[FG] Trendelenburg MartenHead of Research Unit Prof. Dr. med.Marten TrendelenburgOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 7 foundShow per page10 10 20 50 Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial. NFP 78 Research Project | 4 Project MembersSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally since December 2019 causing a worldwide pandemic of coronavirus disease 2019 (COVID-19). Systemic hyper-inflammation is a hallmark of severe stages of COVID-19 leading to acute lung injury (ALI), need for mechanical ventilation and ultimately death. The mechanism responsible for virus-induced hyper-activation of the host immune system remains to be fully elucidated. Unregulated complement system activation induced by CoVs plays a crucial role in the pathogenesis of acute lung injury in COVID-19. Similarly, involvement of the kinin-kallikrein system in capillary leakage and subsequent pulmonary angioedema has been suspected. In particular, a reduced activity of angiotensin converting enzyme 2 (ACE2) caused by SARS-CoV-2 leads to a relative abundance of bradykinin degradation products and local pulmonary edema. Lastly, over-activation of the contact activation system may be involved in the observed thromboinflammation. C1 esterase inhibitor (C1INH) is a potent inhibitor of these three plasmatic cascades and has been shown to reduce pulmonary inflammation and death in a CoV mouse model and in human studies of severe sepsis. Aims: To assess the safety and efficacy of recombinant C1INH (conestat alfa, Ruconest®) in addition to standard of care (SOC) in patients hospitalized with severe SARS-CoV-2 compared to SOC only.Hypothesis: Administration of conestat alfa for 72 hours in addition to SOC in patients with severe SARS-CoV-2 pneumonia is safe and associated with a reduced clinical severity on day 7 and a lower risk of disease progression to mechanical ventilation compared to SOC.Methodology: The PROTECT-COVID-19 trial is a randomized, open-label, parallel-group, controlled, multi-center clinical trial. Consecutive patients admitted with COVID-19 not requiring intensive care support will be randomized in a 2:1 ratio to treatment with conestat alfa for 72 hours in addition to SOC or SOC only. The primary endpoint will be the disease severity on the 7-point Ordinal WHO scale on day 7. Secondary endpoints include time to clinical improvement, the proportion of participants alive and not having required invasive or non-invasive ventilation and the incidence of ALI within 14 days after enrolment. Treatment safety and the activity of the above mentioned plasmatic cascades will be assessed. For a 2:1-randomization, a nonparametric analysis by the stratified logrank-test, and an adaptive group sequential analysis, the overall sample size is estimated as 120 = 80 + 40. Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels ap = 0.0221.Potential significance: Targeting multiple inflammatory cascades with conestat alfa early during COVID-19 is an innovative approach to prevent disease progression by ameliorating excessive (thrombo-) inflammation. Interventions that prevent deterioration and mechanical ventilation in COVID-19 are highly desired in a pandemic situation with limited ICU and ventilation support capacity. If treatment with conesta alfa proves to ameliorate pulmonary inflammation and injury, this may be relevant not only on an individual but also on a population level. Complement-dependent pathogenic mechanisms in systemic autoimmunity Research Project | 6 Project MembersSystemic Lupus Erythematosus (SLE) is the archetype of an autoimmune disease and can involve any organ system eventually leading to comorbidities that can also be observed independently of underlying SLE. The complex pathogenic mechanisms leading to and being involved in this autoimmune-inflammatory syndrome are not well understood. However, complement C1q, the first component of the classical pathway, seems to play a central role. By analysing the role of C1q as well as it's interaction with autoantibodies targeting C1q (anti-C1q) in SLE, the primary goals of the proposed projects are to elucidate 1) mechanisms being involved in the initiation of autoimmunity, 2) mechanisms of secondary acceleration of inflammation, and 3) processes being associated with comorbidities.With regard to mechanisms being involved in the initiation of SLE, homozygous C1q deficiency is the strongest genetic risk factor for the development of SLE. Vice versa, in SLE patients without primary C1q deficiency, C1q is consumed during disease flares, deposited in affected tissues and becoming a target of autoantibodies (anti-C1q). By the characterisation of structures targeted by anti-C1q we aim to understand mechanisms leading to the development of SLE.Secondly, C1q mediates and modulates the