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

Publication ,  Journal Article
Hale, LP
Published in: PLoS One
2020

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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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2020

Volume

15

Issue

9

Start / End Page

e0239295

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Macrophage Colony-Stimulating Factor
  • Interleukin-12
  • Interleukin-10
  • Interleukin-1
  • Immunoglobulins
  • General Science & Technology
 

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Hale, L. P. (2020). Deficiency of activation-induced cytidine deaminase in a murine model of ulcerative colitis. PLoS One, 15(9), e0239295. https://doi.org/10.1371/journal.pone.0239295
Hale, Laura P. “Deficiency of activation-induced cytidine deaminase in a murine model of ulcerative colitis.PLoS One 15, no. 9 (2020): e0239295. https://doi.org/10.1371/journal.pone.0239295.
Hale, Laura P. “Deficiency of activation-induced cytidine deaminase in a murine model of ulcerative colitis.PLoS One, vol. 15, no. 9, 2020, p. e0239295. Pubmed, doi:10.1371/journal.pone.0239295.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2020

Volume

15

Issue

9

Start / End Page

e0239295

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Macrophage Colony-Stimulating Factor
  • Interleukin-12
  • Interleukin-10
  • Interleukin-1
  • Immunoglobulins
  • General Science & Technology