published_or_final_version / Medicine / Master / Doctor of Medicine

Systemic lupus erythematosus (SLE) is a chronic, multi-organ autoimmune disease characterized by the production of antibodies against self nuclear antigens. Genetics play a dominant role in disease pathogenesis and functional examination of spontaneously-arising lupus-prone animal models has provided key insights into understanding the genetic complexity of the disease. The overarching goal of the work presented here is to identify the underlying immunologic abnormalities, together with lupus susceptibility loci that produce them, that promote the development of autoimmunity in the lupus-prone New Zealand Black (NZB) background. Chapter 2 identifies the critical role of CD40-CD40L interactions in the pathogenesis of disease in NZB mice. We showed that this interaction is required for the production of class-switched IgG autoantibodies and development of hemolytic anemia and kidney disease. Polyclonal B cell activation, expansion of plasmacytoid dendritic cells (pDC), and elevated gene expression of baff were maintained in CD40L-deficient NZB mice, despite the lack of IgG immune complexes. Chapter 3 utilizes bicongenic mice carrying both NZB chromosomes 1 and 13 to investigate the genetic complexity in disease pathogenesis. In addition to identifying new phenotypes, examination of bicongenic mice showed that chronic stimulation of pDC due to the persistence of nuclear antigens leads to a refractory state with a failure to produce more IFN-α upon subsequent stimulation. Chapter 4 identifies a novel lupus susceptibility locus on NZB chromosome 13 associated with impaired clearance of apoptotic debris, a key initiating step in the development of autoimmunity. Using subcongenic mice, this locus was localized and examined its impact on immune function. Work from this thesis will contribute to understanding the complex immunogenetic mechanisms that lead to development of SLE.

Systemic lupus erythematosus (SLE) is a chronic, multi-organ autoimmune disease characterized by the production of antibodies against self nuclear antigens. Genetics play a dominant role in disease pathogenesis and functional examination of spontaneously-arising lupus-prone animal models has provided key insights into understanding the genetic complexity of the disease. The overarching goal of the work presented here is to identify the underlying immunologic abnormalities, together with lupus susceptibility loci that produce them, that promote the development of autoimmunity in the lupus-prone New Zealand Black (NZB) background. Chapter 2 identifies the critical role of CD40-CD40L interactions in the pathogenesis of disease in NZB mice. We showed that this interaction is required for the production of class-switched IgG autoantibodies and development of hemolytic anemia and kidney disease. Polyclonal B cell activation, expansion of plasmacytoid dendritic cells (pDC), and elevated gene expression of baff were maintained in CD40L-deficient NZB mice, despite the lack of IgG immune complexes. Chapter 3 utilizes bicongenic mice carrying both NZB chromosomes 1 and 13 to investigate the genetic complexity in disease pathogenesis. In addition to identifying new phenotypes, examination of bicongenic mice showed that chronic stimulation of pDC due to the persistence of nuclear antigens leads to a refractory state with a failure to produce more IFN-α upon subsequent stimulation. Chapter 4 identifies a novel lupus susceptibility locus on NZB chromosome 13 associated with impaired clearance of apoptotic debris, a key initiating step in the development of autoimmunity. Using subcongenic mice, this locus was localized and examined its impact on immune function. Work from this thesis will contribute to understanding the complex immunogenetic mechanisms that lead to development of SLE.

Lupus anticoagulants (LA) are immunoglobulins (IgG, IgM, IgA or a mixture) that interfere with in vitro phospholipids (PL) dependent coagulation tests. Variable test results among LA positive individuals are due to the heterogeneous nature of the antibodies and differences in reagent/instrument systems. A laboratory’s ability to differentiate LA from other coagulation abnormalities and to accurately establish PL dependence is determined by the sensitivity and responsiveness of screening assays and specificity of confirmatory tests. The Third International Survey on Lupus Anticoagulants (ISLA-3) was organized to assess current protocols for LA testing and determine the sensitivity and specificity of confirmatory tests. A written survey and samples for evaluation were sent to 41 participants from five continents. A majority of laboratories performed 2 screening tests and all performed mixing studies if a screening test was abnormal. Confirmatory tests were done if mixing studies suggested the presence of an inhibitor. New confirmatory assays proved to be more specific than methods previously in place.Ball State UniversityMuncie, IN 47306 / Center for Medical Education

Event response data that record the timings of randomly occurred events and the strengths of these events are becoming increasingly important in psychology. Although previous researchers such as Kass et al. and Rathbun et al. have developed techniques to model event timings, and that there are social science literature for modeling event times, few researchers have developed techniques to model the event times as well as the strengths of the events. Thus, the present thesis describes a new model that incorporates the use of functional data analysis to estimate a joint occurrence of event intensity, or the instantaneous rate of occurrence, as well as the strengths of the events. The compound log-likelihood model, which is derived by the sum of the event and the response log-likelihood functions, estimates the intensity function and the smoothed function for the response variable simultaneously. In this thesis, we will discuss the incorporation of covariates into the model, and we will also discuss in detail the positive bounded model, which imposes a constraint to the upper bound of the intensity function, as well as the positive model, where no such constraint is imposed. / The model is applied to a set of lupus data that involve the medical histories of 300 lupus sufferers over 20 years to examine the flare intensity and severity of lupus symptoms of each patient. Results of patients 15 and 148 are discussed in this thesis, which reveal that there might be some linear relationship between the patients' intensity rate and the severity of their flares. Finally, the extent to which the maximum likelihood estimation for the model is accurate is tested using simulated data. Results from the simulation show that the model requires a large sample size for a precise estimate.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 1999. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 5 uppsatser.

Thesis (M. Phil.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 61-82) Also available in print.