No description available.

No description available.

Thesis (M. Med. Sc.)--University of Hong Kong, 2006.

published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Thesis (Ph.D.)--University of Melbourne, Dept. of Medical Biology, 2003. / Typescript (photocopy). Includes bibliographical references (leaves 125-151).

Thesis (Ph.D.)--Michigan State University. Dept. of Pharmacology and Toxicology, 2008. / Title from PDF t.p. (viewed on Mar. 30, 2009) Includes bibliographical references (p.157-191). Also issued in print.

Thesis (Ph. D.)--Ohio State University, 2003. / Document formatted into pages. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 Aug. 19.

Thesis (M. Sc.)--University of Canterbury, 2006. / Typescript (photocopy). Includes bibliographical references (leaves 102-122). Also available via the World Wide Web.

Factors regulating the induction and development of B cell–mediated autoimmunity are not well understood. Here, we report that targeted deletion in murine B cells of X-linked Cosmc, encoding the chaperone required for expression of core 1 O-glycans, causes the spontaneous development of autoimmune pathologies due to a breakdown of B cell tolerance. BC-CosmcKO mice display multiple phenotypic abnormalities, including severe weight loss, ocular manifestations, lymphadenopathy, and increased female-associated mortality. Disruption of B cell tolerance in BC-CosmcKO mice is manifested as elevated self-reactive IgM and IgG autoantibodies. Cosmc-deficient B cells exhibit enhanced basal activation and responsiveness to stimuli. There is also an elevated frequency of spontaneous germinal center B cells in BC-CosmcKO mice. Mechanistically, loss of Cosmc confers enhanced B cell receptor (BCR) signaling through diminished BCR internalization. The results demonstrate that Cosmc, through control of core 1 O-glycans, is a previously unidentified immune checkpoint gene in maintaining B cell tolerance.

Indiana University-Purdue University Indianapolis (IUPUI) / Vaccinia virus (VACV), the prototypical poxvirus, was used to eradicate smallpox worldwide and, in recent years, has received considerable attention as a vector for the development of vaccines against infectious diseases and oncolytic virus therapy. Studies have demonstrated that VACV exhibits an extremely strong bias for binding to and infection of primary human antigenpresenting cells (APCs) including monocytes, macrophages, and dendritic cells. However, very few studies have evaluated VACV binding to and infection of primary human B cells, a main type of professional APC. In this study, we evaluated the susceptibility of primary human peripheral B cells at different developmental stages to VACV binding, infection, and replication. We found that VACV exhibited strong binding but little entry into ex vivo B cells. Phenotypic analysis of B cells revealed that plasmablasts were the only subset resistant to VACV binding. Infection studies showed that plasma and mature-naïve B cells were resistant to VACV infection, while memory B cells were preferentially infected. Additionally, VACV infection was increased in larger and proliferative B cells suggesting a bias of VACV infection towards specific stages of differentiation and proliferative ability. VACV infection in B cells was abortive, and cessation of VACV infection was determined to occur at the stage of late viral gene expression. Interestingly, B cell function, measured by cytokine production, was not affected within 24 hours post-infection. In contrast to ex vivo B cells, stimulated B cells were permissive to productive VACV infection. These results demonstrate the value of B cells as a tool to aid in deciphering the intricacies of poxvirus infection in humans. Understanding VACV infection in primary human B cells at various stages of differentiation and maturation is important for the development of a safer smallpox vaccine and better vectors for vaccines against cancers and other infectious diseases.