京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第20056号 / 医科博第74号 / 新制||医科||5(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 浅野 雅秀, 教授 岩井 一宏, 教授 生田 宏一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24476号 / 医博第4918号 / 新制||医||1062(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 小濱 和貴, 教授 川口 義弥 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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The pathogenesis of lupus and other autoimmune diseases driven by antibody-antigen complexes involves interactions between genetic and environmental factors. The genetic factors can be separated into factors that dysregulate adaptive immunity, innate immunity or cell death. One genetic risk factor that can affect both innate and adaptive immunity is the inhibitory Fcγ receptor, FcγRIIB. Reduced or loss of function mutations in FcγRIIB lead to an increased risk of autoimmunity. Using the murine IgG2a specific B cell receptor (BCR) transgenic (Tg) mouse, AM14, our lab discovered that delivery of nucleic acid ligands via the BCR activates B cells by dual engagement of the BCR and endosomal toll like receptors (TLR) 7 and/or 9. Mechanistic studies interrogating the role of downstream signaling effectors and intracellular trafficking in the attenuation of BCR-TLR responses by FcγRIIB were limited by our inability to deliver immune complexes (IC) to non-Tg B cells or form brightly fluorescent IC. To deliver IC to non-Tg B cells, I developed a BCR adapter (BCRAM) that delivers IC to IgM-positive B cells. To track the uptake and trafficking of IC, I developed a panel of antibodies specific for streptavidin (SA). Complexes formed with biotinylated molecules and fluorescent streptavidin could be delivered to AM14 B cells or macrophages and tracked via flow cytometry and/or confocal microscopy. BCRAM and fluorescent IC were used to understand how FcγRIIB attenuated BCR-TLR responses. I found that both DNA IC and RNA IC responses were enhanced by FcγRIIB ablation. Interestingly, a naturally-occurring somatic mutation in the Fc domain of the nucleic acid-binding antibody PL2-3 prevented regulation by FcγRIIB and reduced binding to activating FcγR. Paradoxically, I found that SHIP-1, a negative regulator activated downstream of FcγRIIB engagement, promoted BCR-TLR9 responses independent of FcγRIIB. I hypothesized that FcγRIIB attenuates BCR-TLR9 responses by interfering with sensing by the endosomal TLRs. Using a pH sensing IC, I found that engagement of FcγRIIB leads to residence of the IC in a higher pH compartment. These findings demonstrate that FcγRIIB regulates the activation of autoreactive B cells by modulating the trafficking of nucleic acid containing IC to TLR7 and TLR9 associated intracellular compartments in B cells.

Systemisk lupus erythematosus (SLE) är en kronisk autoimmun sjukdom där immunförsvaret angriper kroppens egen vävnad och förorsakar inflammation. Den drabbar främst kvinnor i fertil ålder och antalet nya fall av SLE är 2–8 per 100 000 invånare årligen i Sverige. Sjukdomens orsak är okänd men tros bero på ett samspel mellan genetiska faktorer, miljöfaktorer och hormonpåverkan. Ökad risk för hjärtinfarkt och stroke syns hos SLE patienter. Markörer som är förknippade med SLE och kardiovaskulär sjukdom och presenterades i detta arbete är IFN-α2a, vaskulär celladhesionsmolekylen (VCAM-1) och S100A8/A9. Sjukdomen kännetecknas av bildandet av stora mängder autoantikroppar mot proteiner med nukleärt ursprung och dubbelsträngat DNA. Anti-fosfolipidantikroppar (aPL) är autoantikroppar som binder till strukturer på fosfolipider eller till komplex av proteiner och fosfolipider. Antikroppar mot kardiolipin (aCL) och mot β2-glykoprotein (aβ2GP1) är exempel på aPL och förekommer hos 20–30 % av SLE patienterna. En ytterligare aPL är anti-fosfatidylserin/protrombin (aPS/PT). aPL förknippas med högre risk för kardiovaskulär sjukdom. Syftet med arbetet var att mäta koncentrationen av IFN-α2a, VCAM-1, S100A8/A9 och aPL, och därefter analysera hur de förhåller sig till varandra samt förekomst av kardiovaskulär sjukdom. Koncentrationer av nämnda markörer och aPL mättes med olika immunoassays i 199 prover som tagits vid olika tidpunkter från 66 