| 1. |
- Fiskesund, Roland
(författare)
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Anti-phosphorylcholine antibodies in cardiovascular disease
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the industrialized countries and a growing concern for the developing world. The underlying cause of almost all CVD is atherosclerosis, a process that is characterized by a low-grade inflammation in the artery walls. This inflammation is believed to be initiated by components of low density lipoproteins which, upon oxidation, display pro-inflammatory self-neo epitopes such as malonyldialdehyde (MDA) and phosphorylcholine (PC). Antibodies directed against the PC-epitope (anti-PC) have been researched for several decades but the relatively recent realization that these antibodies also recognize oxidized phospholipids has revolutionized the field and opened up a whole new avenue of investigation. Anti-PC has been shown to aid the clearance of apoptotic cells and prevent the formation of foam cells by clearing oxidized low density lipoprotein. Murine studies with PC-vaccination have shown strong beneficial effects on experimental atherosclerosis in vivo and human epidemiology has consistently linked anti-PC insufficiency to CVD. All humans have detectable anti-PC IgM in serum, though the concentration varies greatly between individuals. Our group has previously shown that people with low serum/plasma levels of anti-PC IgM have increased risk of CVD and the subgroup analysis had indicated that this association was particular strong with regard to the incidence of stroke. In paper I, we tested this hypothesis in a stroke material from northern Sweden. A significant association between low plasma level of anti-PC IgM at baseline and incident stroke was seen for the whole group at anti-PC levels below the 30th percentile (OR 1.62; CI 1.11 to 2.35). Analyses of gender-specific associations indicated fairly strong associations for females, especially at the lowest 30th percentile (OR 2.65; CI 1.41 to 4.95). However, no association was noted for men. Paper II focused on the properties of different anti-PC antibody classes/subclasses. We report that anti-PC IgM, IgA and IgG1 (but not IgG2) were negatively associated with IMT-progression, which is a surrogate marker for atherosclerosis development. Examination of binding profiles revealed that the protective isotypes (IgM, IgA and IgG1) have a different fine-specificity than the non-protective IgG2. Analysis of serum samples taken four years apart in study participants showed that anti-PC IgM titers, essentially, do not change over time. In this paper, we also demonstrate that anti-PC IgM inhibits LPC-induced cell death in vitro and propose that this is yet another protective mechanism. For paper III, I had successfully designed a PC-specific probe to identify, isolate and characterize PC-reactive B cells from ten healthy human donors. We found that all ten had mounted somatically mutated antibodies towards PC utilizing a broad variety of immunoglobulin-genes. PC-reactive B cells were primarily found in the IgM+ memory subset though significant numbers were also detected among naïve, IgG+ and CD27+CD43+ B cells. From the isolated B cells, we derived several human monoclonal antibodies (mAbs) with proven PC specificity. In conclusion, the future of CVD treatment lies with immunomodulation and the premise of this thesis represents one avenue of research in the quest for novel diagnostic tools and improved treatment options. My work has focused on understanding the properties and molecular ontogeny of human anti-PC antibodies. Though this thesis represents one important step in the direction of clinical application, much more research is needed before we will see use of anti-PC mAbs or PC-vaccination in the treatment of patients.
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| 2. |
- Fiskesund, Roland, et al.
(författare)
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Low levels of antibodies against phosphorylcholine predict development of stroke in a population-based study from northern Sweden
- 2010
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 41:4, s. 607-612
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Natural immunoglobulin M antibodies specific for phosphorylcholine (anti-PC) have been implicated in atherosclerosis. We have shown previously that high levels of anti-PC predict a slower progression of atherosclerosis in humans and that low levels of anti-PC are associated with higher risk for cardiovascular disease. Here we determine the association between anti-PC and the incidence of stroke. METHODS: Using a nested case control study design, we examined 227 incident cases (125 men and 102 women) of first-time stroke and 455 age- and sex-matched controls identified during a 13-year time period (1985 to 1999) within the population-based cohorts of the Västerbotten Intervention Project (VIP) and the World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease (WHO MONICA) project in Northern Sweden. Odds ratios of stroke with 95% CIs with adjustments for age, gender, smoking, serum cholesterol, diabetes, body mass index, and blood pressure were determined. Anti-PC levels were measured using ELISA. RESULTS: A significant association between low levels of anti-PC at baseline and incident stroke was seen for the whole group of anti-PC levels below the 30th percentile (multivariately adjusted odds ratio, 1.62; CI, 1.11 to 2.35). Analyses of gender-specific associations indicated fairly strong associations for females, especially at the lowest 30th percentile (multivariately adjusted odds ratio, 2.65; CI, 1.41 to 4.95). No associations were noted for men. CONCLUSION: Low anti-PC is a novel independent risk marker for development of stroke. Measurements of anti-PC could be used to identify immunodeficient subjects at an increased risk for stroke. The possibility that such subjects might be targets for novel modes of treatment such as immunotherapies deserves further investigation.
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| 3. |
- Karsten, Stella, et al.
(författare)
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MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells
- 2021
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Ingår i: Cell Death & Differentiation. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1350-9047 .- 1476-5403.
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Tidskriftsartikel (refereegranskat)abstract
- T cell-driven diseases account for considerable morbidity and disability globally and there is an urgent need for new targeted therapies. Both cancer cells and activated T cells have an altered redox balance, and up-regulate the DNA repair protein MTH1 that sanitizes the oxidized nucleotide pool to avoid DNA damage and cell death. Herein we suggest that the up-regulation of MTH1 in activated T cells correlates with their redox status, but occurs before the ROS levels increase, challenging the established conception of MTH1 increasing as a direct response to an increased ROS status. We also propose a heterogeneity in MTH1 levels among activated T cells, where a smaller subset of activated T cells does not upregulate MTH1 despite activation and proliferation. The study suggests that the vast majority of activated T cells have high MTH1 levels and are sensitive to the MTH1 inhibitor TH1579 (Karonudib) via induction of DNA damage and cell cycle arrest. TH1579 further drives the surviving cells to the MTH1[superscript low] phenotype with altered redox status. TH1579 does not affect resting T cells, as opposed to the established immunosuppressor Azathioprine, and no sensitivity among other major immune cell types regarding their function can be observed. Finally, we demonstrate a therapeutic effect in a murine model of experimental autoimmune encephalomyelitis. In conclusion, we show proof of concept of the existence of MTH1[superscript high] and MTH1[superscript low] activated T cells, and that MTH1 inhibition by TH1579 selectively suppresses pro-inflammatory activated T cells. Thus, MTH1 inhibition by TH1579 may serve as a novel treatment option against autoreactive T cells in autoimmune diseases, such as multiple sclerosis.
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