).
Fig 4
Fig 4. Survival of T/I and TIA mice as a function of age.
To prevent unnecessary suffering, morbidity that triggered humane endpoints was used as a surrogate for mortality, as described in Materials and Methods. Kaplan-Meier analysis demonstrates that TIA mice have a significantly shorter mean survival (13 weeks) than T/I mice (21 weeks; p = 0.0001, log-rank test).
Fig 5
Fig 5. Incidence and multiplicity of colonic neoplasia in T/I versus TIA mice.
A. The number of tumors per mouse is shown for T/I (n = 19) and TIA mice (n = 41). Each point represents a single mouse. The p value shown is the result of a multivariable analysis that adjusted for age when neoplasia was ascertained (Poisson regression analysis). B. The number of tumors per mouse is shown as a function of age at euthanasia for the same cohort illustrated in panel A. Each point represents a single mouse, however some points are not visible due to multiple mice with the same age and tumor count.
Fig 6
Fig 6. Colonic metaplasia of Brunner’s glands and duodenal inflammation in TIA mice.
A. The pyloric region of the glandular stomach (left of dashed line) and the duodenum (right of dashed line) are shown. The duodenal mucosa demonstrates mucosal epithelium and Brunner’s glands with loss of villous architecture and histology similar to that seen in the colon (colonic metaplasia). B. A higher magnification views demonstrates the metaplastic epithelium and surrounding lamina propria and submucosa with marked chronic and active inflammation, similar to what was observed in the colon of these mice. Images shown are from a 9 week mouse, where some residual cells (arrows) exhibit morphology typical of Brunner’s glands. Older mice with such metaplasia typically lacked residual identifiable Brunner’s glands. Scale bar represents 500 μm in A and 50 μm in B.
Fig 7
Fig 7. Stomach inflammation in TIA mice.
The dashed line in A represents the boundary between the forestomach and the glandular stomach. A higher magnification view in B shows inflamed gastric glands that resemble crypt abscesses, with thinning of glandular epithelium and neutrophils present within the dilated lumens, as indicated by arrows. Scale bar represents 500 μm in A and 50 μm in B.
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References

    1. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. New Engl J Med. 1990;323: 1228–1233. 10.1056/NEJM199011013231802 - DOI - PubMed
    1. Munkholm P. Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther. 2003;18: 1–5. - PubMed
    1. Nordenholtz KE, Stowe SP, Stormont JM, Stowe MM, Chessin LN, Shah AN, et al. The cause of death in inflammatory bowel disease: a comparison of death certificates and hospital charts in Rochester, New York. Am J Gastroenterol. 1995;90: 927–932. - PubMed
    1. Soderlund S, Brandt L, Lapidus A, Karlen P, Brostrom O, Lofberg R, et al. Gastroenterol. 2009;136: 1561–1567. - PubMed
    1. Upton DC, Gregory BL, Arya R, Unniraman S. AID: a riddle wrapped in a mystery inside an enigma. Immunol Res. 2011;49: 14–24. 10.1007/s12026-010-8190-x - DOI - PubMed

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This work was supported by the United States National Institutes of Health (http://www.nih.gov), grant number CA-170069 to LPH. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of this manuscript.