patienter, och korrelation analyserades med icke-parametriska metoder. Resultatet visar förväntade signifikanta korrelationer mellan sjukdomsaktivitet och IFN-α2a, VCAM-1 samt S100A8/A9. Alla undersökta aPL korrelerade med varandra. IgG antikroppar korrelerade bättre än IgM med IFN-α2a, VCAM-1, S100A8/A9 och sjukdomsaktiviteten. IFN-α2a hade en signifikant korrelation med VCAM-1, aCL-IgG och aPS/PT-IgG. VCAM-1 korrelerade däremot med IFN-α2a, aCL-IgG, aβ2GP1-IgG och aPS/PT-IgG. Ingen association mellan kardiovaskulär sjukdom och de undersökta markörerna samt aPL i patienternas första prov kunde påvisas. / Systemic lupus erythematosus (SLE) is a chronical autoimmune disease in which the body’s immune system attacks healthy tissue and causes inflammation. The disease affects mainly women of childbearing age with 2 to 8 new cases per 100 000 inhabitants yearly in Sweden. One main feature of SLE is the expression of autoantibodies specific to autoantigens with nuclear origin. The cause of SLE is unknown but it is thought to involve a combination of genetic factors, environmental factors, and hormonal influence. Risk of myocardial infarction and stroke is increased in SLE. Markers that are associated with SLE and cardiovascular disease and got presented in this paper are IFN-α2a, Vascular cell adhesion molecule-1 (VCAM-1) and the complex S100A8/A9. Antiphospholipid antibodies (aPLs) are a type of antibodies which binds to structures on phospholipids or to complex of proteins and phospholipids. Antibodies against cardiolipin (aCL) and β2-glycoprotein (aβ2GP1) are two aPLs which can be found in 20-30 % of SLE patients. Another example of aPLs is antiphosphatidylserine/prothrombin (aPS/PT). aPLs are associated with higher risk for CVD. The aim of this study was to study mentioned markers and aPLs to acquire better understanding of how they relate to each other and to CVD. The concentrations of these markers and aPLs were measured in 199 different samples which were taken from 66 patients and correlations were analyzed with non-parametric statistical methods. Results have shown as expected significant correlations for the biomarkers IFN-α2a, VCAM-1 and S100A8/A9 with disease activity. All aPLs have shown strong correlation to each other. IgG correlated better than IgM with the different biomarkers and disease activity. IFN-α2a had strong correlation to VCAM-1, aCL-IgG, and aPS/PT-IgG. VCAM-1 on the other hand had significant correlation to IFN-α2a, aCL-IgG, aβ2GP1-IgG and aPS/PT-IgG. No association could be found in this study between CVD and the studied markers, and aPLs in the first sample of each patient.

Inflammatory diseases such as PCOS, autoimmune diseases, irritable bowel syndrome, etc. are all highly uncomfortable diseases with several negative side effects. By adding antioxidants and omega-3 fatty acids to patients with inflammatory diseases diets, studies show that symptoms of these diseases will lessen. The objective of this study is to create a banana bread with increased omega-3 fatty acids and increased antioxidants to be served on trays of patients with inflammatory diseases and for patients to make at home to decrease symptoms related to inflammation. The experimental food should be an equal substitute for the control flavor, aroma, and texture wise. The control banana bread was substituted for an anti-inflammatory banana bread with the addition of cinnamon, dark chocolate, extra eggs, and pecans. The banana bread was made without dairy and grain for celiac patients and lactose intolerant patients. Both variations were equally accepted according to the hedonic scale, completed by 9 participants. Research was continued to confirm the of increased omega-3 fatty acids within the anti-inflammatory bread. Furthermore, walnuts were switched for pecans to test the antioxidant and fatty acid composition of both variations. Overall, we found that the walnut variation had more fatty acids, but pecans had more antioxidants. Our research suggests that both variations can be used to accommodate patients with inflammatory diseases. Further research can be done for long-term research for inflammatory disease patients that swapped the control for the variations.

