Dendritic cells in HLA-B27 transgenic rat model of spondyloarthropathy

immunology, dendritic cells, spondyloarthropathy, HLA-B27

Utriainen, Lotta Maria ; Milling, Simon

University:University of Glasgow

Department:Institute of Infection Immunity and Inflammation

关键词: immunology, dendritic cells, spondyloarthropathy, HLA-B27;   

Others  :  http://theses.gla.ac.uk/3396/1/2012UtriainenPhD.pdf

来源: University of Glasgow

【 摘 要 】

The Spondyloarthritides (SpAs) are a group of related inflammatory disorders that share common clinical features and a genetic predisposing factor, the MHC class I gene HLA-B27. Rats transgenic for the human HLA-B27 and beta 2 microglobulin genes (B27-TG rats) develop a multisystem inflammatory disease, offering a model for studying SpA. Several lines of evidence from both humans and rats suggest that intestinal inflammation and the commensal microbiota in the gut are important in disease development. The intestine is the site of entry for vast amounts of antigens, and the intestinal immune system has evolved to be tolerant towards harmless non-self antigens, but still retain the ability to mount protective immune responses against invading pathogens. Dendritic cells (DCs) are professional antigen presenting cells residing in the intestinal tissue at sites of antigen entry, and continuously migrate from the intestine into the mesenteric lymph nodes, via lymph, where they interact with naïve T cells. Hence, DCs have important role in maintaining the balance between tolerance and immunity in the intestine.The aim of this thesis was to investigate the roles of migrating intestinal lymph DCs (L-DCs) in disease development in the B27-TG rat. These DCs were collected by thoracic duct cannulation and their phenotype and functions were investigated. In addition, mesenteric lymph node (MLN) and bone marrow derived DCs (BMDCs) were compared between B27-TG and non-TG animals.B27-TG animals lack one of the three subsets of L-DCs, the MHCIIhi CD103+ CD172alo cells, in the pseudo-afferent lymph, and the remaining L-DCs appear more activated. The proportion of this subset was also reduced in the MLNs of B27-TG animals. The CD172alo DC subset has been implicated in the induction and maintenance of intestinal tolerance, and thus lack of this subset could lead to breakdown in tolerance and to systemic disease. In addition, BMDCs cultured with mouse Flt3L survived less well than non-TG BMDCs, and this defect could be reversed by addition of the apoptosis inhibitor Q-VD into the cultures. This indicated there could be a defect in the development of B27-TG DCs from their bone marrow precursors. Furthermore, B27-TG BMDCs stimulated significantly less proliferation from naïve CD4+ T cells than their non-TG counterparts in a mixed leukocyte reaction. In spite of this, more IL- 17F and less IFN-gamma were detected in the B27-TG BMDC - T cell co-cultures compared to non-TG DCs, indicating skewing of the immune response from Th1 to Th17. Together, these results reveal previously unrecognised defects in HLA-B27+ DCs both in vivo and in vitro, which could have a role on SpA disease pathogenesis. This opens up new exciting avenues of research for the future.