uptake of apoptotic cells, a mechanism that is defective in SLE patients. In the context of a defective clearance, dying cells can become antigenic and trigger the autoimmune response. In previous studies I could show that anti-C1q specifically recognize C1q when being bound to apoptotic cells and that anti-C1q induce a proinflammatory phenotype in macrophages being associated with reduced phagocytic capacity. To explore mechanisms of secondary inflammation, I will further investigate how C1q and anti-C1q interact with other mediators of inflammation.Thirdly, our previous analyses of bone marrow-derived human anti-C1q identified sequence homologies with von Willebrand Factor (vWF). In analogy to anti-C1q, vWF also binds to C1q leading to consecutive platelet rolling and adhesion, thus establishing a novel link between C1q and primary hemostasis. The focus of the third part of our project is to elucidate this link, in particular with regard to comorbidities as observed in SLE. Taken together, the proposed projects will elucidate the role of complement C1q and anti-C1q in interaction with other mediators of inflammation and factors that have been implicated in the pathogenesis of SLE. These data will also improve the understanding of immune-mediated pathology occurring related to but independently of autoimmunity. Significance of mannose-binding lectin and the lectin pathway in acute and recurrent ischemia/repefusion injury Research Project | 4 Project MembersMannose-binding lectin (MBL), a circulating pattern-recognition protein of the lectin pathway of complement is involved in the clearance of microorganisms and apoptotic cells. The concentration of functional MBL multimers is profoundly influenced by several polymorphisms in the MBL2 gene on chromosome 10, resulting in remarkable variations in serum MBL concentrations in apparently healthy individuals. Beyond infections, recent experimental studies have acknowledged additional important roles of MBL in atherosclerosis and ischemia/reperfusion (IR) injury. However, human data are scarce. This proposal aims to characterise in more depth the role of MBL and the lectin pathway in three human diseases, in which acute or repetitive I/R injury and/or atherosclerosis contribute to pathophysiology and outcome: systemic lupus erythematosus.primary (SLE), systemic sclerosis (SSc), and primary open angle glaucoma (POAG). In the SLE cohort sub-study, association of MBL deficiency with vascular events will be investigated in subjects from the well characterized Swiss SLE cohort. This is of importance, as SLE patients have an increased cardiovascular mortality and morbidity compared to the average individual. In the SSc cohort sub-study, activity of the lectin pathway including levels of MBL and the ficolins will be correlated with disease activity and organ involvement in individuals from a large European SSc cohort. Our preliminary data from a previous small Australian SSc cohort indicates that MBL deficiency might be associated with less organ damage. Hence, it might be worth to explore inhibition of the MBL or the lectin pathway in the future. In the POAG case-control sub-study, activity of the complement system in general and the lectin pathway in particular will be examined in POAG cases compared to healthy controls. This is of interest, as vascular dysfunction and repetitive I/R injury seem to be a hallmark in the pathogenesis of POAG, and current treatment options are limited. This project will lead to a more comprehensive understanding of the pathogenesis and the importance of MBL and the lectin pathway in I/R injury in SLE, SSc and POAG. Furthermore, it might facilitate future therapeutic interventions like inhibition of MBL or the lectin pathway to ameliorate I/R injury in these settings. Antibodies against complement C1q in systematic lupus erythematosus (SLE) Research Project | 1 Project MembersOur major goal is to understand pathogenic mechanisms in Systemic Lupus Erythematosus (SLE) in which a number of factors and systems have been shown to play an important role. Studying the origin and consequences of autoantibodies against the first component of the classical pathway of complement (C1q) offers the exceptional opportunity to elucidate the interplay of some of them, i.e. complement, apoptosis, Ebstein-Barr-Virus (EBV) and the coagulation system. A major hypothesis of the pathogenesis of SLE assumes that the disease is driven by a defective clearance of dead and dying cells. In the context of an altered clearance, dying cells could become antigenic and initiate an autoimmune response. Complement has been shown to play an important role in the clearance of apoptotic cells and the deficiency of one of the early components of the classical pathway of complement is strongly associated with the development of SLE. However, most SLE patients have no primary complement deficiency. In contrast, hypocomplementemia in SLE patients is a secondary event and most often associated with autoantibodies against C1q (anti-C1q). As we could show, anti-C1q strongly correlate with severe lupus nephritis suggesting that the occurrence of anti-C1q is necessary for the development of proliferative lupus nephritis. 