41 research outputs found
Immune mechanisms and potential immunological treatment in atherosclerosis
No full textOur immune system is an important and central part of the defence mechanisms of our body. It carries out various important functions such as protecting us from invading microorganisms, removing dead cells, and producing antibodies for future defence. For this, proper synchronization between the innate and adaptive immunity is required. Our innate immune system acts as the first line of defence by eliminating non-specifically various pathogens and by activating antigen-presenting cells (APCs) that inform B-cells and T-cells of the adaptive immune system. B-cells can exhibit more specific actions against pathogens by an intricately regulated production of antibodies directed against antigens expressed by the pathogens. T-cells can produce cytokines and chemokines to alarm the complete immune system recruiting immune cells such as natural killer cells, mast cells and neutrophils. The immune system can also produce antibodies against self-antigens (autoantibodies). Autoantibodies can have pathogenic effects that cause autoimmune diseases such as Systemic Lupus Erythematosis. Interestingly, it has been shown recently that autoantibodies can also have protective effects alleviating diseases such as lupus nephritis and atherosclerosis. This thesis focuses specifically on homeostatic functions of the human autoantibodies anti-phoshorylcholine (anti-PC) and anti-malondialdehyde (anti-MDA) and their prevalence in cardiovascular disease (CVD) and chronic kidney disease (CKD).1. Study I: Investigates the role of anti-PC and anti-MDA antibodies in patients undergoing hemodialysis and explores the associations with all-cause mortality in both males and females, also their relation to inflammation.2. Study II: Evaluates the potential of natural immunization in hibernating bears, tigers, and polar bears with respect to the levels of anti-PC and anti-MDA antibodies.3. Study III: Evaluates the role of antibodies against anti-PC antibodies among 60-Year-Olds with its clinical role and simulated interactions.4. Study IV: Investigates the role of anti-PC antibody levels in Covid-19 patients and also investigates the interaction of spike protein with phosphorylcholine by using an in silico approach.List of scientific papersI. Samal SK, Qureshi AR, Rahman M, Stenvinkel P and Frostegard J. Different subclasses and isotypes of antibodies against phosphorylcholine in haemodialysis patients: association with mortality. Clin exp Immunol. 2020;201:94. https://doi.org/10.1111/cei.13441 II. Samal SK, Qureshi AR, Rahman M, Stenvinkel P and Frostegard J. Antibodies against Malondialdehyde in Haemodialysis Patients and Its Association with Clinical Outcomes: Differences between Subclasses and Isotypes. J Clin Med. 2020;9:753. https://doi.org/10.3390/jcm9030753 III. Samal SK, Frobert O, Kindberg J, Stenvinkel P and Frostegard J. Potential natural immunization against atherosclerosis in hibernating bears. Sci Rep. 2021;11:12120. https://doi.org/10.1038/s41598-021-91679-1 IV. Samal SK, Panda PK, Vikström M, et al. Antibodies Against Phosphorylcholine Among 60-Year-Olds: Clinical Role and Simulated Interactions. Frontiers in Cardiovascular Medicine. 2022; 9. https://doi.org/10.3389/fcvm.2022.809007 V. Samal SK*, Busch M*, Panda KP, Kumar N, Timmermans S, Schurgers LJ, Reutelingsperger CR, Paassen PV*, Frostegård J*. Antibodies against phosphorylcholine are associated with less severe disease in COVID-19: clinical role and simulated interactions using In-silico methods. *Denotes equal author contribution. [Manuscript]</p
Structural vaccinology approaches to enhance efficacy, stability, and delivery of protective antigens
No full textDeveloping safe and effective vaccinations is an active area of pharmaceutical research, and vaccines have become a powerful tool in the fight against infectious disease pandemics. Using inactivated or weakly active microbes characterizes the first generation of “culture-based” vaccines. The safety of this approach could be better, and modern medical procedures need for much more oversight. It was in the late 1800s that naturally occurring antibodies were initially identified. Paul Ehrlich first proposed the idea of “horror autotoxins,” in which pathogenic autoantibodies damage our cells’ structures. Stratis Avrameas initially coined the word “Gnothi seauton” in 1991 to describe the necessity of self-organizations, such as a body’s