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| 2. |
- Carlsson, Emma
(författare)
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The importance of psychological and physical stressors on diabetes-related immunity in a young population – an interdisciplinary approach
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The prevalence of immunological disorders such as type 1 diabetes (T1D) is increasingly common amongst children, adolescents and young adults. There is also an increase in psychosomatic symptoms (depression, insomnia, anxiety, headaches and fatigue etc.) as well as a decrease in physical activity amongst young people, affecting the well-being and overall health of our younger population. It is therefore important to study the effects of psychological and physical stressors on the immune system, to evaluate their impact on juvenile health.Aim: This thesis explores the impact of psychological and physical stressors on the cellular immune system with special focus on diabetes-related immunity in a young population, using an interdisciplinary approach.Method: When exploring the impact of psychological and physical stressors such as psychological stress due to exposure to psychological stressful experiences or degree of physical activity/training on the cellular immune system in children, adolescents and young women, peripheral blood mononuclear cells (PBMC) were stimulated with antigens (tetanus toxoid (TT) and β-lactoglobulin (βLG)) as well as diabetes-related autoantigens (insulin, heat shock protein 60 (HSP60), tyrosine phosphatase-2 (IA-2) and glutamic acid decarboxylase 65 (GAD65)) and secreted cytokines and chemokines were measured by multiplex fluorochrome technique (Luminex). Populations of Thelper (Th) cells (CD4+), T-cytotoxic (Tc) cells (CD8+), B cells (CD19+), Natural Killer (NK) cells (CD56+CD16+) as well as regulatory T (Treg) cells (CD4+CD25+FoxP3+CD127-), and their expression of CD39 and CD45RA were studied by flow cytometry. Diabetes-related parameters (glucose, C-peptide,proinsulin, pancreatic polypeptide and peptide YY) were measured to studyβ-cell activity and appetite regulation and cortisol was used as a biological marker for psychological and physical stress.Results: Children in families exposed to psychological stress showed an imbalanced cellular immune response as well as an increased immune response towards diabetes-related autoantigens. Also, previous exposure to psychological stress as well as current exposure to psychological stress in young women showed an increased immune response towards diabetes-related autoantigens. Further, previous exposure to psychological stress in young women showed increased numbers of circulating CD56+CD16+ NK cells as wellas decreased numbers of circulating CD4+CD25+FoxP3+CD127- Treg cells. High physical activity in children showed decreased spontaneous immune response as well as a decreased immune response towards diabetes-related autoantigens, while low physical activity in children showed an increased immune response towards diabetes-related autoantigens. Further, endurance training in adolescents, especially in adolescent males and young adolescents, showed an increased immune response towards the diabetes-related autoantigen IA-2.Conclusion: It is evident that psychological and physical stressors such as exposure to psychological stress and degree of physical activity/training impact the cellular immune system. Experiences associated with psychological stress seem to have a negative effect on the cellular immune system in a young population, causing an imbalance in the immune system that could possibly induce diabetes-related immunity. High physical activity in children seems to have a protective effect against diabetes-related immunity. In contrast, low physical activity in children and endurance training in adolescents seems to induce diabetes-related immunity. It is very likely that psychological stressful experiences, low physical activity and intense training such as endurance training all play important roles in the immunological process leading to the development of type 1 diabetes.