1) Recently, we identified a major linear epitope targeted by anti-C1q. The dissection of its core amino acid sequence revealed a striking sequence homology with EBV suggesting cross-reactivity through molecular mimicry. This is a particularly interesting observation since EBV infection is considered to be essential for the occurrence of SLE and might be an important driver for the development of anti-C1q. 2) We could also demonstrate that binding of anti-C1q to C1q leads to complement activation via the classical pathway. However, since our previous studies showed that bone marrow-derived, affinity matured anti-C1q specifically bind to C1q bound on early apoptotic cells, it is likely that they interfere not only with the activation but also with other important functions of complement, e.g. the clearance of apoptotic cells. 3) Independently, our analyses of bone marrow-derived anti-C1q identified sequence homologies with von Willebrand Factor (vWF) suggesting that, at least in specific situations, vWF might also bind to C1q. In fact, we could demonstrate binding of vWF to bound C1q. Considering the binding characteristics of anti-C1q, C1q bound to apoptotic cells might allow the binding of vWF and consequently trigger platelet aggregation. Such a finding would for the first time demonstrate a direct link between an activating molecule of the complement cascade and a component of primary hemostasis. As a consequence, in this proposal we aim to examine 1) whether EBV-derived peptides can induce antibodies cross-reacting with C1q through molecular mimicry in vivo and to compare phage display derived anti-C1q and anti-EBV from SLE patients on a molecular level. 2) We will study the consequences of the binding of anti-C1q to C1q for phagocytic cells by the analysis of characteristics of macrophages and immature dendritic cells exposed to C1q-coated apoptotic cell material in the presence or absence of anti-C1q. 3) We will investigate the binding characteristics of vWF to C1q and its functional relevance. Taken together, the proposed projects based on the analysis of anti-C1q will help to understand the role of complement C1q, apoptosis, EBV and primary hemostasis in SLE. Considering the important role of these factors in SLE, data generated in this project will significantly improve the understanding of pathogenic mechanisms of the disease, including the understanding of driving factors and alterations in coagulation as frequently observed in SLE patients. Waste disposal in the pathogenesis of Systemic Lupus Erythematosus (SLE): The role of anti-C1q antibodies Research Project | 1 Project MembersNo Description available SHCS #637 Evaluation of the role of Mannose binding lectin (MBL) in HIV infected patients with and without CMV disease Research Project | 2 Project MembersNo Description available The Swiss SLE cohort study Research Project | 1 Project MembersThe aim of the project is to establish a Swiss cohort of patients with Systemic lupus erythemaosus (SLE) providing clinical data and biological samples for research on the pathogenesis, diagnostic procedures and treatment of SLE. The proposed structure of SSCS aims to reflect the particular interdisciplinary character of the disease as well as the federal structure of the health system. All patients with definitive or probable SLE according to the criteria of the American College of Rheumatology (ACR) will be included upon informed consent. Collected data consist of an essential dataset containing basic data on current and former disease manifestations, an extended dataset on disease activity and biological parameters, supplementary datasets on diagnostic procedures and treatment, and a quality-of-life questionnaire. Patient data is anonymised and then transferred to a central database. Serum, plasma, peripheral blood mononuclear cells (PBMC) and genomic nucleic acids are collected and stored at the recruiting centres until a central biobank will be established. Collection of follow-up data and blood samples will take place routinely every twelve months or earlier in case of flares. A cohort of well characterised SLE patients is likely to become an important investigational and long-term tool for clinical as well as experimental research on mechanisms of disease, disease manifestations, clinical outcomes and new therapeutic approaches. All Swiss medical institutions taking care of SLE patients are invited to participate. SSCS will serve as an interdisciplinary network between experimental and clinically oriented scientists, between different departments, between university and non-university hospitals, and between hospitals and practitioners. Existing or evolving scientific questions on SLE and on systemic autoimmunity in general may be addressed by separate research projects using SSCS' resources. 