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Immunological consequences of C1q and anti-c1q immune complexes in secondary cellular inflammation
Get PDFThe complement system comprises numerous plasma proteins that are finely orchestrated in a network of at least three separate pathways, namely the classical, lectin, and alternative pathway. This system represents a cornerstone of the innate immune system and plays a crucial role in first-line defense against invading pathogens. Additionally, the complement system displays other functions, including self-tolerance.
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease with heterogeneous clinical manifestations and pathogenic mechanisms that are not fully understood. Although genetic deficiencies in the early components of the classical pathway (i.e., C1q, C1r, C1s, C4, and C2) are rare in humans, they are strongly associated with the development of monogenic SLE, particularly hereditary homozygous C1q deficiency. For instance, studies with mice deficient in C1q have strengthened this observation because affected animals developed an SLE-like disease. However, primary deficiency for C1q is uncommon in humans. Instead, most patients with SLE suffer from secondary hypocomplementemia associated with C1q autoantibodies (anti-C1q) present in 20–50% of patients. Notably, anti-C1q appear to play a role particularly in lupus nephritis (LN) since individuals with renal involvement have displayed increasing levels of anti-C1q before exacerbation and pronounced anti-C1q deposition in the glomeruli. However, exactly how anti-C1q contribute to disease activity and LN remains unclear.
Therefore, this dissertation investigates the immunological consequences of C1q and anti-C1q forming immune complexes in secondary cellular inflammation in the context of SLE and examines the following questions:
Part I – Do anti-C1q induce pro-inflammatory cytokine secretion in peripheral blood mononuclear cells (PBMCs) in the presence of activated T cells?
Although C1q alone has anti-inflammatory effects on human immune cells (i.e., monocytes, macrophages, dendritic cells [DC], and T cells), our group previously demonstrated a pro-inflammatory phenotype in human monocyte-derived macrophages (HMDMs) induced by C1q/anti-C1q complexes in vitro. However, the immunological consequences of C1q and C1q/anti-C1q complexes on other immune cells is unknown. Thus, in the first part of my thesis, I investigated the immunological effects of C1q and C1q/anti-C1q complexes in PBMCs with concomitant T cell activation. In an in vitro model for anti-C1q-mediated autoimmunity, I demonstrated that C1q/anti-C1q complexes produced an upregulation of tumor necrosis factor (TNF), interleukin 10 (IL-10), and interferon-γ (IFNγ) secretion in PMBCs. Specifically, activated T cells elicited a cell–cell contact-mediated increase in TNF and IFNγ secretion in monocytes. Moreover, the co-stimulatory pair cluster of differentiation (CD)40–CD154 was essential for the release of TNF in C1q/anti-C1q-conditioned monocytes. The latter depended on the tumor necrosis factor receptor-associated factors (TRAF) 6 and Janus family kinase (JAK) 3-signal transducer and activator of transcription (STAT) 5 signaling pathways.
Part II – What are the phenotypical characteristics of low and high C1q-producing HMDMs and what are the autocrine and paracrine effects of de novo synthesized C1q?
Unlike most proteins in the complement system, the majority of C1q is of non-hepatic origin. Instead, C1q synthesis predominantly occurs locally in tissue-resident myeloid cells, such as macrophages and DCs. Regarding the regulation of C1q synthesis, our group previously reported a continued de novo synthesis of C1q in HMDMs, mediated by C1q and C1q/anti-C1q. Although the overall concentration of C1q increased, not all HMDMs were equally involved in the production of new C1q. In the second part, I sought to define the heterogenous phenotypes of HMDMs and explore the potential autocrine and paracrine effects of the newly secreted C1q on immune cells. Combining transcriptional analysis of C1q mRNA and experiments inhibiting protein synthesis and secretion produced contradictory data that do not suggest de novo synthesis of C1q. Beyond this, coating of biotin-labeled C1q (C1q-biotin) revealed a considerable amount of the molecule in the cell culture medium to be derived from the plate. Together, the findings presented in this part of this thesis do not support the proposed notion of de novo synthesis of C1q in HMDMs triggered by C1q and C1q/anti-C1q complexes.
Part III – Do epitope-specific anti-C1q associate with specific SLE disease manifestations?
