Systemisk lupus erythematosus, (SLE) ingår i gruppen reumatiska sjukdomar och är en av ca 80 diagnoser inom området reumatologi. SLE är en kronisk , inflammatorisk, autoimmun sjukdom som orsakar inflammation i olika delar av kroppens organ. SLE förekommer i båda könen och alla åldrar,men sjukdomen är sju gånger vanligare bland kvinnor än hos män. Det oförutsägbara förloppet av denna kroniska sjukdom, dess symtom och eventuellt bieffekter av behandling kan betydande påverka patientens fysiska och psykiska välbefinnande. Tidigare studier har visade att patienter med diagnosen SLE hade ett behov av och efterfrågade kunskap om egenvård för att kunna nå en bättre livskvalitet. Förhoppningen var att om egenvård kommer i fokus i patientutbildningar för denna patientgrupp kan deras livskvalitet höjas. Föreliggande studie kartlägger vilken kunskap kvinnliga patienter i Uppsala län med SLE uppfattar att de hade om egenvård, samt hur mycket kunskap de uppfattade att de önskade inom egenvårdsområden. Studien omfattade följande områden; smärta, fysisk träning, kronisk trötthet och stress. Vidare berörde studien viket intresse det fanns att deltaga i patientutbildning som berör SLE och egenvård. Studien begränsade sig till kvinnliga patienter av den anledningen att det är flest kvinnor med den diagnosen. Det var 39 kvinnliga deltagare i denna studie. Deltagarna fick vis postenkäter besvara 12 frågor. Frågeformuläret var specifikt utformat för denna studie. Deltagarna ombads skatta i vilken grad de uppfattade att de hade kunskap och önskade kunskap inom olika egenvårdsområden. Resultatet av denna studie visade att patienter med SLE önskar mer kunskap än vad de redan har om områden som berör egenvård. Över hälften som deltog var intresserade av att vara med i patientutbildning.

Inflammation has been implicated in the development of cardiovascular disease and a potential underlying mechanism in the pathogenesis of impaired vascular function. Two different but complementary approaches were utilized to determine the role of inflammation on vascular function. First, to evaluate the effect of acute inflammation, we induced muscle damage to both small and large muscle mass and measured vascular function every 24 hours for up to 5 days of recovery. Eccentric exercise-induced muscle damage, in both small and large muscle mass, resulted in a transient increase in central arterial stiffness. Next, patients with systemic lupus erythematosus (SLE) were studied as a model of chronic inflammation. Measurements of vascular function were compared in habitually-exercising and sedentary SLE patients, and age-matched healthy controls. Individuals with SLE demonstrated lower vascular function than healthy controls. When SLE patients were grouped by exercise status, habitually-exercising SLE patients exhibited similar vascular function to healthy controls, and lower overall disease activity compared with sedentary SLE patients, supporting the beneficial effect of regular exercise in this population. Inflammatory biomarkers were associated with measures of macro- and microvascular function. In conclusion, acute muscle damage and chronic disease-related inflammation have a potent effect on measures of vascular function, suggesting that inflammation plays a role in the pathogenesis of vascular dysfunction and is an important biomarker for cardiovascular risk. / text