1 1 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 7 foundShow per page10 10 20 50 Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial. NFP 78 Research Project | 4 Project MembersSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally since December 2019 causing a worldwide pandemic of coronavirus disease 2019 (COVID-19). Systemic hyper-inflammation is a hallmark of severe stages of COVID-19 leading to acute lung injury (ALI), need for mechanical ventilation and ultimately death. The mechanism responsible for virus-induced hyper-activation of the host immune system remains to be fully elucidated. Unregulated complement system activation induced by CoVs plays a crucial role in the pathogenesis of acute lung injury in COVID-19. Similarly, involvement of the kinin-kallikrein system in capillary leakage and subsequent pulmonary angioedema has been suspected. In particular, a reduced activity of angiotensin converting enzyme 2 (ACE2) caused by SARS-CoV-2 leads to a relative abundance of bradykinin degradation products and local pulmonary edema. Lastly, over-activation of the contact activation system may be involved in the observed thromboinflammation. C1 esterase inhibitor (C1INH) is a potent inhibitor of these three plasmatic cascades and has been shown to reduce pulmonary inflammation and death in a CoV mouse model and in human studies of severe sepsis. Aims: To assess the safety and efficacy of recombinant C1INH (conestat alfa, Ruconest®) in addition to standard of care (SOC) in patients hospitalized with severe SARS-CoV-2 compared to SOC only.Hypothesis: Administration of conestat alfa for 72 hours in addition to SOC in patients with severe SARS-CoV-2 pneumonia is safe and associated with a reduced clinical severity on day 7 and a lower risk of disease progression to mechanical ventilation compared to SOC.Methodology: The PROTECT-COVID-19 trial is a randomized, open-label, parallel-group, controlled, multi-center clinical trial. Consecutive patients admitted with COVID-19 not requiring intensive care support will be randomized in a 2:1 ratio to treatment with conestat alfa for 72 hours in addition to SOC or SOC only. The primary endpoint will be the disease severity on the 7-point Ordinal WHO scale on day 7. Secondary endpoints include time to clinical improvement, the proportion of participants alive and not having required invasive or non-invasive ventilation and the incidence of ALI within 14 days after enrolment. Treatment safety and the activity of the above mentioned plasmatic cascades will be assessed. For a 2:1-randomization, a nonparametric analysis by the stratified logrank-test, and an adaptive group sequential analysis, the overall sample size is estimated as 120 = 80 + 40. Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels ap = 0.0221.Potential significance: Targeting multiple inflammatory cascades with conestat alfa early during COVID-19 is an innovative approach to prevent disease progression by ameliorating excessive (thrombo-) inflammation. Interventions that prevent deterioration and mechanical ventilation in COVID-19 are highly desired in a pandemic situation with limited ICU and ventilation support capacity. If treatment with conesta alfa proves to ameliorate pulmonary inflammation and injury, this may be relevant not only on an individual but also on a population level. Complement-dependent pathogenic mechanisms in systemic autoimmunity Research Project | 6 Project MembersSystemic Lupus Erythematosus (SLE) is the archetype of an autoimmune disease and can involve any organ system eventually leading to comorbidities that can also be observed independently of underlying SLE. The complex pathogenic mechanisms leading to and being involved in this autoimmune-inflammatory syndrome are not well understood. However, complement C1q, the first component of the classical pathway, seems to play a central role. By analysing the role of C1q as well as it's interaction with autoantibodies targeting C1q (anti-C1q) in SLE, the primary goals of the proposed projects are to elucidate 1) mechanisms being involved in the initiation of autoimmunity, 2) mechanisms of secondary acceleration of inflammation, and 3) processes being associated with comorbidities.With regard to mechanisms being involved in the initiation of SLE, homozygous C1q deficiency is the strongest genetic risk factor for the development of SLE. Vice versa, in SLE patients