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| 3. |
- Hjorth, Maria, 1978-
(författare)
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Immunological profile and aspects of immunotherapy in type 1 diabetes
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D) is a chronic, autoimmune disease caused by a T cell mediated attack on the insulin producing pancreatic ß-cells. Even though reasonable quality of life can be acquired with modern insulin therapy, prevention of acute and late serious complications is facilitated by preservation of residual insulin secretion. Preventing β-cell destruction is therefore an important goal of T1D therapy. Characterisation of immunological changes in the course of T1D is essential for understanding the underlying pathogenic mechanisms and for evaluating the efficacy of therapeutic intervention. This thesis aimed to study the immune profile in individuals at increased risk of T1D and in patients diagnosed with the disease. In addition, the immunological effects of treatment with the B vitamin, Nicotinamide, and by antigen-specific immunotherapy using GAD65, have been studied in high-risk individuals and in T1D patients, respectively.We have found that individuals at high risk of T1D had an increased T helper (Th) 1 like immune profile, defined by high secretion of interferon (IFN) -γ. At the time of clinical onset of T1D, the Th1 dominance was diminished. We further demonstrate that children with newly diagnosed T1D had a suppressed Th1 like profile, detected by chemokine and chemokine receptor profile. This was accompanied by an induced population of CCR7+ and CD45RA+ naïve, CD8+cytotoxic T (Tc) cells and a reduced CD45RO+ memory Tc cell pool. It has previously been shown that oral Nicotinamide had no clinical effect in prevention of T1D. However, we found that the treatment was associated with a decreased secretion of IFN-γ. We have previously shown that subcutaneous injections with GAD-alum in T1D children induced a better preservation of endogenous insulin secretion compared with placebo. Here, we demonstrate that the treatment induced an early antigen-specific Th2 and regulatory immune profile. After a few months, and still after more than two years, the recall response to GAD65 was characterised by a broader range of cytokines. GAD-alum treatment also induced a GAD65-specific CD4+CD25highFOXP3+ cell population and reduced the levels of CD4+CD25+ cells. In conclusion, a Th1 like immune profile in pre-diabetic individuals indicates an imbalance of the immune system. At time of clinical onset, and in the period afterwards, reduction of the Th1 associated immune response could be an effect of a suppressed destructive process, selective recruitment of effector T cells to the pancreas or a defective immune regulation. The protective effect of GAD-alum in T1D children seems to be mediated by an early skewing of GAD65-induced responses towards a Th2 phenotype. Further, induction of GAD65-specific T cells with regulatory characteristics might be able to suppress autoreactive responses and inflammation in the pancreas.
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| 4. |
- Lindholm, Heléne
(författare)
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Repurposing digitoxin in the treatment of pancreatic ductal adenocarcinoma : genotypic and phenotypic features as biomarkers for digitoxin sensitivity in vitro
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing worldwide. The dismal prognosis and lack of effective treatments urges for increased research efforts in developing new treatment regimens. Since the development of new cancer treatments are expensive and time consuming, repurposing drugs is preferable when possible. This strategy will also be of great value for people in low income countries, to increase the availability of effective cancer treatments to affordable costs. Digitoxin, a cardiac glycoside, has been shown to have anti-cancer effects. It binds to the α subunit of the Na+/K+-ATPase, leading to increased concentrations of intracellular calcium and eventually cell death. There seems also to be other mechanisms elicited in cancer cells by digitoxin. The α subunit occurs in three isoforms, of which α3 has the highest affinity to digitoxin and frequently found over-expressed in tumor cells compared to normal cells.PDAC cancer cells, both cell lines and tumors, differ in their genotype and in the metabolic subtype, proliferation rate and inflammatory status. To be able to individualize treatment regimens it is important to be aware of the specific vulnerabilities (genotypic or phenotypic characteristics increasing the sensitivity to digitoxin) of each PDAC tumor/cell line. This research aims to investigate the potential of using digitoxin as an anti-cancer treatment in PDAC, and analyze its effects on cell viability, metabolism and inflammatory status in PDAC cell lines in vitro with the goal to find biomarkers for digitoxin sensitivity.The analyses of the effects of digitoxin was performed in five cell lines derived from PDAC tumors, either from primary tumors or metastases. Cell lines derived from PDAC are sensitive to digitoxin treatment to different degrees. High expression of α3 seems to be indicative for digitoxin sensitivity, as do a high proliferation rate seen in cell lines derived from primary tumors. Both subunit expression and proliferation rate should be further evaluated in PDAC tumors to confirm their potential to be used as biomarkers clinically.In the hunt for the working mechanism behind the anti-cancer effects of digitoxin, the choline pathway, a pathway commonly affected in tumors was enlightened in the metabolomics study, affected in all five cell lines tested. Choline metabolites are important for maintaining the cell membrane and are involved in energy metabolism using lipids. Digitoxin induced an up-regulation of choline and glycerophosphocholine, which rendered us to propose a novel theory about possible interactions between two functional complexes in the cell membrane, the Na+/K+-ATPase/EGFR/c-Src and the EGFR/c-Src – Chkα. The hypothesis is that when digitoxin binds to the Na+/K+-ATPase it leads to inactivation of Chkα with a subsequent decrease in the synthesis of phosphocholine and phosphatidylcholine. Since cancer cells rely on abundance of choline metabolites, we believe an inhibition of this pathway to be deleterious for these cells.Finally, we conclude that digitoxin has great potential as an anti-cancer treatment for some patients with pancreatic ductal adenocarcinoma. To optimize treatment results, a thorough investigation of the tumor genotype and phenotype must be done for each patient. To further increase treatment success, combination of digitoxin with other treatments for synergistic effects could be beneficial.
