Browsing by Subject "SLE"
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Item Open Access PAM3 supports the generation of M2-like macrophages from lupus patient monocytes and improves disease outcome in murine lupus(Elsevier, 2019) Saeb, S.; Steinmann, P.; Javili, AliIn this manuscript, we employ interface enhanced computational homogenization to explore and detail on a number of unfamiliar characteristics that composites can exhibit at different length scales. Here, the interface between the constituents is general in the sense that both displacement and traction jumps across the interface are admissible. We carry out numerous computational investigations using the finite element method for a broad range of various material parameters. Our numerical results reveal that the effective response of a microstructure embedding general interfaces is intuitively unpredictable and highly complex. In particular, for certain ranges of material parameters the overall response shows insensitivity with respect to either microstructure size or stiffness-ratio between inclusion and matrix. This unique behavior is observed likewise for two- and three-dimensional unit-cells. Our findings provide a valuable guideline to design tunable composites utilizing interfaces.Item Open Access Survey of factor V leiden and prothrombin gene mutations in systemic lupus erythematosus(Springer-Verlag, 2001) Topaloglu, R.; Akıerli, C.; Bakkaloglu, A.; Aydıntug, O.; Ozen, S.; Besbas, N.; Ozcelik, T.The two most common hereditary risk factors for thrombosis are factor V Leiden mutation and a prothrombin gene mutation. There is indeed a thrombotic tendency in patients with systemic lupus erythematosis (SLE) and it is not always associated with antiphospholipid antibodies. We aimed to determine the relationship between both factor V Leiden and prothrombin gene mutations and SLE. Using polymerase chain reaction (PCR) the factor V Leiden and prothrombin gene mutations were evaluated in 55 patients (20 children and 35 adults) with SLE. Although seven patients were found to have factor V Leiden mutation in the heterozygous state, two had the heterozygous G→A (20210) prothrombin gene mutation. Although one had these two mutations concurrently, these two patients did not have thrombosis. The factor V Leiden mutation frequency (12.7%) was higher than that of our general population (7.1%). On the other hand, seven of the patients with SLE had a thrombotic event. Although of these seven, four (57%) had factor V Leiden mutation, three (43%) had no mutation. Of 48 patients with no thrombotic history, only three had the factor V mutation (6.25%). The prevalence of the factor V Leiden mutation in SLE patients with and without thrombosis was significantly different by Fisher’s exact test (p<0.05). The risk of venous thrombosis in patients with factor V Leiden increased threefold compared to that in those without factor V Leiden mutation (odds ratio 20.1; CI 2.99–133.6). Although factor V Leiden mutation seems to play a role in the development of venous thrombosis in SLE, the development of thrombosis in SLE is multifactorial.Item Open Access TLR agonists on autoimmunity, cancer and M1/M2 macrophage polarization(2019-07) Horuluoğlu, Begüm HanMacrophages play an important role in the initiation of immune responses and the maintenance of immune homeostasis. Alterations in their phenotype, function and activation state have been implicated in the pathogenesis of autoimmune and inflammatory diseases. An increased M1:M2 ratio is associated with the development of several autoimmune diseases including Systematic Lupus Erythematosus (SLE), vasculitis and myositis. Previous work showed that the TLR2/1 agonist PAM3CSK4 (PAM3) could stimulate normal human monocytes to preferentially differentiate into immunosuppressive M2-like rather than inflammatory M1-like macrophages. This work seeks to investigate the ability of PAM3 to induce M2 macrophage differentiation from patient monocytes and evaluate the therapeutic efficacy of PAM3 in a murine model of lupus. Our findings revealed that patients with indicated autoimmune diseases have a significant increase in monocytes of the inflammatory subtypes coupled with a decrease in non-inflammatory classical monocytes compared to healthy controls. Additionally, in the absence of stimulant patient monocytes differentiated into more M1-like macrophages. Nevertheless, phenotypic analysis of in vitro generated macrophages revealed that, PAM3 stimulation induced M2-like macrophage differentiation without any difference from patient and healthy monocytes. Phenotypic analysis was further supported by the high endocytic abilities and secretion of anti-inflammatory cytokines instead of pro-inflammatory cytokines by PAM3 generated macrophages. Lupus-prone NZB x NZW F1 mice responded similarly to weekly PAM3 treatment. Upon PAM3 treatment the increased M1:M2 ratio, which was observed in PBS treated group, was decreased to normal levels. The increase in M2 macrophages was accompanied by decreased autoantibody and inflammatory cytokines along with an increase in anti-inflammatory cytokine production. Moreover, kidney damage was significantly suppressed and M2 macrophages were detected in the kidneys of PAM3 treated group. PAM3 treatment prolonged to survival of NZB/W significantly, at 45 weeks of age %60 of mice were still alive whereas in PBS group only %5 were. Our results indicate that, PAM3 induces immunosuppressive macrophages and thus could represent a novel approach to the therapy of autoimmune diseases. The second part of this thesis focused on enhancing the immunomodulatory effects of TLR9 ligands, CpG ODN upon encapsulation within liposomes as cancer vaccine adjuvants. Although both D and K ODN are strictly dependent on TLR9, K ODN trigger pDCs to mature and secrete TNFα while D ODN stimulate pDC to produce IFNα. When cells are incubated with a mixture of K and D ODN, K masks the activity of D. The use of both K and D ODN would be of benefit when preparing vaccine adjuvants and for immunotherapy. Our data indicate that simultaneous delivery of D ODN loaded into neutral liposomes plus K ODN loaded into cationic liposomes improved rather than masked IFNα production while continuing to support TNFα by PBMCs. Liposomal encapsulation did not alter the subcellular localization of either class of ODN, but internalization studies revealed that cationic liposome encapsulation slows and reduces the uptake of K ODN whereas neutral encapsulation of D increases their uptake by pDCs. The efficiency of K plus D liposome combinations was examined in a murine tumor vaccine model. The liposome combinations induced pronounced Th1-biased anti-OVA immunity and led to a significant reduction of B16-OVA tumors following inoculation. Our findings, demonstrate that the beneficial features of D and K ODN could be obtained simultaneously by appropriate liposomal formulation, further extending the breadth of CpG ODN-dependent immunotherapy.