without primary C1q deficiency, C1q is consumed during disease flares, deposited in affected tissues and becoming a target of autoantibodies (anti-C1q). By the characterisation of structures targeted by anti-C1q we aim to understand mechanisms leading to the development of SLE.Secondly, C1q mediates and modulates the uptake of apoptotic cells, a mechanism that is defective in SLE patients. In the context of a defective clearance, dying cells can become antigenic and trigger the autoimmune response. In previous studies I could show that anti-C1q specifically recognize C1q when being bound to apoptotic cells and that anti-C1q induce a proinflammatory phenotype in macrophages being associated with reduced phagocytic capacity. To explore mechanisms of secondary inflammation, I will further investigate how C1q and anti-C1q interact with other mediators of inflammation.Thirdly, our previous analyses of bone marrow-derived human anti-C1q identified sequence homologies with von Willebrand Factor (vWF). In analogy to anti-C1q, vWF also binds to C1q leading to consecutive platelet rolling and adhesion, thus establishing a novel link between C1q and primary hemostasis. The focus of the third part of our project is to elucidate this link, in particular with regard to comorbidities as observed in SLE. Taken together, the proposed projects will elucidate the role of complement C1q and anti-C1q in interaction with other mediators of inflammation and factors that have been implicated in the pathogenesis of SLE. These data will also improve the understanding of immune-mediated pathology occurring related to but independently of autoimmunity. Significance of mannose-binding lectin and the lectin pathway in acute and recurrent ischemia/repefusion injury Research Project | 4 Project MembersMannose-binding lectin (MBL), a circulating pattern-recognition protein of the lectin pathway of complement is involved in the clearance of microorganisms and apoptotic cells. The concentration of functional MBL multimers is profoundly influenced by several polymorphisms in the MBL2 gene on chromosome 10, resulting in remarkable variations in serum MBL concentrations in apparently healthy individuals. Beyond infections, recent experimental studies have acknowledged additional important roles of MBL in atherosclerosis and ischemia/reperfusion (IR) injury. However, human data are scarce. This proposal aims to characterise in more depth the role of MBL and the lectin pathway in three human diseases, in which acute or repetitive I/R injury and/or atherosclerosis contribute to pathophysiology and outcome: systemic lupus erythematosus.primary (SLE), systemic sclerosis (SSc), and primary open angle glaucoma (POAG). In the SLE cohort sub-study, association of MBL deficiency with vascular events will be investigated in subjects from the well characterized Swiss SLE cohort. This is of importance, as SLE patients have an increased cardiovascular mortality and morbidity compared to the average individual. In the SSc cohort sub-study, activity of the lectin pathway including levels of MBL and the ficolins will be correlated with disease activity and organ involvement in individuals from a large European SSc cohort. Our preliminary data from a previous small Australian SSc cohort indicates that MBL deficiency might be associated with less organ damage. Hence, it might be worth to explore inhibition of the MBL or the lectin pathway in the future. In the POAG case-control sub-study, activity of the complement system in general and the lectin pathway in particular will be examined in POAG cases compared to healthy controls. This is of interest, as vascular dysfunction and repetitive I/R injury seem to be a hallmark in the pathogenesis of POAG, and current treatment options are limited. This project will lead to a more comprehensive understanding of the pathogenesis and the importance of MBL and the lectin pathway in I/R injury in SLE, SSc and POAG. Furthermore, it might facilitate future therapeutic interventions like inhibition of MBL or the lectin pathway to ameliorate I/R injury in these settings. Antibodies against complement C1q in systematic lupus erythematosus (SLE) Research Project | 1 Project MembersOur major goal is to understand pathogenic mechanisms in Systemic Lupus Erythematosus (SLE) in which a number of factors and systems have been shown to play an important role. Studying the origin and consequences of autoantibodies against the first component of the classical pathway of complement (C1q) offers the exceptional opportunity to elucidate the interplay of some of them, i.e. complement, apoptosis, Ebstein-Barr-Virus (EBV) and the coagulation system. A major hypothesis of the pathogenesis of SLE assumes that the disease is driven by a defective clearance of dead and dying cells. In the context of an altered clearance, dying cells could become antigenic and initiate an autoimmune response. Complement has been shown to play an important role in the clearance of apoptotic cells and the deficiency of one of the early components of the classical pathway of complement is strongly associated with the development of SLE. However, most SLE patients have no primary complement deficiency. In contrast, hypocomplementemia in SLE patients is a secondary event and most often associated with autoantibodies against C1q (anti-C1q). As we could show, anti-C1q strongly correlate with severe lupus nephritis suggesting that the occurrence of anti-C1q is necessary for the development of proliferative lupus nephritis. 