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| 5. |
- Rundqvist, Louise
(författare)
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Aspects of regular long-term endurance exercise in adolescents, with focus on cardiac size and function, hormones, and the immune system
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The long-term effects of starting high-intensity training at younger ages are largely unknown. The present studies focused on adolescents who had performed regular endurance exercise for several years at an elite level and compared those subjects with a control group of adolescents of similar age and sex who had not engaged in regular exercise. The knowledges generated by this research will contribute to further understanding of some of the physiological effects of strenuous regular exercise during adolescence.Aim: The overall aim of this research was to investigate endurance-trained adolescents, focusing on cardiac size and function, hormones associated with growth and metabolism, and impact on the immune system.Methods: All participants underwent echocardiography at rest as well as immediately and 15 minutes after amaximal cardiopulmonary exercise test. Blood samples were taken at rest and analyzed for biomarkers such as hormones, immune cell surface markers, and secreted cytokines and chemokines. The study design was crosssectional (Papers I, III, and IV) and comparative, with a quantitative approach in all four studies. The evaluationin Paper II used a pre-post test design with measurements of cardiac parameters before and after a maximal treadmill test. The studies in Papers I–III compared endurance-trained (active group) and untrained (controls) adolescents matched by age and sex, whereas the analysis in Paper IV considered differences between the sexes in the endurance-trained adolescents.Results: Compared with controls, the endurance-trained adolescents showed increased size of all four heart chambers, as well as improved cardiac systolic function at rest. Considering cardiac changes from baseline to immediately after exercise, the systolic and diastolic patterns were similar in both groups, although the diastolic function was more enhanced in the active group. Strong associations between peak oxygen uptake and cardiac size and function could be seen both at rest and after exercise. Circulating hormones at rest did not differ between the two groups. No correlation between insulin-like growth factor 1 and cardiac size was found among the endurance-trained adolescents. Compared with endurance-trained girls, endurance-trained boys exhibited an elevated response to a potent type 1 diabetes-related autoantigen. Conversely, compared with the trained boys, the trained girls showed an increased number of circulating immune cells and increased secretion of C-peptide and proinsulin.Conclusions: There are many benefits associated with regular exercise, and the present research did not provide any data to oppose that statement. Factors such as increased cardiac size at rest and exercise-related effects on cardiac functions do occur and therefore should be expected in endurance-trained adolescents with high peak oxygen uptake. Indeed, this should be interpreted as a sign of physiological adaptation and not as pathophysiology. The greater cardiac dimensions observed in these subjects could not be related to increased resting levels of hormones associated with growth and metabolism. The endurance-trained adolescents did show some sex-related differences with regard to their immune response at rest.
