The Association of Cancer Development in Patients with Systemic Lupus Erythematosus by Rose Michelle Coley MPH, Walden University, 2011 BS, University of Mount Olive, 2008 Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Public Health Walden University March 2016 Both cancer and autoimmune diseases have been associated with numerous factors that may independently lead to the development of either disease. When these factors overlap the difficulty in assessing association is compounded. The numerous factors that are thought to cause systemic lupus erythematosus (SLE), which leads to the development of cancer, makes the study of an association between the 2 diseases challenging. The purpose of this study was to examine whether the risk of cancer development increased in SLE patients compared to the risk in non-SLE patients. Researchers have not shown consistent relationships of cancer development in patients with SLE; however, consideration of the various factors that contribute to the diseases is necessary to measure an association between the 2 diseases. This study used the Clinical Practice Research database (CPRD), a large, population-based database to test the relationship between SLE and cancer. A matched retrospective cohort study among SLE (n=3025) and non-SLE (n=180555) patients was conducted using the propensity score methodology to help balance the differences between the comparison groups. The propensity score methodology created a similar distribution of observed baseline covariates between the 2 groups. With adjustment for age, the predictor variable of SLE indicates that a patient with SLE is still 2.7 times more likely to develop cancer than is a non-SLE patient. The study outcomes could promote positive social change by reinforcing current recommendations for cancer screenings in persons with SLE, which could enhance the ability to detect cancer early enough to decrease mortality because of cancer in persons with SLE.

Abstract not available

Multiple checkpoints control the survival and activation of auto-reactive B cells. The discovery of the TNF family cytokine BAFF has been crucial to understanding peripheral B cell tolerance mechanisms. Homeostatic levels of BAFF are tightly regulated to maintain tolerance in the periphery. Chronically increased levels of BAFF lead to the survival of autoreactive B cells. Autoimmune patients display elevated serum BAFF levels. BAFF Tg mice model this situation with systemically high levels of BAFF and the subsequent development of two separate but related autoimmune syndromes; systemic lupus erythematosus (SLE) and Sj??gren???s syndrome (SS). The work conducted in this thesis further investigates the defects in tolerance down-stream of self-reactive B cell survival, which may contribute to autoimmune disease development in BAFF Tg mice. Expansion of the Marginal zone (MZ) B cell population correlates with the pathogenesis of several models of autoimmune disease. BAFF Tg mice are unique in that they not only display an increased splenic MZ B cell population, but also MZ B cells are found in the salivary glands of mice developing SS. The examination of genes differentially regulated between MZ and Follicular (Fo) B cells led to the investigation of sphingosine-1-phosphate receptor biology. The expression of S1P receptors was shown to be required for the positioning of MZ B cells in the spleen. Chronic BAFF stimulation alters the retention of MZ B cells through the alteration of S1P receptors and decreased integrin activation. The alteration of S1P receptors and increased ligand sensitivity leads to the accumulation of MZ B cells in the inflamed salivary glands of BAFF Tg mice. This works provides a potential mechanism for the tissue specificity seen in systemic autoimmune disease. The provision of T cell help to auto-reactive B cells is thought to underlie the development of SLE. BAFF Tg mice deficient in T cells surprisingly developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did however require signals through the toll-like receptor (TLR)-associated signalling adaptor, MyD88, which controlled the production of pathogenic autoantibodies. Therefore, autoimmunity in BAFF Tg mice results from altered B cell tolerance, which requires TLR signalling and is independent of T cell help. It is likely that autoimmune patients with elevated levels of BAFF show a similar basis for disease.

<p>Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune diseases affecting 0.05-2% of the population worldwide. </p><p>Genetic studies detected linkage with SLE in the 2q37 region, and intensive family-based and case-control association studies in several populations identified that allele A of the SNP PD-1.3 located in the immunoreceptor PDCD1 (PD-1) gene, increases risk of the disease by 2.6-fold in Caucasians (p<0.00001) and by 3.5-fold in Mexicans (p=0.0009). </p><p>The same allele was found to be a risk factor for lupus nephritis, a severe clinical manifestation of SLE. In Swedish and European-American females with SLE, patients with the allele A had nephritis 1.8 times (p=0.01) more often than patients with allele G .</p><p>Moreover, the allele A was also found 1.8 times (p=0.005) more often in RA patients, negative for the known risk-factors, rheumatoid factor and the shared epitope, than in other groups of patients and controls. </p><p>Functional studies demonstrated that the mechanism behind the SNP PD-1.3 is related to the disruption of the binding site for RUNX transcription factors in the regulatory region. Expression of the PD-1 and RUNX genes was altered in the activated T cells of SLE patients compared to controls.</p><p>The Tumor Necrosis Factor Receptor 2 (TNFR 2) gene was studied as a second candidate gene for both SLE and RA. The results of our studies in SLE and RA patients and controls from Sweden and Mexico do not support the association of the polymorphism TNFR 2 M196R with these diseases. Other polymorphisms in this gene and other genes in this region should therefore be studied.</p>