1) Recently, we identified a major linear epitope targeted by anti-C1q. The dissection of its core amino acid sequence revealed a striking sequence homology with EBV suggesting cross-reactivity through molecular mimicry. This is a particularly interesting observation since EBV infection is considered to be essential for the occurrence of SLE and might be an important driver for the development of anti-C1q. 2) We could also demonstrate that binding of anti-C1q to C1q leads to complement activation via the classical pathway. However, since our previous studies showed that bone marrow-derived, affinity matured anti-C1q specifically bind to C1q bound on early apoptotic cells, it is likely that they interfere not only with the activation but also with other important functions of complement, e.g. the clearance of apoptotic cells. 3) Independently, our analyses of bone marrow-derived anti-C1q identified sequence homologies with von Willebrand Factor (vWF) suggesting that, at least in specific situations, vWF might also bind to C1q. In fact, we could demonstrate binding of vWF to bound C1q. Considering the binding characteristics of anti-C1q, C1q bound to apoptotic cells might allow the binding of vWF and consequently trigger platelet aggregation. Such a finding would for the first time demonstrate a direct link between an activating molecule of the complement cascade and a component of primary hemostasis. As a consequence, in this proposal we aim to examine 1) whether EBV-derived peptides can induce antibodies cross-reacting with C1q through molecular mimicry in vivo and to compare phage display derived anti-C1q and anti-EBV from SLE patients on a molecular level. 2) We will study the consequences of the binding of anti-C1q to C1q for phagocytic cells by the analysis of characteristics of macrophages and immature dendritic cells exposed to C1q-coated apoptotic cell material in the presence or absence of anti-C1q. 3) We will investigate the binding characteristics of vWF to C1q and its functional relevance. Taken together, the proposed projects based on the analysis of anti-C1q will help to understand the role of complement C1q, apoptosis, EBV and primary hemostasis in SLE. Considering the important role of these factors in SLE, data generated in this project will significantly improve the understanding of pathogenic mechanisms of the disease, including the understanding of driving factors and alterations in coagulation as frequently observed in SLE patients. Waste disposal in the pathogenesis of Systemic Lupus Erythematosus (SLE): The role of anti-C1q antibodies Research Project | 1 Project MembersNo Description available SHCS #637 Evaluation of the role of Mannose binding lectin (MBL) in HIV infected patients with and without CMV disease Research Project | 2 Project MembersNo Description available The Swiss SLE cohort study Research Project | 1 Project MembersThe aim of the project is to establish a Swiss cohort of patients with Systemic lupus erythemaosus (SLE) providing clinical data and biological samples for research on the pathogenesis, diagnostic procedures and treatment of SLE. The proposed structure of SSCS aims to reflect the particular interdisciplinary character of the disease as well as the federal structure of the health system. All patients with definitive or probable SLE according to the criteria of the American College of Rheumatology (ACR) will be included upon informed consent. Collected data consist of an essential dataset containing basic data on current and former disease manifestations, an extended dataset on disease activity and biological parameters, supplementary datasets on diagnostic procedures and treatment, and a quality-of-life questionnaire. Patient data is anonymised and then transferred to a central database. Serum, plasma, peripheral blood mononuclear cells (PBMC) and genomic nucleic acids are collected and stored at the recruiting centres until a central biobank will be established. Collection of follow-up data and blood samples will take place routinely every twelve months or earlier in case of flares. A cohort of well characterised SLE patients is likely to become an important investigational and long-term tool for clinical as well as experimental research on mechanisms of disease, disease manifestations, clinical outcomes and new therapeutic approaches. All Swiss medical institutions taking care of SLE patients are invited to participate. SSCS will serve as an interdisciplinary network between experimental and clinically oriented scientists, between different departments, between university and non-university hospitals, and between hospitals and practitioners. Existing or evolving scientific questions on SLE and on systemic autoimmunity in general may be addressed by separate research projects using SSCS' resources. 