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| 6. |
- Diaz Cruz, Maria Araceli
(författare)
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Exploring vitamin D and steroid hormone receptors – from healthy elderly to prostate cancer cells
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The genetic background together with environmental factors and lifestyle are key contributors to the health of an individual. Genetic background is inherited and irreversible unless mutations occur. However, lifestyle habits (i.e., diet, stress, physical activity, smoking, and alcohol consumption) are modifiable factors that contribute to health or disease by affecting methylation of DNA, which regulates transcription of genes.One of the most relevant lifestyle habits for health is maintaining adequate vitamin D levels in the body as vitamin D promotes calcium and phosphate absorption, supports the nervous and immune system function, and protects bone and muscle structure. Extreme low levels of vitamin D, vitamin D deficiency, has become a global public health concern, especially in the elderly population as vitamin D deficiency can lead to several health problems such as bone fracture, decreased muscle strength, cardiovascular and autoimmune diseases, depression, and breast, pancreatic, and prostate cancer.Prostate cancer is an uncontrolled growth of cells within the prostate gland in the male reproductive system. Human prostate carcinomas are sensitive to androgens, and hormonal ablation therapy gives a temporary remission, followed by a relapse to an androgen-insensitive state. This indicates that steroid hormones, especially androgens, play a significant role in human prostatic carcinogenesis. The molecular effect of vitamin D as a steroid hormone and which steroid hormone receptor (SHR) mediates this effect are not fully understood.This research project aims to increase our knowledge about SHRs, primarily the vitamin D receptors, in both health and disease, focusing on genomic, epigenomic, and transcriptomic perspectives in healthy elderly individuals and prostate cancer cells.The results from the studies in this thesis could help us understand the importance of a healthy lifestyle, which includes vitamin D for health, where we found specific methylation markers involved in the down-regulation of cancer pathways that are associated with high physical activity and vitamin D supplementation. We have further confirmed that SHRs rarely work in isolation but rather as a crosstalk at the genomic level to regulate their transcription. Hopefully, this will help clarify the modulation of transcriptional responses in SHRs and explain the development of steroid hormone-dependent cancers such as prostate cancer. Last, but not least, we revealed that genetic and transcriptional markers are associated with the putative vitamin D receptor the protein disulfide isomerase family A member 3 (PDIA3). The genetic markers were detected in a healthy elderly population under vitamin D supplementation. The transcriptional markers, PDIA3, and a novel discovered isoform of PDIA3 (PDIA3N) were related to the androgen and cancer stage of prostate cancer cells and therefore are proposed as candidate markers for clinical diagnosis of prostate cancer.Altogether, these findings support the relevance of studying vitamin D and steroid hormone receptors, especially the PDIA3 receptor, to understand some of the factors related to healthy aging and the etiology and progression of prostate cancer.
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| 7. |
- Kivling, Anna
(författare)
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Combinations of type 1 diabetes, celiac disease and allergy : An immunological challenge
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The immune system is composed of a complex network of different cell types protecting the body against various possible threats. Among these cells are T-helper (Th) cells type 1 (Th1) and type 2 (Th2), as well as T regulatory (Treg) cells. Th1 and Th2 are supposed to be in balance with each other, while Tregs regulate the immune response, by halting it when the desired effect, i.e. destroying the threat, is acquired. However, sometimes this intricate interplay in the immune system is disturbed, leading to diseases as type 1 diabetes (T1D), celiac disease or allergic disease. According to the paradigm claiming that Th1- and Th2-cells inhibit each other a coexistence of a Th1-deviated disease and a Th2-deviated disease seems unlikely.This thesis aimed to examine the immune response with focus on subsets of T-cells in children with T1D, celiac disease, allergy, or a combination of two of these diseases, in comparison to reference children (healthy).In line with previous findings we observed that children with celiac disease showed a decreased spontaneous Th2-associated secretion, whereas children with allergic disease showed increased birch- and cat-induced Th2-associated response.The most remarkable results in this thesis are those observed in children with combinations of diseases. The combination of T1D and celiac disease decreased the Th1-associated response against several antigens, but instead displayed a more pronounced Treg-associated response. Further, in children with combined T1D and allergy an increased Th1- and Th2-associated response was seen to a general stimulus, and an increased birch-induced Th1-, Th2-, Treg- and pro-inflammatory response. In contrast, the combination of allergy and celiac disease showed a decreased spontaneous Th1-, Th2-, Treg- and pro-inflammatory response.In conclusion, we observed that two Th1-deviated diseases in combination suppress the immune response and increase the regulatory activity. Further it seems that allergy has the ability to shift the immune response in diverging directions depending on which disease it is combined with. The observed suppressive effect might be due to exhaustion of the immune system from the massive pressure of two immunological diseases in combination, while the pronounced Treg response might be caused by an attempt to compensate for the dysfunction. These results shed some light on the intriguing and challenging network that constitutes the immune system, and hopefully give clues regarding disease prevention and treatment.
