Periodic Reporting for period 2 - ARCAID (Amsterdam Rheumatology Center for AutoImmune Diseases)
Période du rapport: 2022-01-01 au 2024-12-31
Autoimmune rheumatic diseases are characterized by inflammation, affecting connecting or supporting structures of the body and lead to disabling and painful conditions affecting the quality of life, loss of (work-) productivity and high costs. It is hard to translate understanding of the immunological processes to improved diagnostics or therapeutic healthcare interventions.
ARCAID aims to be a top-class research institute where ESRs will be skilled through excellent training programs set up along four trivial pillars in translational research;
I. Application of state-of-the-art technologies on human and murine biosamples;
II. Delineating the molecular and cellular mechanisms underlying pathophysiology of disease;
III. Development of improved computational procedures for data analysis and interpretation;
IV. Discovery of novel markers to improve diagnostics, prognostics and therapy response to aid the development of personalised medicine.
In conclusion, ARCAID ESRs have shown great progress, showing both expected and unexpected results that contributed to new directions, methodological innovations that will support science efforts world-wide, and potential impacts in science, medicine, and in the wider socio-economic context. All fellows will receive their PhD, enhancing their job opportunities in Europe and beyond.
ARCAID aims to be a top-class research institute where ESRs will be skilled through excellent training programs set up along four trivial pillars in translational research;
I. Application of state-of-the-art technologies on human and murine biosamples;
II. Delineating the molecular and cellular mechanisms underlying pathophysiology of disease;
III. Development of improved computational procedures for data analysis and interpretation;
IV. Discovery of novel markers to improve diagnostics, prognostics and therapy response to aid the development of personalised medicine.
In conclusion, ARCAID ESRs have shown great progress, showing both expected and unexpected results that contributed to new directions, methodological innovations that will support science efforts world-wide, and potential impacts in science, medicine, and in the wider socio-economic context. All fellows will receive their PhD, enhancing their job opportunities in Europe and beyond.
Pillar I: Learning how to apply common (e.g. flowcytometry, quantitative PCR, cell culture, basic microscopy) and state-of-the-art technologies (e.g. single cell sequencing, metabolomics, CyTOF, advanced microscopy and PET-MRI imaging) on cells and tissues to solve important research questions. A special focus was the acquisition, processing and use of human biosamples.
Pillar II: built upon I by learning to interpret the obtained data to setup additional functional studies aimed at delineating the molecular and cellular mechanisms underlying pathophysiology of disease.
Pillar III: Training in the application of machine-learning, bioinformatics and big data in the different translational research studies.
Finally, Pillar IV: Translating our research findings of novel (imaging) markers and drug targets to clinical applications, aiming for more accurate diagnostics, personalised medicine, and more effective therapies, contributing to improved health care for patients with autoimmune inflammatory diseases.
Below, we outlined a small sample of ARCAID results, indicating the research pillars they attributed to:
An affibody targeting TNF was successfully tested for PET-CT imaging (I). Series of luminescent probes tested hold potential for macrophage-targeted imaging in RA, enabling early diagnosis and disease monitoring (I,II). Semi-automated algorithms for synovial tissue delineation in rat PET/CT scans were developed, enabling more precise and reproducible analysis in preclinical models and focused on the evaluation of a PET tracer for imaging angiogenesis in arthritis (I,II). Protocols for full-length high throughput sequencing to study the B cell repertoire were developed and molecular targets in the autoantibody-producing B cells and specific inhibitors of cellular activation and differentiation identified.(I,III)
Monocyte-derived macrophages were developed into a spheroid-based model allowing the study of angiogenesis and inflammatory processes. Models of inflammatory bowel disease and a physiological relevant LN model with native properties was developed which can be used to asses antigen-specific immune functionality in the future. (I,II)
The adipogenic capacity of LNSCs is compromised early in RA development, pointing to stem cell exhaustion of LNSCs as a key aging hallmark in RA and RA-risk individuals. Microarray analysis (I) defined a pre-RA signature. Drug repurposing platforms were used to identify drugs capable of reversing this pathologic profile (II). Some inhibitors were identified as promising candidates to counteract the pre-RA signature providing a framework for preventive interventions in high-risk populations. Differences in the lymphocyte composition of PBMCs were demonstrated between individuals with SLE and healthy subjects (II,IV).
Neutrophils may play an important role in individuals with early arthritis and LN fibroblasts from RA and RA-risk individuals may have a reduced capacity to maintain Tregs in an autologous system. A defective DNA repair response in synovium of RA-risk individuals may contribute to ongoing chronic inflammation and could serve as a therapeutic target for intervention (II).
ENCORE (Enhancing Computational Reproducibility) was developed and the robustness of six state-of-the-art deconvolution algorithms specifically tailored for spatially resolved transcriptomics data analyzed. It was shown to be important to chose the appropriate method to study clonal families (CFs) in B-cell receptor repertoire analysis (III).
A specific NF-κB gene signature in the B cells of AAV patients with active disease was found with a suggested role in excessive B cell responses that may contribute to the pathogenesis (I, II, IV). Risk factors for developing RA were identified based on combinations of individual characteristics and serology (autoantibodies), opening up the realistic possibility of preventative treatments (I, II, IV). Selective action of S1P modulators in retaining lymphocytes within LNs was demonstrated which may potentially reduce gut inflammation (I, II). An app was developed to help clinicians to treat patients with SLE according to the ‘treat-to-target’(T2T) principle, and the performance studied in practice settings (IV). A comparative analysis of several anti-angiogenic compounds using in vitro models highlighted the need for advanced models to accurately assess the therapeutic potential of these compounds (I-IV).