Bakgrund: Systemisk lupus erythematosus (SLE) är en autoimmun reumatisk sjukdom med en varierande symtombild till följd av att flera olika organ kan drabbas. Det är en sjukdom som går i skov och sjukdomens påverkan skiljer sig över tid samt på individnivå. Syfte: Syftet med litteraturstudien var att beskriva personers upplevelse av att leva med SLE. Metod: Tretton kvalitativa vetenskapliga artiklar analyserades med en kvalitativ innehållsanalys med manifest ansats. Resultat: Analysen resulterade i fyra kategorier; att förstå och hantera symtom, att vilja bevara och skapa relationer, att känna brist på stöd och förståelse, att anpassa tillvaron och acceptera ett annorlunda liv. Slutsats: Kunskap och fördjupad förståelse för upplevelsen av att leva med SLE är viktigt för att möjliggöra att hälso-och sjukvårdspersonal kan ge personcentrerad vård och omvårdnad som bygger på stöd och förståelse. Fortsatt omvårdnadsforskning kan bidra till att utveckla relevanta omvårdnadsinterventioner som stöd för personer som lever med SLE.

Systemic sclerosis (SSc) is a complex autoimmune connective tissue disorder. SSc presents with severe pathological clinical manifestations, including vasculature abnormalities, dysregulation of the immune system, and excessive extracellular matrix deposition that results in tissue fibrosis. How immune system abnormalities impact SSc remains poorly understood. Here we sought to explore the role of co-inhibitory receptors (co-IRs), which are important regulators of autoimmune responses. Previous studies showed altered co-IR expression in various autoimmune diseases, including SSc. Here we show that T cells co-expressing the co-IRs programmed cell death protein 1 (PD-1) and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) are expanded in lung tissue obtained from SSc patients, as compared to healthy controls (HC). Furthermore, we found a significant association between the frequency of PD-1+TIGIT+ CD4+ T cells and lung disease in SSc patients. In addition, PD-1+TIGIT- and PD-1+TIGIT+ CD4+ cells in SSc patients showed an altered balance in cytokine production, characterized by reduced secretion of Interferon-γ, a cytokine with known anti-fibrotic properties, and increased levels of Interleukin-4, which is known for its pro-fibrotic activities. To test the impact of this changed cytokine balance on fibroblast biology, we co-cultured PD-1+TIGIT- and PD-1+TIGIT+ CD4+ T cells with normal dermal fibroblasts and found that PD-1+TIGIT- and PD-1+TIGIT+ T cells from SSc patients showed a reduced capacity to suppress collagen production, compared to the same subsets from HC subjects. Thus, co-IR-expressing T cells from SSc patients show features of dysfunction and may have lost anti-fibrotic activities. To further define the phenotype and functions of co-IR-expressing T cells subsets in SSc patients, we next designed a comprehensive immunophenotyping panel for full spectrum flow cytometry (FSFC) that included detection of lineage-defining transcription factors. Using this novel panel and an unbiased analysis approach, we compared T cell subset composition in peripheral blood mononuclear cells from HC subjects, and SSc and systemic lupus erythematosus (SLE) patients. Our analysis revealed broad shifts such as a decrease in the naïve CD4+ and CD8+ T cell compartment in SSc and in SLE patients. Importantly, changes in specific T cell subsets that were discovered in SLE patients, but not SSc patients, had a broad increase in T helper (Th)1 and T cytotoxic (Tc)1 subsets and a decrease in Th2/Tc2 subsets compared to HC subjects. Interestingly, we found a distinct Tc1 subset with exhaustion characteristics that was significantly reduced in both SSc and SLE patients compared to HC subjects. In the γδ T cell population, we found that while T-bet+ Vδ2 cells were decreased in SSc and SLE patients, the T-bet+ Vδ1 subset showed proliferative characteristics and was increased in SLE. Importantly, our analysis revealed differences in specific T cell subsets between SSc patients treated with immunosuppressants vs untreated patients, including an increase in Th17 cells in diffuse cutaneous SSc (dcSSc) patients that were not treated with immunosuppressants, and an increase in memory regulatory T cells in both dcSSc and limited cutaneous SSc (lcSSc) patients that were not treated with immunosuppressants. Our study demonstrates the value of a multiparameter FSFC panel in the identification of differentially represented and novel subsets of T cells in SSc and other autoimmune diseases. We demonstrated that T cell subset composition is altered in the peripheral blood of SSc patients and show that features of specific T cell subsets’ dysfunction are potentially contributing to SSc pathophysiology.