A Single Polysaccharide from the Human Commensal Bacteroides fragilis Protects Against Experimental CNS Demyelinating Disease

June 19, 2017 | Autor: Dennis Kasper | Categoria: Immunology, Clinical immunology, Demyelinating disease
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Abstracts inflammation. We examined whether myeloid-derived regulatory cells (MDRC) are significant sources of NO and O2.− in the airways of asthmatic and COPD subjects and whether MDRC and their free radical products can modulate the activation and function of CD4+ T cells. Bronchoalveolar lavage (BAL) cells and fluid were collected from nonsmoking normal, asthmatic, and COPD subjects. MDRC were identified using markers for cell surface antigens and purified by FACS. Specific reactive fluorescent probes were used to identify NO- and O2.−producing myeloid subpopulations. Metabolites of the iNOS, arginase, and NADPH oxidase pathways were measured in myeloid cell culture supernatants and BAL fluid. Using specific inhibitors, we tested whether MDRC can modulate autologous T cell proliferation in an iNOS-, arginase-, or NADPH oxidasedependent fashion. The NO-producing cells were CD11b+HLADR− diaminofluorescein−FM diacetate+ and included 3 further subsets based on the expression of CD14 and CD16. The frequencies of these subsets differed in the three study groups. Superoxide-producing cells were CD11c+CD11b+HLA-DR+dihydroxyethidium+ and included CD163+ and CD163− subsets. The NO-producing myeloid cells suppressed T-cell proliferation via iNOS, while the O2.−-producing cells enhanced T cell proliferation in vitro in an arginase- and superoxide-dependent fashion. Thus immunoregulatory NO- or O2.−-producing MDRC are present in the human airway and have potential to be novel targets for asthma and COPD therapy. Supported by NHLBI 1F32HL095341-01A and UAB CCTS 5UL1RR025777-02. doi:10.1016/j.clim.2010.03.154

T.41. Osteopontin Polymorphisms in Juvenile Idiopathic Arthritis and Pediatric Systemic Lupus Erythematosus Ornella Rullo 1, Jennifer Woo 1, Alice Hoftman 2, Qiong Fu 1, Angela Presson 1, Deborah McCurdy 1, Betty Tsao 1. 1 University of California, Los Angeles, Los Angeles, CA; 2 Children's Hospital of Orange County, Orange, CA Osteopontin (OPN), also named SPP1 or Eta-1, and originally identified as a bone matrix protein, has recently emerged as a proinflammatory cytokine. Posttranscriptional regulatory sequences are often found in 3′ untranslated regions (UTR); therefore, we investigated the association between OPN levels and two SLE-associated 3′ UTR polymorphisms in pediatric patients. Plasma OPN levels were tested by ELISA in 72 pediatric patients with systemic lupus erythematosus (pSLE; age b 22 years), 16 oligoarticular juvenile idiopathic arthritis (oJIA) patients and 45 young, healthy controls. Increased plasma OPN was seen in pSLE (mean ± SD = 14 ± 4 ng/ml) and oJIA (18 ± 6 ng/ml) compared with healthy controls (10 ± 3 ng/ml) (P = 0.002 and P b 0.0001, respectively); oJIA had the highest levels among these samples (P = 0.0002). In a multivariate regression analysis of the pSLE patients, both polymorphisms were independently associated with increased plasma OPN: the major allele of rs1126772 (P = 0.004) and the minor allele of rs9138 (P = 0.02). The OPN rs1126772 major allele was associated with arthritis in pSLE (P = 0.02), but not nephritis. Furthermore, the rs1126772 major allele was associated with

S51 chronic damage in pSLE (P = 0.008) but not disease activity, as assessed by validated instruments at the time of blood draw. In conclusion, the 3′ UTR polymorphism rs1126772 was associated with increased plasma OPN, arthritis and chronic damage, but not nephritis, in pSLE. These data suggest that 3′ UTR polymorphisms may regulate OPN levels and contribute to pediatric manifestations of arthritis. doi:10.1016/j.clim.2010.03.155

T.42. A Single Polysaccharide from the Human Commensal Bacteroides fragilis Protects Against Experimental CNS Demyelinating Disease Javier Ochoa-Reparaz 1, Yan Wang 1, Daniel Mielcarz 1, Sakhina Haque-Begum 1, Dennis Kasper 2, Lloyd Kasper 1. 1 Dartmouth Medical School, Lebanon, NH; 2Harvard Medical School, Boston, MA Recent studies have revealed the importance of the gut commensal populations in the balance of peripheral immunity and that polysaccharide antigen A (PSA) derived from the human commensal Bacteroides fragilis induces protection against experimental colitis. We showed before that recolonization of mice with PSA-producing B. fragilis, but not with PSA-deficient B. fragilis reduced the severity of EAE, in a Treg cell-dependent manner. We now investigate the capacity for the purified PSA to protect against experimental autoimmune encephalomyelitis (EAE) in mice. Wild-type and TLR2−/− C57BL/6 mice were immunized with purified PSA as a prophylactic as well as a therapeutic against EAE. Treatments with PSA reduced the EAE severity. We observed significant increases in CD103+CD11chigh dendritic cells and FoxP3+Treg cells in cervical lymph nodes of protected mice compared to PBS-untreated mice. We observed a lack of accumulation for both cell populations in the CNSassociated lymph nodes in mice not subjected to EAE induction. We analyzed the combined effect of PSA and EAE induction on cytokine expression and secretion in the dendritic cells and Treg cells that accumulated in the CNS. Further, we assessed the effect of TLR2−/− deficiency in the protection conferred by PSA and in the function of CD103+CD11chigh DCs. Our results demonstrate a profound immunologic effect by PSA in controlling EAE. This therapeutic approach may provide a safe and noninvasive mucosal vaccination for those with MS and perhaps other autoimmune diseases. doi:10.1016/j.clim.2010.03.156

T.43. Specific Phenotypical Markers for Human Polarized Macrophages Carmen Ambarus, Sarah Krausz, Marco van Eijk, Jorg Hamann, Paul-Peter Tak, Dominique Baeten. Academic Medical Center – University of Amsterdam, Amsterdam, Netherlands Background: The concept of polarization describes macrophage heterogeneity under specific microenvironmental

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