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by production of a wide range of autoantibodies, multiple organ involvement and by local formation or tissue deposition of immune complexes (ICs) in the inflamed organs. In contrast to most systemic inflammatory conditions, and despite raised levels of pro-inflammatory cytokines, SLE flares are rarely reflected by elevated C-reactive protein (CRP), an important acute-phase reactant in man with homologs in vertebrates and several invertebrates. As a part of the innate immune system, CRP binds certain molecules exposed on the surface of dying cells/apoptotic bodies and on the surface of pathogens and mediates their elimination by uptake in the reticuloendothelial system. CRP also interacts with IgG-containing immune complexes, binds Fc receptors and activates the complement system via C1q. The aims of this thesis were to investigate the complement activation properties of CRP; to elucidate if anti-CRP antibodies occur in SLE and, if so, whether anti-CRP antibody levels correlate with disease activity in SLE; to test the hypothesis that autoantibodies to pro-inflammatory cytokines prevent rise of CRP; and to survey if autoantibodies to certain nuclear antigens or to CRP correlate with cytokine-inducing properties of ICs from SLE sera. We have demonstrated that CRP bound to phosphorylcholine is a powerful activator of the classical complement pathway already in the CRP concentration range 4 to 10 mg/L, but with a marked inhibition at CRP levels above 150 mg/L. Autoantibodies to the monomeric form of CRP were found in approximately 40 percent of SLE patients and in a few sera from patients with primary Sjögren’s syndrome, but not in rheumatoid arthritis or in inflammatory bowel disease. The anti-CRP antibody levels showed significant correlations to several laboratory and clinical measurements, and anti-CRP positivity was associated with renal involvement in SLE. Native CRP levels were not correlated with anti-CRP or anti-cytokine antibody levels. Hence, the presence of antibodies to monomeric CRP or to CRP-inducing cytokines is an unlikely explanation to the relative failure of CRP response in patients with active lupus. However, antibodies to TNFα were found in subnormal levels at disease flares, whereas antibodies to TGFβ were found in supranormal levels as compared to healthy subjects. In contrast to antibodies against CRP and DNA, anti-SSA and anti-SSB antibodies may regulate the inflammatory process in SLE by enhancing IC formation and subsequent production of cytokines such as IL-6, IL-10 and IL-12p40. Hypothetically, anti-CRP autoantibodies may be of pathogenic importance, for instance by binding to monomeric CRP on cell and tissue surfaces and thereby increasing the risk of extrahepatic deposition of apoptotic material and in situ formation of ICs. / On the day of the defence data the status of article I was Submitted and the tile was "C-reactive protein activates or inhibits the classical complement pathway in a concentration dependent manner" and the status of article V was: Submitted.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Antinuclear antibodies (ANA) are used in screening and diagnosis of autoimmune connective tissue disorders including systemic lupus erythematosus (SLE). CNS related disorders are prevalent in SLE patients (–80%) and ANA binds specific sites within the brain. To investigate ANA infiltration across the blood-brain barrier (BBB), an ANA injectable Lewis rat model was created using 3 rat groups (saline, ANA, and ANA with histamine; since histamine promotes BBB permeability). ANA serum levels were tested for all three rat groups and rats injected with histamine demonstrated signs of histadelia. Brain slices were obtained and examined for the presence of ANA using immunofluorescence. ANA infiltration across the BBB was observed in ANA injected groups. Though the ANA and ANA histamine groups were significantly different from controls (p<0.034, p<0.030, respectively), no significance between ANA and ANA histamine groups was observed. This model could further be used to examine BBB permeability and potential drug therapy. / Department of Physiology and Health Science

Systemic Lupus Erythematosus (SLE) is a multi-organ autoimmune disorder that may result in death due to cardiac dysfunction. This dysfunction often occurs due to an endocarditis, known as Libman-Sacks, which presents on heart valves. The condition is hard to clinically diagnose and is often observed postmortem. Heart damage has been observed in the NP-SLE Lewis rat model positive for SLE. However, research has not been done in this model on the correlation between SLE and Libman-Sacks endocarditis. Numbers of occurrence have ranged from 3-50% in SLE patients. The presence of Libman-Sacks endocarditis should likewise occur in 3-50% of NP-SLE Lewis rats. There will be seven NP-SLE Lewis rats, five negative serum control rats, and five saline injected control rats. By performing this controlled study in rats, the correlation between SLE and Libman-Sacks will be better understood. / Department of Physiology and Health Science

Human autoimmune diseases are hallmarked by inappropriate loss-of-tolerance and self-attacking response of the immune system. Studies included in this thesis are focusing on the implication and functional impact of genetic factors in three autoimmune diseases rheumatoid arthritis (RA), asthma, and systemic lupus erythematosus (SLE). Using genetic association studies, we found in study I and II that sequence variants of the interferon regulatory factor 5 (IRF5) gene were associated with RA and asthma, and the associations were more pronounced in certain disease subtypes. Distinct association patterns or risk alleles of the IRF5 gene variants were revealed in different diseases, indicating that IRF5 contributes to disease manifestations in a dose-dependent manner. In study III, we found that seven out of eight genetic risk loci for SLE, which were originally identified in East Asian populations, also conferred disease risk with the same risk alleles and comparable magnitudes of effect sizes in Caucasians. Remarkable differences in risk allele frequencies were observed for all associated loci across ethnicities, which seems to be the major source of genetic heterogeneity for SLE. In study IV we explored an exhaustive spectrum of sequence variants in the genes inhibitor of kappa light polypeptide gene enhancer in B-cells kinase epsilon (IKBKE) and interferon induced with helicase C domain 1 (IFIH1) by gene resequencing, and identified nine variants in IKBKE and three variants in IFIH1 as genetic risk factors for SLE. One of the associated variants may influence splicing of IKBKE mRNA. In study V we provided genome-wide transcriptional regulatory profiles for IRF5 and signal transducer and activator of transcription 4 (STAT4) using chromatin immunoprecipitation-sequencing (ChIP-seq). The target genes of IRF5 and STAT4 were found to play active roles in pathways related with inflammatory response, and their expression patterns were characteristic for SLE patients. We also identified potential cooperative transcription factors for IRF5 and STAT4, and disease-associated sequence variants which may affect the regulatory function of IRF5 and STAT4. In conclusion, this thesis illuminates the contribution of several genetic risk factors to susceptibility of human autoimmune diseases, which facilitates our understanding of the genetic basis of their pathogenesis.

Thesis (M. Clin. Sc.)--University of Adelaide, 1985. / Includes bibliographical references (leaves 99-106).

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Thesis (M.Med.Sc.)--University of Hong Kong, 2004. / Also available in print.