Two Lysines in the Forkhead Domain of Foxp3 Are Key to T Regulatory Cell Function

Background: The forkhead box transcription factor, Foxp3, is master regulator of the development and function of CD4+CD25+ T regulatory (Treg) cells that limit autoimmunity and maintain immune homeostasis. The carboxyl-terminal forkhead (FKH) domain is required for the nuclear localization and DNA binding of Foxp3. We assessed how individual FKH lysines contribute to the functions of Foxp3 in Treg cells. Methodology/Principal Findings: We found that mutation of FKH lysines at position 382 (K17) and at position 393 (K18) impaired Foxp3 DNA binding and inhibited Treg suppressive function in vivo and in vitro. These lysine mutations did not affect the level of expression of Foxp3 but inhibited IL-2 promoter remodeling and had important and differing effects on Treg-associated gene expression. Conclusions/Significance: These data point to complex effects of post-translational modifications at individual lysines within the Foxp3 FKH domain that affect Treg function. Modulation of these events using small molecule inhibitors ma

The Mutyh Base Excision Repair Gene Influences the Inflammatory Response in a Mouse Model of Ulcerative Colitis

BACKGROUND: The Mutyh DNA glycosylase is involved in the repair of oxidized DNA bases. Mutations in the human MUTYH gene are responsible for colorectal cancer in familial adenomatous polyposis. Since defective DNA repair genes might contribute to the increased cancer risk associated with inflammatory bowel diseases, we compared the inflammatory response of wild-type and Mutyh(-/-) mice to oxidative stress. METHODOLOGY/PRINCIPAL FINDINGS: The severity of colitis, changes in expression of genes involved in DNA repair and inflammation, DNA 8-oxoguanine levels and microsatellite instability were analysed in colon of mice treated with dextran sulfate sodium (DSS). The Mutyh(-/-) phenotype was associated with a significant accumulation of 8-oxoguanine in colon DNA of treated mice. A single DSS cycle induced severe acute ulcerative colitis in wild-type mice, whereas lesions were modest in Mutyh(-/-) mice, and this was associated with moderate variations in the expression of several cytokines. Eight DSS cycles caused chronic colitis in both wild-type and Mutyh(-/-) mice. Lymphoid hyperplasia and a significant reduction in Foxp3(+) regulatory T cells were observed only in Mutyh(-/-) mice. CONCLUSIONS: The findings indicate that, in this model of ulcerative colitis, Mutyh plays a major role in maintaining intestinal integrity by affecting the inflammatory response

Clinical Implications of Pediatric Colonic Eosinophilia

Objective: Pediatric colonic eosinophilia represents a confounding finding with a wide differential. It is often difficult to determine which children may progress to inflammatory bowel disease (IBD), which have an eosinophilic colitis (EC), and which may have no underlying pathology. There is little guidance for the practitioner on the approach to these patients. To define the clinical presentations of colonic eosinophilia and identify factors which may aid in diagnosis we reviewed patients with colonic eosinophilia and the clinicopathologic factors associated with their diagnoses. Mehtods: An 8-year retrospective chart review of children whose histopathology identified colonic eosinophilia (N = 72) compared to controls with normal biopsies (N = 35). Results: Patients with colonic eosinophilia had increased eosinophils/high-power field compared to controls (P 1 colonoscopy and 68% of these had change from initial diagnoses. Conclusions: There are 3 main phenotypes of children with colonic eosinophilia. Signs of chronic systemic inflammation raise suspicion for IBD. Peripheral eosinophilia and male sex are associated with EC. A significant percent of children with colonic eosinophilia do not have colonic disease. Eosinophils/high-power field is not reliable to differentiate etiologies. Repeat colonoscopies may be required to reach final diagnoses