Antonetti, Regina

Abstract Description Inflammatory bowel disease (IBD) affects between 1-3 million people in the United States, and patients present with symptoms including diarrhea, rectal bleeding, and fatigue. ST8Sia6 is a sialic acid transferase that adds terminal a2,8 disialic acids to O-linked glycoproteins, and a SNP in ST8Sia6 is associated with Crohn’s Disease. We have found that ST8Sia6 knockout (KO) and heterozygous (het) mice exhibit a 30-fold increase in small bowel immune infiltrate, along with an increased proportion of Th1 and pathogenic Th17 CD4 cells. These mice also exhibit activated gut epithelia, increased inflammatory cytokines, and increased innate cell activation, indicative of gut inflammation. Both ST8Sia6 KO and het mice exhibit increased weight loss and decreased survival when challenged with low dose dextran sodium sulfate-induced colitis. CellChat pathway analysis demonstrates enhanced TNF and IL-1 pathway activation in ST8Sia6 KO small bowel epithelium as compared to WT mice. In addition, ST8Sia6 KO small bowel epithelium produces significantly more CCL5, which may drive immune cell migration. These data demonstrate a role for ST8Sia6 in regulating gut immune homeostasis. As TNF blockade is a first line therapy for IBD patients, elucidating the role of ST8Sia6 in regulating this pathway is critical for a mechanistic understanding of IBD pathogenesis, and this may help to improve immunotherapy options for the disease. Funding Sources NIH R01CA243545 & NIH 5T32DK124190 Topic Categories Basic Autoimmunity (BA)

Abstract Inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) affects between 1–3 million people in the United States and costs an estimated $11–28 billion in national healthcare costs. Patients present with symptoms including diarrhea, rectal bleeding, and fatigue. Characterization of molecules that regulate IBD is critical in understanding pathogenesis. ST8Sia6 is a sialic acid transferase that adds terminal a2,8 disialic acids to cell surface glycoproteins, and we have found that ST8Sia6 knockout (KO) mice exhibit increased spontaneous small bowel (SB) lamina propria CD4 TH1 polarization, increased inflammatory cytokine production, decreased IgA class switching of SB plasma cells, and alterations of the SB innate lymphoid cells, indicative of gut inflammation. Moreover, adult ST8Sia6 KO mice have shortened small and large bowels, likely due to baseline inflammation. These mice do not exhibit overt baseline symptoms, but ST8Sia6 KO mice exhibit increased weight loss and decreased survival when challenged with dextran sodium sulfate (DSS)-induced colitis, which was also enhanced when co-housed with wildtype (WT) mice. DSS-challenged ST8Sia6 KO mice exhibit increased histological damage and immune infiltration of the gut as compared to WT controls. Accelerated DSS-induced colitis is also observed when ST8Sia6-deficient bone marrow is transplanted into WT recipients, indicating that the effect is mediated specifically by immune cells. This data demonstrates a role for ST8Sia6 in regulating the host immune response to IBD, and further elucidating this role will aid in developing a mechanistic understanding of IBD pathogenesis and in understanding potential immunotherapies for the disease. R01CA243545, 5T32DK124190-03

Abstract Inflammatory bowel disorders (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) affect between 1–3 million people in the United States with prevalence on the rise. Patients present with symptoms including diarrhea, abdominal cramps, and weight loss. Many factors are implicated in pathogenesis, including host immune response. Identification of molecules that regulate IBD is critical in understanding pathogenesis. ST8Sia6 is a sialic acid transferase that adds terminal a2,8 disialic acids to cell surface glycoproteins, and we have found that ST8Sia6 knockout (KO) mice exhibit increased spontaneous small bowel lamina propria CD4 TH1 polarization, increased inflammatory cytokine production, and decreased IgA class switching of Peyer’s patch B cells, indicative of inflammation. Additionally, adult ST8Sia6 KO mice have shortened small bowels, likely due to baseline inflammation. These mice do not exhibit obvious baseline symptoms, but ST8Sia6 KO mice exhibit increased weight loss and decreased survival when challenged with dextran sodium sulfate (DSS)-induced colitis, which was also enhanced when co-housed with wildtype (WT) mice and after antibiotic treatment. These DSS-challenged ST8Sia6 KO mice exhibit increased histological damage and immune infiltration of the gut as compared to WT controls. The accelerated DSS-colitis is also observed when ST8Sia6-deficient bone marrow is transplanted into WT recipients, indicating that the effect is mediated specifically by immune cells. This data demonstrates a role for ST8Sia6 in regulating the host immune response to inflammatory bowel disorders, and further elucidating this role will aid in developing a mechanistic understanding of IBD pathogenesis. Supported by grants from NIH R01 CA243545