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Systemic lupus erythematosus (SLE) is associated with premature onset of coronary heart disease and endothelial dysfunction. To date the mechanisms underlying this remain unclear. We hypothesise there is premature biological ageing in patients with SLE as evidenced by a reduction in the mean telomere length of PBMC. Premature biological ageing is also evident in the vasculature of patients with SLE and reflected by relatively shortened telomeres of cells involved in vascular repair and regeneration i.e. endothelial progenitor cells (EPC). Furthermore, senescent EPC result in cellular imbalance with a relatively reduced number and/or function of circulating healthy EPC. We studied 200 SLE patients longitudinally over an average of 5.8 (5.2, 6.3) years and demonstrated progression of carotid plaque burden in 17.5%. Baseline traditional CHD risk factors did not influence plaque progression. We measured CD34/CD133+ EPC using flow cytometry in 54 SLE patients and 49 controls in cross-sectional study and demonstrated no significant difference between the groups. We further investigated number and function of EPC by enumerating colony-forming unit (CFU) in culture in 39 SLE patients and 27 controls and demonstrated a significant reduction in CFU number in SLE [median (IQR) CFU 5.7 (2.3, 8.0) in SLE vs. 10.0 (5.7, 15.0) in controls; p= 0.0016] and this difference was particularly marked in those under the age of 40 years [4 (2, 8) vs. 10.5 (7, 19), p= 0.03]. We measured relative telomere length of PBMC in SLE compared to age-matched controls using real-time qPCR in a cross-sectional study and demonstrated a significant reduction in SLE patients [0.97 (0.47, 1.57) and 1.53 (0.82, 2.29), p = P = 0.0008]. Further, telomere length of DNA extracted from CFU after 7 days in culture was quantified in a preliminary study of 5 SLE patients and 5 controls and demonstrated a trend to telomere length reduction in SLE patients. In conclusion there was evidence of significant progression of carotid plaque is in this cohort of female SLE patients. Further there is evidence of abnormal endothelial repair and premature senescence in SLE. Results support the hypothesis that there is a premature senescent phenotype in SLE and as such may present a novel therapeutic target to attenuate the risk of CHD in SLE.

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder associated with the development of immune complexes that deposit in multiple organ systems. The deposition of immune complexes is associated with tissue damage, most commonly seen in the form of kidney damage as lupus nephritis. IRF5 is an SLE susceptibility gene that is causal to type one interferon inflammatory cytokine production. We hypothesized that the peak luminescence of Donkey anti-mouse IgG Alexa-594 and for Goat anti-mouse C3-FITC in FcγRIIB-/- Yaa mice can show the disease state of SLE in murine models at which disease is most active. This thesis demonstrates that peak luminosity in FcγRIIB-/- Yaa mice is at 4.5 months of age. IHC staining was done to show the deposition of IgG and C3 protein in the glomeruli of FcγRIIB-/- Yaa at various ages. It also shows that the disease manifests between the ages of 2-4.5 months of age due to the differences in fluorescence intensity.

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Objectives: Systemic lupus erythematosus is a systemic, long-term autoimmune condition that has chronic inflammatory effects in connective tissue throughout the body. There are numerous studies that have examined the association between systemic lupus erythematosus and chronic periodontitis, with varying conclusions. The purpose of this cross-sectional study is to evaluate and compare the risk for periodontitis in patients with SLE to patients without SLE. Materials and Methods: Medical and dental records were retrospectively reviewed for patients that had been admitted to the Temple University School of Dentistry from 2010 to 2018. A roster of 22 SLE positive patients were generated from the Temple University patient database and matched to a control population of 22 patients without SLE. Periodontal probing depths were then documented and used to evaluate periodontal statuses in both test and control groups. Sites with probing depths ³5mm were considered to be at increased risk for periodontal breakdown. Prevalence was defined as the percentage of individuals having at least one site with a ³5mm probing depth, and extent was defined as the average percentage of sites with increased periodontitis risk. The number of missing teeth in patients from each group were also recorded as a secondary outcome. Results: The prevalence of ³5mm probing depths in SLE and control groups was 50% (10/20) and 40.9% (9/22), respectively. Calculations of relative risk (1.22) and odds ratio (1.44) were not statistically significant between the two populations (p>0.05). The extent of ≥5mm probing depths was 1.5% in SLE patients and 3.7% in healthy patients, which was also not significant between groups (p>0.05). SLE patients were missing an average of 9.6 teeth per individual compared to 3.8 in healthy patients (p<0.05). Conclusions: The results of the present study indicate that patients with SLE do not have an increased risk for periodontitis when compared to patients without SLE. Risk analysis on the prevalence and the extent of deeper probing depths were not statistically different between SLE and control groups. Further studies with a larger sample size and elimination of unseen confounders are needed in order to validate our results. An interesting observation was the finding that SLE patients have a significantly greater number of missing teeth. The exact mechanism through which SLE patients experience periodontal breakdown and increased tooth loss is an avenue that warrants future research. / Oral Biology

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The New Zealand Black (NZB) mouse chromosome 13 (c13) is linked to development of autoimmunity. B6 mice containing a portion of NZBc13 (B6.NZBc13 (c13)) develop a lupus phenotype that includes: autoantibody production, increased B and T cell activation, and marginal zone B cell and myeloid dendritic cell expansions. c13 mice have a B cell intrinsic dsRNA-sensing defect, leading to increased TLR3 expression and survival. The role of the aberrant dsRNA sensing in the generation of the c13 autoimmune phenotype was assessed by generating c13 mice with TLR3 knocked out (c13.TLR3KO). Marginal zone B cell expansion and B cell activation were attenuated in c13.TLR3KO mice, but other cellular phenotypes were not affected. Autoantibody production was partially reduced. These results indicate that altered dsRNA-sensing contribute to a portion of the altered cellular phenotypes in c13 mice, but that other susceptibility loci in the c13 interval are required for full development of autoimmunity.

The New Zealand Black (NZB) mouse chromosome 13 (c13) is linked to development of autoimmunity. B6 mice containing a portion of NZBc13 (B6.NZBc13 (c13)) develop a lupus phenotype that includes: autoantibody production, increased B and T cell activation, and marginal zone B cell and myeloid dendritic cell expansions. c13 mice have a B cell intrinsic dsRNA-sensing defect, leading to increased TLR3 expression and survival. The role of the aberrant dsRNA sensing in the generation of the c13 autoimmune phenotype was assessed by generating c13 mice with TLR3 knocked out (c13.TLR3KO). Marginal zone B cell expansion and B cell activation were attenuated in c13.TLR3KO mice, but other cellular phenotypes were not affected. Autoantibody production was partially reduced. These results indicate that altered dsRNA-sensing contribute to a portion of the altered cellular phenotypes in c13 mice, but that other susceptibility loci in the c13 interval are required for full development of autoimmunity.

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