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| 8. |
- Rydén, Anna, 1981-
(författare)
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Immune profile from high-risk to onset of Type 1 diabetes
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D) is most often diagnosed early in life and is usually the result of an autoimmune attack on the insulin producing β-cells of the pancreas, leading to a lack of insulin secretion and life-long insulin treatment. The search for possible targets pin-pointing the β-cell destruction is a constant endeavour in the pursuit to prevent T1D onset. Hence, characterisation of the immunological profile and changes therein, during the pre-diabetic phase and disease course, is of outmost importance for the understanding of the immunological processes involved in T1D pathogenesis.The aim of this thesis was to investigate the immunological profile, focusing on markers associated with T helper (Th) cells, pro-inflammation and regulatory T cells (Treg), in individuals with a high risk of developing T1D, and in children with newly diagnosed T1D for up to two years post diagnosis. In addition, we wanted to efficiently expand Tregs and detect any difference in T cell number and composition among T1D, high-risk and healthy individuals.We found that high-risk individuals that later developed T1D had a lower mRNA expression of the regulatory associated markers forkhead box protein 3 (FOXP3), cytotoxic T lymphocyte associated antigen (CTLA)-4 and transforming growth factor (TGF)-β, following stimulation with the major autoantigen glutamic acid decarboxylase (GAD)65, in combination with higher secretions of the chemotactic pro-inflammatory cytokine machrophage inflammatory protein (MIP)-1β, in comparison with high-risk individuals remaining undiagnosed.In addition to a markedly altered immune profile during the pre-diabetic phase, T1D seems to present with an intense up-regulation of regulatory (FOXP3, TGF-β and CTLA-4) and pro-inflammatory (e.g. tumour necrosis factor-α) markers and a suppression of Th1 (e.g. interferon-γ) and Th2-associated immunity (e.g. interleukin-13). This up-regulation of regulatory markers, however, seems to occur too late in the immunological process to suppress the autoimmune attack directed against the pancreatic β-cells, and is probably reflecting the strong activation seen at onset of disease, rather than a cause of disease. Furthermore, we found low levels of circulating soluble CTLA-4 together with a positive correlation between soluble CTLA-4 protein secretion and mRNA expression in T1D, in parallel to a negative relation in healthy individuals. Moreover, low C-peptide was accompanied by low mitogen-induced soluble CTLA-4 protein, and vice versa, pointing to a link between clinical process, i.e. β-cell degradation and ability to secrete the regulatory molecule soluble CTLA-4 upon mitosis.Our study also suggests that T1D children in our cohort were associated with a lower percentage of CD4+CD25+CD127lo/-Tregs, however, the ones they had expanded well and even acquired a higher FOXP3 expression. We found an altered composition of CD4+ subsets, biased towards a higher CD4+CD25- ratio to Tregs.In conclusion, the pre-diabetic phase seems to be accompanied by lower mRNA expression of regulatory associated markers in combination with higher secretions of the chemotactic pro-inflammatory cytokine MIP-1β, acknowledging the importance of studying this period in order to characterise the origin of T1D development. In addition, T1D seems to present with an intense up-regulation of regulatory and pro-inflammatory markers and a suppression of Th1 and Th2-associated immunity followed by low levels of circulating soluble CTLA-4 and, suggestively, lower percentage of CD4+CD25+CD127lo/-Tregs. Whereas we found an altered composition of CD4+ subsets, biased towards a higher CD4+CD25- ratio to Tregs, the importance of said alteration remains to be shown.
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| 9. |
- Tompa, Andrea
(författare)
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Pinpointing biomarkers of importance for children with combined type 1 diabetes and celiac disease
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D) and celiac disease are both characterized by an autoimmune feature. The diseases also share the same risk genes, and thereby patients have an increased risk of developing the other disease subsequently. The pattern of peripheral T and B cell subsets and soluble immune markers (cytokines, chemokines, acute phase proteins, adipocytokines and matrix metalloproteinases) are not yet well characterized in children with a combination of the common pediatric immunological disorders, T1D and celiac disease. To better understand the complex pathophysiology, it is important to gain a deeper knowledge of alterations present in the peripheral immune profile in children with these autoimmune diseases. Pinpointing biomarkers, e.g. peripheral immune markers, can hopefully contribute to the improvement of prognosis, diagnosis, and disease management. Flow cytometry is useful for studying different immune cells, but several pre-analytical factors may affect the outcome. In order to generate reliable results, it is important to evaluate the impact of different pre-analytical factors that possibly can lead to in vitro alterations of the immune cells.Aim: The overall aim of this thesis was to increase