Transcriptomic datasets from three patient cohorts identified key differentially expressed genes in fibrostenotic Crohn’s disease (CD). Immune infiltrate in was analyzed in colitis-associated cancer (CAC) vs non-IBD cancer patients by immunohistochemistry (II-IV).
A rare alternatively spliced mRNA transcript of HLA-B27 may contribute to the unfolding protein response that is believed to trigger SpA (II). An in-vivo model of SpA demonstrated in the pre-clinical phase molecular changes in axial and peripheral joints and popliteal LN. (II, IV).
Sex hormones play a protective role in modulating the immune response to SARS-CoV-2 infection possibly explaining why older and obese individuals are at greater risk of developing severe COVID-19. Pathogenic antibodies exclusively produced by severe COVID-19 patients contribute to disease progression by inducing an excessive proinflammatory phenotype of alveolar macrophages and glycosylated antibodies contributing to the development of severe symptoms around seroconversion II,IV)
Pillar II: built upon I by learning to interpret the obtained data to setup additional functional studies aimed at delineating the molecular and cellular mechanisms underlying pathophysiology of disease.
Pillar III: Training in the application of machine-learning, bioinformatics and big data in the different translational research studies.
Finally, Pillar IV: Translating our research findings of novel (imaging) markers and drug targets to clinical applications, aiming for more accurate diagnostics, personalised medicine, and more effective therapies, contributing to improved health care for patients with autoimmune inflammatory diseases.
Below, we outlined a small sample of ARCAID results, indicating the research pillars they attributed to:
An affibody targeting TNF was successfully tested for PET-CT imaging (I). Series of luminescent probes tested hold potential for macrophage-targeted imaging in RA, enabling early diagnosis and disease monitoring (I,II). Semi-automated algorithms for synovial tissue delineation in rat PET/CT scans were developed, enabling more precise and reproducible analysis in preclinical models and focused on the evaluation of a PET tracer for imaging angiogenesis in arthritis (I,II). Protocols for full-length high throughput sequencing to study the B cell repertoire were developed and molecular targets in the autoantibody-producing B cells and specific inhibitors of cellular activation and differentiation identified.(I,III)
Monocyte-derived macrophages were developed into a spheroid-based model allowing the study of angiogenesis and inflammatory processes. Models of inflammatory bowel disease and a physiological relevant LN model with native properties was developed which can be used to asses antigen-specific immune functionality in the future. (I,II)
The adipogenic capacity of LNSCs is compromised early in RA development, pointing to stem cell exhaustion of LNSCs as a key aging hallmark in RA and RA-risk individuals. Microarray analysis (I) defined a pre-RA signature. Drug repurposing platforms were used to identify drugs capable of reversing this pathologic profile (II). Some inhibitors were identified as promising candidates to counteract the pre-RA signature providing a framework for preventive interventions in high-risk populations. Differences in the lymphocyte composition of PBMCs were demonstrated between individuals with SLE and healthy subjects (II,IV).
Neutrophils may play an important role in individuals with early arthritis and LN fibroblasts from RA and RA-risk individuals may have a reduced capacity to maintain Tregs in an autologous system. A defective DNA repair response in synovium of RA-risk individuals may contribute to ongoing chronic inflammation and could serve as a therapeutic target for intervention (II).
ENCORE (Enhancing Computational Reproducibility) was developed and the robustness of six state-of-the-art deconvolution algorithms specifically tailored for spatially resolved transcriptomics data analyzed. It was shown to be important to chose the appropriate method to study clonal families (CFs) in B-cell receptor repertoire analysis (III).
A specific NF-κB gene signature in the B cells of AAV patients with active disease was found with a suggested role in excessive B cell responses that may contribute to the pathogenesis (I, II, IV). Risk factors for developing RA were identified based on combinations of individual characteristics and serology (autoantibodies), opening up the realistic possibility of preventative treatments (I, II, IV). Selective action of S1P modulators in retaining lymphocytes within LNs was demonstrated which may potentially reduce gut inflammation (I, II). An app was developed to help clinicians to treat patients with SLE according to the ‘treat-to-target’(T2T) principle, and the performance studied in practice settings (IV). A comparative analysis of several anti-angiogenic compounds using in vitro models highlighted the need for advanced models to accurately assess the therapeutic potential of these compounds (I-IV).
Transcriptomic datasets from three patient cohorts identified key differentially expressed genes in fibrostenotic Crohn’s disease (CD). Immune infiltrate in was analyzed in colitis-associated cancer (CAC) vs non-IBD cancer patients by immunohistochemistry (II-IV).
A rare alternatively spliced mRNA transcript of HLA-B27 may contribute to the unfolding protein response that is believed to trigger SpA (II). An in-vivo model of SpA demonstrated in the pre-clinical phase molecular changes in axial and peripheral joints and popliteal LN. (II, IV).
Sex hormones play a protective role in modulating the immune response to SARS-CoV-2 infection possibly explaining why older and obese individuals are at greater risk of developing severe COVID-19. Pathogenic antibodies exclusively produced by severe COVID-19 patients contribute to disease progression by inducing an excessive proinflammatory phenotype of alveolar macrophages and glycosylated antibodies contributing to the development of severe symptoms around seroconversion II,IV)
We could only outline a few of the most direct translational results, but the work done by the ARCAID ESRs over the past 4 years has shown great progress, in the projects, but also beyond the state of the art, showing (un-)expected results contributing to new directions, methodological innovations that will support science efforts world-wide, and potential impacts in science, medicine, and in the wider socio-economic context. All fellows will receive a PhD, enhancing their job opportunities in Europe and beyond.ARCAID has given them opportunities in terms of personal development they would not have had outside the project.