Anti-C1q are high-affinity polyclonal autoantibodies that predominantly recognize epitopes located in the collagen-like region (CLR) of C1q. There is weak to no binding of anti-C1q to soluble C1q, whereas attachment of C1q to a target allows anti-C1q to access neo-epitopes. However, the specificity of the autoantibodies has yet to be determined. In the last part of this thesis, we explored epitopes of C1q and investigated whether epitope-specific anti-C1q were associated with specific clinical presentations. In the first step, we investigated the epitope-specificity of patient-derived anti-C1q using a high-resolution epitope mapping approach. By using peptide microarrays to map the epitopes of anti-C1q, we identified three peptides of the C1q A-chain and three of the C1q B-chain with increased immunoglobulin (Ig) G binding. Next, screening a large SLE patient cohort by a newly established peptide-based enzyme-linked immunosorbent assay (ELISA) revealed that certain peptide-specific antibodies associated with selected disease manifestations. Notably, anti-C1q directed against the N-terminal C1q A-chain improved discrimination between controls and SLE beyond the conventional determination of anti-C1q
Fractional Liouville equations and Calogero-Moser NLS
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Shaping and interpretation of Dpp morphogen gradient by endocytic trafficking
Get PDFDpp/BMP is a morphogen that controls patterning and growth in the Drosophila wing disc. Contrast with the extracellular and nuclear regulation, how Dpp morphogen gradient is shaped and interpreted by endocytic trafficking remains unclear. To address this, here we generate novel fluorescent protein tagged dpp alleles that allow to visualize both extracellular and intracellular Dpp distribution. Using these alleles, we found that, while blocking endocytosis expanded the extracellular Dpp gradient and impaired Dpp signaling, blocking early endosome expanded not only the extracellular Dpp gradient but also Dpp signaling range due to impaired downregulation of activated receptors. We show that blocking multivesicular body (MVB) formation, but not late endosome, expanded Dpp signaling and caused accumulation of the intracellular Dpp without affecting the extracellular Dpp gradient. These results indicate that, while the early endocytosis acts as a sink for Dpp and initiates Dpp signaling, termination of Dpp signaling at MVB is required for interpretation of the extracellular Dpp gradient. Taken together, our results reveal that extracellular Dpp morphogen gradient is shaped and interpreted by distinct endocytic trafficking pathways
Nursing Care For Patients With Cirrhosis
Get PDFLiver cirrhosis represents a major cause of morbidity and mortality, causes a marked impairment of quality of life of patients and their caregivers, and causes a major burden for health systems. Currently, nurses still play in most countries a limited role in the care of patients with cirrhosis which is mainly restricted to the care of patients hospitalized for acute complications of the disease. The current manuscript reviews the established and potential new and innovative roles that nurses can play in the care of patients with liver cirrhosis. In the hospital setting, specialized nurses become an integral part of interprofessional teams to improve the quality of care and outcomes of patients with cirrhosis. In the primary care setting, nurses should play an important role in the care of patients with compensated cirrhosis and also facilitate early diagnosis of cirrhosis in subjects at risk of liver diseases. This review calls for an improved global liver diseases education program for nurses and increased awareness among all healthcare providers and policy makers of the positive impacts of advanced or specialist nursing practice in this domain
The moral implications of human and animal vulnerability
Get PDFIn this open access book, Angela K. Martin thoroughly addresses what human and animal vulnerability are, how and why they matter from a moral point of view, and how they compare to each other. By first defining universal and situational human vulnerability, Martin lays the groundwork for investigating whether sentient nonhuman animals can also qualify as vulnerable beings. She then takes a closer look at three different contexts of animal vulnerability: animals used as a source of food, animals used in research, and the fate of wild animals
High efficiency preparation of monodisperse plasma membrane derived extracellular vesicles for therapeutic applications
Get PDFExtracellular vesicles (EVs) are highly interesting for the design of next-generation therapeutics. However, their preparation methods face challenges in standardization, yield, and reproducibility. Here, we describe a highly efficient and reproducible EV preparation method for monodisperse nano plasma membrane vesicles (nPMVs), which yields 10 to 100 times more particles per cell and hour than conventional EV preparation methods. nPMVs are produced by homogenizing giant plasma membrane vesicles following cell membrane blebbing and apoptotic body secretion induced by chemical stressors. nPMVs showed no significant differences compared to native EVs from the same cell line in cryo-TEM analysis, in vitro cellular interactions, and in vivo biodistribution studies in zebrafish larvae. Proteomics and lipidomics, on the other hand, suggested substantial differences consistent with the divergent origin of these two EV types and indicated that nPMVs primarily derive from apoptotic extracellular vesicles. nPMVs may provide an attractive source for developing EV-based pharmaceutical therapeutics