1 1
Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of critical SARS-CoV-2 infection in hospitalized patients with COVID-19: a randomized, parallel-group, openlabel, multi-center exploratory trial. NFP 78 Research Project | 4 Project MembersSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally since December 2019 causing a worldwide pandemic of coronavirus disease 2019 (COVID-19). Systemic hyper-inflammation is a hallmark of severe stages of COVID-19 leading to acute lung injury (ALI), need for mechanical ventilation and ultimately death. The mechanism responsible for virus-induced hyper-activation of the host immune system remains to be fully elucidated. Unregulated complement system activation induced by CoVs plays a crucial role in the pathogenesis of acute lung injury in COVID-19. Similarly, involvement of the kinin-kallikrein system in capillary leakage and subsequent pulmonary angioedema has been suspected. In particular, a reduced activity of angiotensin converting enzyme 2 (ACE2) caused by SARS-CoV-2 leads to a relative abundance of bradykinin degradation products and local pulmonary edema. Lastly, over-activation of the contact activation system may be involved in the observed thromboinflammation. C1 esterase inhibitor (C1INH) is a potent inhibitor of these three plasmatic cascades and has been shown to reduce pulmonary inflammation and death in a CoV mouse model and in human studies of severe sepsis. Aims: To assess the safety and efficacy of recombinant C1INH (conestat alfa, Ruconest®) in addition to standard of care (SOC) in patients hospitalized with severe SARS-CoV-2 compared to SOC only.Hypothesis: Administration of conestat alfa for 72 hours in addition to SOC in patients with severe SARS-CoV-2 pneumonia is safe and associated with a reduced clinical severity on day 7 and a lower risk of disease progression to mechanical ventilation compared to SOC.Methodology: The PROTECT-COVID-19 trial is a randomized, open-label, parallel-group, controlled, multi-center clinical trial. Consecutive patients admitted with COVID-19 not requiring intensive care support will be randomized in a 2:1 ratio to treatment with conestat alfa for 72 hours in addition to SOC or SOC only. The primary endpoint will be the disease severity on the 7-point Ordinal WHO scale on day 7. Secondary endpoints include time to clinical improvement, the proportion of participants alive and not having required invasive or non-invasive ventilation and the incidence of ALI within 14 days after enrolment. Treatment safety and the activity of the above mentioned plasmatic cascades will be assessed. For a 2:1-randomization, a nonparametric analysis by the stratified logrank-test, and an adaptive group sequential analysis, the overall sample size is estimated as 120 = 80 + 40. Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels ap = 0.0221.Potential significance: Targeting multiple inflammatory cascades with conestat alfa early during COVID-19 is an innovative approach to prevent disease progression by ameliorating excessive (thrombo-) inflammation. Interventions that prevent deterioration and mechanical ventilation in COVID-19 are highly desired in a pandemic situation with limited ICU and ventilation support capacity. If treatment with conesta alfa proves to ameliorate pulmonary inflammation and injury, this may be relevant not only on an individual but also on a population level.
