Pigtail macaques (PTM) rapidly progress to AIDS after SIV infection. Given the strong association between HIV/SIV disease progression and microbial translocation and immune activation, we assessed whether high basal levels of immune activation and microbial translocation exist in PTM. We found that prior to SIV infection, PTM had high levels of microbial translocation that correlated with significant damage to the structural barrier of the GI tract. Moreover, this increased microbial translocation correlated with high levels of immune activation and was associated with high frequencies of IL-17-producing T cells. These data highlight the relationship between mucosal damage, microbial translocation and systemic immune activation in the absence of HIV/SIV replication and underscore the importance of microbial translocation in the rapid course of disease progression in SIV-infected PTM. Furthermore, these data suggest that PTM may be an ideal model to study therapeutic interventions aimed at decreasing microbial translocation-induced immune activation.

SummaryInflammatory bowel disease (IBD) is characterized by damage to the gut mucosa and systemic inflammation. We sought to evaluate the role of chronic inflammation on circulating T-cell activation in human subjects with Crohn's disease and ulcerative colitis. We studied 54 patients with IBD and 28 healthy controls. T-cell activation and cycling were assessed in whole blood samples by flow cytometry. Levels of lipopolysaccharide (LPS) were measured in serum by Limulus amoebocyte lysate assay, and plasma levels of inflammatory markers and LPS-binding proteins were measured by ELISA. The proportions of circulating CD4 + and CD8 + T lymphocytes in cycle (Ki67 + ) are increased in patients with IBD compared with these proportions in controls. CD8 + T cells from patients with IBD are also enriched for cells that expressed CD38 and HLA-DR, and proportions of these cells are related to plasma levels of interleukin-6 and C-reactive protein in these patients. Intracellular interleukin-2 and interferon-c levels were elevated in resting and polyclonally activated CD4 + and CD8 + T cells in patients with IBD when compared with levels from healthy controls. Surprisingly, we did not find increased levels of LPS in the serum of patients with IBD. We did, however, find a signature of recent microbial translocation, as levels of LPS-binding protein are increased in the plasma of patients with IBD compared with plasma levels in healthy controls; LPS-binding protein levels are also directly related to proportions of CD38 HLA-DR-expressing CD4 + and CD8 + T cells. Local damage to the gastrointestinal tract in IBD may result in systemic inflammation and T-cell activation.

Background Antimicrobial peptides (AMPs) maintain a sterile environment in intestinal crypts, limiting microbial colonization and invasion. Decreased AMP expression is proposed to increase the risk for inflammatory bowel disease. Expression and function of inducible AMPs, human β-defensin 2 and 3 (hBD-3), remain poorly characterized in healthy and chronically inflamed intestine. Methods hBD-2 and hBD-3 peptide concentrations in serum and intestinal biopsies of ulcerative colitis, Crohn's Disease (CD), and healthy subjects were measured by ELISA. HBD-2 and hBD-3 mRNA was quantified by qPCR in biopsies from the terminal ileum (TI) of CD patients and healthy controls. HBD-3 peptide localization in the TI was visualized by confocal microscopy. Results Immunoreactive hBD-3 peptide is present in the TI and colon in healthy subjects. In the TI of CD patients, hBD-3, but not hBD-2 peptide, is increased four-fold, whereas hBD-2 peptide is elevated in the serum. hBD-3 mRNA in the CD TI remains unchanged and does not correlate with hBD-3 peptide expression. hBD-3 is localized to Paneth cell granules and the apical surface of the healthy columnar epithelium. In CD, hBD-3 peptide location switches to the basolateral surface of the columnar epithelium and is diffusely distributed within the lamina propria. Conclusion hBD-3 peptide throughout the healthy gastrointestinal tract suggests a role in maintaining balance between host defenses and commensal microbiota. Increased and relocalized secretion of hBD-3 toward the lamina propria in the CD TI indicates possible local immunomodulation during chronic inflammation, while increased serum hBD-2 in CD implicates its systemic antimicrobial and immunomodulatory role.