Revolutionizing the public health workforce: a policy brief in retrospect of the world congress on public health Rome 2020
Get PDFBackground: The COVID-19 pandemic dramatically illustrates the consequences of inadequate prioritization of the Public Health Workforce (PHW). This Policy Brief introduces a Call for Action following the plenary session entitled "Revolutionising the Public Health Workforce (PHW) as Agents of Change" as part of the 2020 World Congress on Public Health.Policy Options and Recommendations: In order to revolutionize the PHW, five long-term key approaches are proposed: 1. Transforming public health competencies through transdisciplinary education and inter-professional training; 2. Revolutionizing educational systems by shifting the public health paradigm; 3. Linking public health education and work opportunities; 4. Overcoming the paradoxical shortage and overproduction of graduates and 5. Developing adaptable, multisectoral agents of change.Conclusion: Public health education of the future requires a paradigm shift towards a holistic understanding of public health, characterized by transdisciplinary education, inter-professional training and a closer integration of academia, health services, and communities
Microbiological quality and antimicrobial resistance of Bacteria species recovered from ready-to-eat food, water samples, and palm swabs of food vendors in Accra, Ghana
Get PDFThis study sought to investigate microbial quality and antimicrobial resistance of bacteria species from Ready-to-Eat (RTE) food, water, and vendor palm swab samples. Between 2019 and 2020, RTE food, water and vendor palm swab samples were collected from food vending sites in Accra, Ghana. Samples were cultured and confirmed using the Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF). Antimicrobial susceptibility testing (AST) was conducted using disk diffusion method. Beta-lactamase and Diarrheagenic Escherichia coli (DEC) genes were determined using Polymerase Chain Reaction (PCR). Total plate count (TPC) and Total coliform count (TCC) were performed on food and water samples. In total, 179 RTE food, 72 water and 10 vendor palm swab samples were collected. Enterobacter spp. (16.8 %), Citrobacter spp. (10.1 %), Enterococcus faecalis (7.8 %), Pseudomonas spp. (6.7 %) and Klebsiella pneumoniae (4.0 %) occurred in food. Isolates from water and palm were Klebsiella pneumoniae (20.8 %), Aeromonas spp. (16.7 %) and Enterobacter cloacae (11.1 %). Resistance to Amoxicillin-clavulanate, Tetracycline, Azithromycin, Sulfamethoxazole-trimethoprim, and Nitrofurantoin were common among Enterobacterales. High mean TPC and TCC showed in some RTE food and different water types used in vending depicting their unsafe condition for consumption and usage. The bla(SHV) and bla(TEM) genes were present in some Enterobacterales from food and water. The lt gene was identified in two food samples. AMR organisms associated with nosocomial infections in the samples investigated, calls for continuous surveillance in the food industry in Ghana. Also, the unsafe outcome of RTE food and water depicts the need for the enforcement of Ghana's food safety laws
Pre-referral rectal artesunate is no "magic bullet" in weak health systems
Get PDFSevere malaria is a potentially fatal condition that requires urgent treatment. In a clinical trial, a sub-group of children treated with rectal artesunate (RAS) before being referred to a health facility had an increased chance of survival. We recently published in BMC Medicine results of the CARAMAL Project that did not find the same protective effect of pre-referral RAS implemented at scale under real-world conditions in three African countries. Instead, CARAMAL identified serious health system shortfalls that impacted the entire continuum of care, constraining the effectiveness of RAS. Correspondence to the article criticized the observational study design and the alleged interpretation and consequences of our findings.Here, we clarify that we do not dispute the life-saving potential of RAS, and discuss the methodological criticism. We acknowledge the potential for confounding in observational studies. Nevertheless, the totality of CARAMAL evidence is in full support of our conclusion that the conditions under which RAS can be beneficial were not met in our settings, as children often failed to complete referral and post-referral treatment was inadequate.The criticism did not appear to acknowledge the realities of highly malarious settings documented in detail in the CARAMAL project. Suggesting that trial-demonstrated efficacy is sufficient to warrant large-scale deployment of pre-referral RAS ignores the paramount importance of functioning health systems for its delivery, for completing post-referral treatment, and for achieving complete cure. Presenting RAS as a "magic bullet" distracts from the most urgent priority: fixing health systems so they can provide a functioning continuum of care and save the lives of sick children.The data underlying our publication is freely accessible on Zenodo