endogenous antibody collection, for homeostasis. There are limits to structural vaccinology (SV) despite its great potential. To start, there needs to be more structural and immunological knowledge about the host immune responses that the virus induces, which makes this technology susceptible to potential vulnerabilities. For instance, mapping an epitope onto preexisting dengue structures in one known configuration proved that the epitope remained inaccessible. New advancements have proven that vaccinations based on structures can be effective. When traditional approaches fail, structural understanding is necessary to overcome the obstacles. Based on the research that is now available, structural knowledge is necessary for stabilizing antigens that are flexible. The advancement of antibody treatments can also benefit from SV. One possible solution to the cold-chain problem that affects underdeveloped areas on faraway continents is to use SV techniques to make vaccines more thermostable
Synthetic Biology:Refining Human Health
No full textScientists of various disciplines and backgrounds collaborate to conceive and design revolutionary biomolecular components, networks, and pathways, after which they use these innovations to reorganize and reprogram organisms. These re-engineered organisms will fundamentally change our lives over the next few years by helping to reduce the cost of drugs, using “green” sources of fuel, and aiding in the development of treatments for “superbugs” and various diseases including cancer. The rapidly evolving discipline of synthetic biology is dedicated to discovering entirely new systems of life or totally reworking current systems to use the minimum number of components possible. A number of enabling technologies have contributed to the emergence of synthetic biology, and as a result, a broad field has emerged that encompasses many areas. This chapter is to serve as an introduction to the place and provide a brief look at some of the more noteworthy cases that have occurred so far. It should be noted that DNA assembly and combinatorial variety creation are the fundamental molecular biology approaches utilized in these cases, along with computational modeling to aid in the design of new biological systems
Potential natural immunization against atherosclerosis in hibernating bears
Full text linkAbstract Brown bears (Ursus arctos) hibernate for 5–6 months during winter, but despite kidney insufficiency, dyslipidemia and inactivity they do not seem to develop atherosclerosis or cardiovascular disease (CVD). IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) are associated with less atherosclerosis, CVD and mortality in uremia in humans and have anti-inflammatory and other potentially protective properties. PC but not MDA is exposed on different types of microorganisms. We determine anti-PC and anti-MDA in brown bears in summer and winter. Paired serum samples from 12 free ranging Swedish brown bears were collected during hibernation in winter and during active state in summer and analyzed for IgM, IgG, IgG1/2 and IgA anti-PC and anti-MDA by enzyme linked immunosorbent assay (ELISA). When determined as arbitrary units (median set at 100 for summer samples), significantly raised levels were observed in winter for anti-PC subclasses and isotypes, and for IgA anti-PC the difference was striking; 100 IQR (85.9–107.9) vs 782.3, IQR (422.8–1586.0; p < 0.001). In contrast, subclasses and isotypes of anti-MDA were significantly lower in winter except IgA anti-MDA, which was not detectable. Anti-PCs are significantly raised during hibernation in brown bears; especially IgA anti-PC was strikingly high. In contrast, anti-MDA titers was decreased during hibernation. Our observation may represent natural immunization with microorganisms during a vulnerable period and could have therapeutic implications for prevention of atherosclerosis
In silico design of an epitope-based vaccine ensemble for fasliolopsiasis