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune diseases affecting 0.05-2% of the population worldwide. Genetic studies detected linkage with SLE in the 2q37 region, and intensive family-based and case-control association studies in several populations identified that allele A of the SNP PD-1.3 located in the immunoreceptor PDCD1 (PD-1) gene, increases risk of the disease by 2.6-fold in Caucasians (p&lt;0.00001) and by 3.5-fold in Mexicans (p=0.0009). The same allele was found to be a risk factor for lupus nephritis, a severe clinical manifestation of SLE. In Swedish and European-American females with SLE, patients with the allele A had nephritis 1.8 times (p=0.01) more often than patients with allele G . Moreover, the allele A was also found 1.8 times (p=0.005) more often in RA patients, negative for the known risk-factors, rheumatoid factor and the shared epitope, than in other groups of patients and controls. Functional studies demonstrated that the mechanism behind the SNP PD-1.3 is related to the disruption of the binding site for RUNX transcription factors in the regulatory region. Expression of the PD-1 and RUNX genes was altered in the activated T cells of SLE patients compared to controls. The Tumor Necrosis Factor Receptor 2 (TNFR 2) gene was studied as a second candidate gene for both SLE and RA. The results of our studies in SLE and RA patients and controls from Sweden and Mexico do not support the association of the polymorphism TNFR 2 M196R with these diseases. Other polymorphisms in this gene and other genes in this region should therefore be studied.

Autoimmune diseases occur in up to 3-5% of the general population and represent a diverse collection of diseases with regards to clinical manifestations. The unifying factor of autoimmune diseases is tissue and organ damage as a result of an immune response mounted against self-antigens. Systemic lupus erythematosus (SLE) is considered a prototype of human systemic autoimmune diseases. The etiology of SLE is as yet largely unknown, but both epidemiological and genetic data suggest an interplay between numerous and varying genetic and environmental factors. There is compelling evidence for a strong genetic component in SLE. The disease has a high λsibs value and familial clustering is apparent. Multiple susceptibility loci have been identified, some of which are syntenic between humans and mice and some of which overlap with other autoimmune diseases.   This thesis is based on analysis of Icelandic multicase SLE families and Swedish SLE patients. Paper I is a study of the association of C4A protein deficiency (C4AQ0) with SLE in the multicase families and shows a significantly increased frequency of C4AQ0 in the families. The genetic basis for C4AQ0 varies and C4AQ0 is found on different MHC haplotypes, pointing to C4AQ0 as an independent risk factor for SLE. Paper II describes the association of low MBL serum levels with SLE in the families and identifies low MBL as risk factor for SLE in families that carry the defect. Low MBL was furthermore found to mediate an additive risk when found in combination with C4AQ0. In paper III cellular expression the PD-1 co-inhibitory receptor on T cells was studied. A polymorphism in the PDCD1 gene, PD-1.3A was previously associated with SLE in the multicase families. The polymorphism is thought to disrupt expression of the gene and may lead to decreased expression of the PD-1 receptor. The study demonstrates lower PD-1 expression in SLE patients and relatives in correlation to the PD-1.3A genotype. Paper IV is a compiled analysis of the SLE families, including PD-1.3A, C4AQ0, low MBL, autoimmune diseases and autoantibody profiles. The study demonstrates clustering of different autoimmune diseases and autoantibodies in families that are heterogenic with regards to the genetic susceptibility factors, PD-1.3A, C4AQ0 and low MBL.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Medicine / Master / Doctor of Medicine

Η παρούσα διατριβή είχε ως στόχο τη μελέτη των Th1 και Th2 τύπου κυτταροκινών σε αυτοάνοσες νόσους και τη διερεύνηση του τρόπου με τον οποίο η έκφρασή τους επηρεάζεται από παράγοντες όπως πεπτιδικά ανάλογα της βασικής πρωτείνης της μυελίνης και ανοσοτροποποιητικοί παράγοντες όπως το μόριο της λεπτίνης. Η μελέτη αυτών των παραγόντων εστιάστηκε στη νόσο της Σκλήρυνσης Κατά Πλάκας, επειδή πρόκειται για οργανοειδικό CD4+ Τ κυτταρομεσολαβούμενο αυτοάνοσο νόσημα με χαρακτηριστικό Th1 κυτταροκινικό προφίλ. Αυτά τα χαρακτηριστικά, σε συνδυασμό με το γεγονός ότι διαθέτει το καλύτερα μελετημένο αντίστοιχο ζωικό μοντέλο, την Επαγόμενη Αλλεργική Εγκεφαλομυελίτιδα, καθιστούν τη νόσο αυτή ένα ιδανικό πειραματικό σύστημα για την επίτευξη του στόχου της παρούσας εργασίας. / -

Although the etiology surrounding many autoimmune diseases remains unknown, the underlying characteristic of many of these diseases is a disruption in the balance of pro- and anti- inflammatory cytokines It is well established that the dysregulation of the IL-12 family of cytokines, an increase in IL-12/IL-23 and a decrease in IL-27 production has been implicated in these conditions. We used ELISA, RT-PCR, Immunofluorescence and Western immunoblotting in conjunction with pharmalogical inhibitors and siRNA to demonstrate the role of SHP-1/Src in the regulation of IL-12, IL-23, IL-27 and IL-10 in LPS-stimulated human THP-1 cells, monocytes and MDMs. My results show for the first time that Src kinase activity relies on SHP-1 activity, and together this complex functions in TLR4-mediated MyD88 and TRIF pathways. Furthermore Src exhibits a dual role as a positive regulator for anti-inflammatory IL-10/IL-27 and as a negative regulator of pro-inflammatory IL-12/IL-23 downstream of TLR4. Moreover, the involvement of PI3K and JNK MAPK, dependent on SHP-1/Src complex, in the regulation of IL-12 family and IL-10 downstream of TLR4 was shown.