our knowledge of peripheral immune marker patterns in children with a combined diagnosis of T1D and celiac disease, with a focus on T and B cell subsets and soluble immune markers; by immunological methods evaluated and adapted for this purpose.Methods: This thesis comprises methodological and cross-sectional studies. The methodological studies are based on whole blood collected from sixty blood donors to examine the impact of pre-analytical factors (anticoagulant, sample handling time, isolation and cryopreservation) that may affect the immune cells (Study I, II). The cross-sectional studies include blood samples collected from a total of 103 participants (children with T1D and/or celiac disease or no diagnosis at all). The pattern of peripheral B (Study II) and T (Study III) cell subsets were examined by flow cytometry. Nearly thirty soluble immune markers were quantified in serum by Luminex technology (Study IV).Results: Peripheral lymphocytes were stable in whole blood samples up to 24 hours, regardless of the anticoagulant. Generally, T and B cell subsets were not affected by isolation and cryopreservation. Children with combined T1D and celiac disease had higher percentages of terminally differentiated memory T helper cells, lower percentages of effector memory T cytotoxic cells and lower expression of suppressive immune markers on regulatory T cells compared with the other study groups. Further, children with combined T1D and celiac disease had a higher percentage of memory B and lower percentages of naive B cells than children with either T1D or celiac disease. Contrary, children with single diagnoses had an inverted naive/memory B cell pattern compared to children with combined diagnoses. Several of the "classical" (cytokines, chemokines), as well as "non-classical" (acute phase proteins, adipocytokines, matrix metalloproteinases) immune markers, were lower in children with combined diagnoses compared to the other study groups.Conclusions: Based on our results, we conclude that whole blood samples stored up to 24 hours are feasible for flow cytometric analysis of lymphocyte subsets, regardless of the type of anticoagulant. Further, isolated and cryopreserved immune cells are feasible for flow cytometric analysis of T and B cell subsets. Impairment in the T and B cells mediated immune regulation in children with combined T1D and celiac disease seems to be clearly divergent from those seen in children with exclusively one of these two autoimmune diseases. Children with combined T1D and celiac disease appear to have a suppressed immune profile, including "classical" and "non-classical" immune markers. The methodological studies provide deeper knowledge of how reliable results can be obtained in studies of peripheral immune cells, e.g., in children with autoimmune diseases. The knowledge obtained by this thesis also brings a better understanding of the pattern of peripheral immune markers in T1D and/or celiac disease. This could potentially contribute to promoting the improvement of prognosis, diagnosis, and disease management.
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| 10. |
- Jonson, Carl-Oscar, 1978-
(författare)
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The Importance of CTLA-4 and HLA Class II for Type 1 Diabetes Immunology
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 Diabetes (T1D) is a serious chronic disease that results from an autoimmune destruction of the insulin-producing beta cells. Sweden has the second highest incidence of T1D in the world, and it affects more and more children each year. Genes controlling key functions of the immune system regulation of autoimmunity has been associated to T1D. Polymorphism in the Human Leukocyte Antigen (HLA) Class II is a major risk determinant for T1D but also Cytotoxic T lymphocyte Antigen 4 (CTLA-4) polymorphism can affect predisposition. Immune responses towards Glutamic Acid Decarboxylase 65 (GAD65), Insulin, insulinoma-associated antigen 2 (IA-2) and Heat Shock protein 60 have all been implicated in T1D pathogenesis.We aimed to study the effect and role of CTLA-4 and HLA Class II in the T1D immunity. By focusing on the immune responses associated to T1D in healthy children with risk genotypes we aimed to study immunological effects of T1D risk.We found that HSP60-peptide induced a higher IFN- response in subjects with risk associated CTLA-4 +49GG allele while GAD65 induced IL-4 secretion was lower in risk subjects. Individuals with T1D neutral HLA showed higher IFN- responses to GAD65 than DR3-DQ2 and DR4-DQ8 positive children. We did also detect that T1D patients have reduced IFN- responses to GAD65 compared to healthy children. Interestingly, HLA and CTLA-4 risk genotype seem to reduce those responses to become similar to responses of T1D patients. We also found that CTLA-4 and HLA risk is associated to reduced percentages of lymphocytes expressing intracellular CTLA-4 in healthy children. In another study we recorded maintained levels of CTLA-4 and TGF- mRNA responsiveness to GAD65 in recent onset T1D patients receiving ECP treatment although clinical outcome was certainly limited.In conclusion, HLA Class II risk genes but also CTLA-4 +49A/G to some extent, influence CTLA-4 capacity and T1D protective antigen-specific responses in a manner that might explain the genes’ predisposing and pathogenic capability.
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