Full text linkIntroductionFasciolopsiasis, a food-borne intestinal disease is most common in Asia and the Indian subcontinent. Pigs are the reservoir host, and fasciolopsiasis is most widespread in locations where pigs are reared and aquatic plants are widely consumed. Human infection has been most commonly documented in China, Bangladesh, Southeast Asia, and parts of India. It predominates in school-age children, and significant worm burdens are not uncommon. The causal organism is Fasciolopsis buski, a giant intestinal fluke that infects humans and causes diarrhoea, fever, ascites, and intestinal blockage. The increasing prevalence of medication resistance and the necessity for an effective vaccination make controlling these diseases challenging.MethodsOver the last decade, we have achieved major advances in our understanding of intestinal fluke biology by in-depth interrogation and analysis of evolving F. buski omics datasets. The creation of large omics datasets for F. buski by our group has accelerated the discovery of key molecules involved in intestinal fluke biology, toxicity, and virulence that can be targeted for vaccine development. Finding successful vaccination antigen combinations from these huge number of genes/proteins in the available omics datasets is the key in combating these neglected tropical diseases. In the present study, we developed an in silico workflow to select antigens for composing a chimeric vaccine, which could be a significant technique for developing a fasciolopsiasis vaccine that prevents the parasite from causing serious harm.Results and discussionThis chimeric vaccine can now be tested experimentally and compared to other vaccine candidates to determine its potential influence on human health. Although the results are encouraging, additional validation is needed both in vivo and in vitro. Considering the extensive genetic data available for intestinal flukes that has expanded with technological advancements, we may need to reassess our methods and suggest a more sophisticated technique in the future for identifying vaccine molecules
Antibodies Against Phosphorylcholine Among 60-Year-Olds : Clinical Role and Simulated Interactions
No full textAimsAntibodies against phosphorylcholine (anti-PC) are implicated as protection markers in atherosclerosis, cardiovascular disease (CVD), and other chronic inflammatory conditions. Mostly, these studies have been focused on IgM. In this study, we determined IgG, IgG1, and IgG2 anti-PC among 60-year-olds. MethodsBased on a 7-year follow-up of 60-year-olds (2,039 men and 2,193 women) from Stockholm County, we performed a nested case-control study of 209 incident CVD cases with 620 age- and sex-matched controls. Anti-PC was determined using ELISA. We predicted the binding affinity of PC with our fully human, in-house-produced IgG1 anti-PC clones (i.e., A01, D05, and E01) using the molecular docking and molecular dynamics simulation approach, to retrieve information regarding binding properties to PC. ResultsAfter adjustment for confounders, IgG and IgG2 anti-PC showed some significant associations, but IgG1 anti-PC was much stronger as a protection marker. IgG1 anti-PC was associated with an increased risk of CVD below 33rd, 25th, and 10th percentile and of stroke below 33rd and 25th, and of myocardial infarction (MI) below 10th percentile. Among men, a strong association with stroke was determined below the 33rd percentile [HR 9.20, CI (2.22-38.12); p = 0.0022]. D05 clone has higher binding affinity followed by E01 and A01 using molecular docking and further have been confirmed during the course of 100 ns simulation. The stability of the D05 clone with PC was substantially higher. ConclusionIgG1 anti-PC was a stronger protection marker than IgG anti-PC and IgG2 anti-PC and also separately for men. The molecular modeling approach helps in identifying the intrinsic properties of anti-PC clones and atomistic interactions with PC
Antibodies against Malondialdehyde in Haemodialysis Patients and Its Association with Clinical Outcomes: Differences between Subclasses and Isotypes
No full textPatients on haemodialysis (HD-patients) have an increased risk of premature death. Low levels of IgM antibodies against malondialdehyde (anti-MDA) are associated with increased risk of cardiovascular disease (CVD) with underlying potential mechanisms described. Here, we studied subclasses and isotypes of anti-MDA in 210 HD-patients with mortality as outcome (56% men, median age 66, Interquartile range (IQR) 51–74 years, vintage time 29 (15–58) months, mean follow up period of 41 (20–60)months). Patients were also divided into inflamed c-reactive protein (CRP >5.6 mg/mL) and non-inflamed. Antibody levels were measured by ELISA. In multivariate risk analysis, patients in low tertile of IgM anti-MDA sub-distribution hazard ratio (sHR 0.54); 95% confidence interval (CI: 0.34–0.89) inversely and significantly associated with all-cause mortality after five years, after adjusting for confounders. Low tertile of IgG (sHR 0.48, 95%CI: 0.25–0.90, p = 0.02) and IgG1 (sHR 0.50, CI: 0.24–1.04, p = 0.06) was associated low mortality among non-inflamed patients. In contrast, anti-MDA IgG2 among inflamed patients was significantly associated with increased mortality, IgG2(sHR 2.33, CI: 1.16–4.68, p = 0.01). IgM anti-MDA was a novel biomarker among HD-patients with low levels being associated with mortality, while low levels of IgG and IgG1 but not IgA anti-MDA were associated with mortality only among non-inflamed patients. IgG2 anti-MDA was a significant risk marker among inflamed patients, which could be related to infection
Antibodies against malondialdehyde among 60-year-olds: prediction of cardiovascular disease
No full textAbstract Malondialdehyde (MDA) is generated in oxidized LDL. It forms covalent protein adducts, and is recognized by antibodies (anti-MDA). We previously studied IgM anti-MDA, and here we focus on IgG, IgG1 and IgG2 anti-MDA in predicting cardiovascular disease (CVD). We determined, by ELISA, anti-MDA in a 7-year follow-up of 60-year-old men and women from Stockholm County (2039 men, 2193 women). We identified 210 incident CVD cases (defined as new events of myocardial infarction (MI), and hospitalization for angina pectoris) and ischemic stroke, and 620 age- and sex-matched controls. IgG anti-MDA was not associated with CVD. Median values only differed significantly for IgG1 anti-MDA among men, with lower levels among cases than controls (p = 0.039). High IgG1 anti-MDA (above 75th percentile) was inversely associated with CVD risk after adjustment for smoking, body mass index, type 2 diabetes, hyperlipidemia, and hypertension, (OR and 95% CI: 0.59; 0.40–0.89). After stratification by sex, this association emerged in men (OR and 95% CI: 0.46; 0.27–0.77), but not in women. IgG2 anti-MDA were associated with protection in the whole group and among men though weaker than IgG1 anti-MDA. IgG2 anti-MDA above the 75th percentile was associated with an increased risk of MI/angina in women (OR and 95% CI: 2.57; (1.08–6.16)). IgG1 and less so IgG2 anti-MDA are protection markers for CVD and MI/angina in the whole group and among men. However, IgG2 anti-MDA was a risk marker for MI/angina among women. These findings could have implications for both prediction and therapy
Effects of Atorvastatin on T‐Cell Activation and Apoptosis in Systemic Lupus Erythematosus and Novel Simulated Interactions With C‐Reactive Protein and Interleukin 6
No full textObjective We study activation of T helper 17 (Th17) and regulatory T (Treg) cells and induction of apoptosis in cells from patients with systemic lupus erythematosus (SLE) compared with controls and effects of atorvastatin and its simulated interactions with other compounds. Methods Mononuclear cells from 10 patients with SLE and 10 controls were cultured in conditions that induce Th17 and/or Treg cell polarization and/or apoptosis and were studied by FACScan. Gene expression was determined by quantitative real‐time reverse transcription–polymerase chain reaction. Cytokines in plasma were determined by enzyme‐linked immunosorbent assay. The Search Tool for Interactions of Chemicals (STITCH) was used to retrieve information regarding the binding properties of atorvastatin. Results Among patients with SLE, the proportion of Th17 (CD4+IL17+) cells was higher compared with controls after activation, with Th17 or Treg polarizing cytokines, phorbol myristate acetate, and ionomycin. In contrast, Treg cells (CD4+CD25+CD127dim/−) frequencies were lower. CD95 stimulation induced relatively more apoptosis in Treg cells and less in Th17 cells, as compared with controls. Addition of atorvastatin normalized Th17/Treg cell balance and apoptosis induction. Accordingly, the ratio of RORC/FoxP3 decreased in patients with SLE. Interleukin 17 and interleukin 6 (IL‐6) levels were increased in patients with SLE. Atorvastatin interacted strongly with C‐reactive protein (CRP) and also significantly with IL‐6. Conclusion There is a higher proportion of Th17 cells and a lower proportion of Treg cells in patients with SLE after activation. Th17 cells were more resistant than Treg cells to CD95‐induced apoptosis in SLE. Atorvastatin normalized these effects. Our findings reveal a novel mechanism behind the imbalance of Th17/Treg cells with implications for treatment in SLE. We determine for the first time simulated interaction between atorvastatin, CRP, and IL‐6, implying a novel role of atorvastatin