Complement-dependent pathogenic mechanisms in systemic autoimmunity Research Project | 6 Project MembersSystemic Lupus Erythematosus (SLE) is the archetype of an autoimmune disease and can involve any organ system eventually leading to comorbidities that can also be observed independently of underlying SLE. The complex pathogenic mechanisms leading to and being involved in this autoimmune-inflammatory syndrome are not well understood. However, complement C1q, the first component of the classical pathway, seems to play a central role. By analysing the role of C1q as well as it's interaction with autoantibodies targeting C1q (anti-C1q) in SLE, the primary goals of the proposed projects are to elucidate 1) mechanisms being involved in the initiation of autoimmunity, 2) mechanisms of secondary acceleration of inflammation, and 3) processes being associated with comorbidities.With regard to mechanisms being involved in the initiation of SLE, homozygous C1q deficiency is the strongest genetic risk factor for the development of SLE. Vice versa, in SLE patients without primary C1q deficiency, C1q is consumed during disease flares, deposited in affected tissues and becoming a target of autoantibodies (anti-C1q). By the characterisation of structures targeted by anti-C1q we aim to understand mechanisms leading to the development of SLE.Secondly, C1q mediates and modulates the uptake of apoptotic cells, a mechanism that is defective in SLE patients. In the context of a defective clearance, dying cells can become antigenic and trigger the autoimmune response. In previous studies I could show that anti-C1q specifically recognize C1q when being bound to apoptotic cells and that anti-C1q induce a proinflammatory phenotype in macrophages being associated with reduced phagocytic capacity. To explore mechanisms of secondary inflammation, I will further investigate how C1q and anti-C1q interact with other mediators of inflammation.Thirdly, our previous analyses of bone marrow-derived human anti-C1q identified sequence homologies with von Willebrand Factor (vWF). In analogy to anti-C1q, vWF also binds to C1q leading to consecutive platelet rolling and adhesion, thus establishing a novel link between C1q and primary hemostasis. The focus of the third part of our project is to elucidate this link, in particular with regard to comorbidities as observed in SLE. Taken together, the proposed projects will elucidate the role of complement C1q and anti-C1q in interaction with other mediators of inflammation and factors that have been implicated in the pathogenesis of SLE. These data will also improve the understanding of immune-mediated pathology occurring related to but independently of autoimmunity.
Significance of mannose-binding lectin and the lectin pathway in acute and recurrent ischemia/repefusion injury Research Project | 4 Project MembersMannose-binding lectin (MBL), a circulating pattern-recognition protein of the lectin pathway of complement is involved in the clearance of microorganisms and apoptotic cells. The concentration of functional MBL multimers is profoundly influenced by several polymorphisms in the MBL2 gene on chromosome 10, resulting in remarkable variations in serum MBL concentrations in apparently healthy individuals. Beyond infections, recent experimental studies have acknowledged additional important roles of MBL in atherosclerosis and ischemia/reperfusion (IR) injury. However, human data are scarce. This proposal aims to characterise in more depth the role of MBL and the lectin pathway in three human diseases, in which acute or repetitive I/R injury and/or atherosclerosis contribute to pathophysiology and outcome: systemic lupus erythematosus.primary (SLE), systemic sclerosis (SSc), and primary open angle glaucoma (POAG). In the SLE cohort sub-study, association of MBL deficiency with vascular events will be investigated in subjects from the well characterized Swiss SLE cohort. This is of importance, as SLE patients have an increased cardiovascular mortality and morbidity compared to the average individual. In the SSc cohort sub-study, activity of the lectin pathway including levels of MBL and the ficolins will be correlated with disease activity and organ involvement in individuals from a large European SSc cohort. Our preliminary data from a previous small Australian SSc cohort indicates that MBL deficiency might be associated with less organ damage. Hence, it might be worth to explore inhibition of the MBL or the lectin pathway in the future. In the POAG case-control sub-study, activity of the complement system in general and the lectin pathway in particular will be examined in POAG cases compared to healthy controls. This is of interest, as vascular dysfunction and repetitive I/R injury seem to be a hallmark in the pathogenesis of POAG, and current treatment options are limited. This project will lead to a more comprehensive understanding of the pathogenesis and the importance of MBL and the lectin pathway in I/R injury in SLE, SSc and POAG. Furthermore, it might facilitate future therapeutic interventions like inhibition of MBL or the lectin pathway to ameliorate I/R injury in these settings.
Antibodies against complement C1q in systematic lupus erythematosus (SLE) Research Project | 1 Project MembersOur major goal is to understand pathogenic mechanisms in Systemic Lupus Erythematosus (SLE) in which a number of factors and systems have been shown to play an important role. Studying the origin and consequences of autoantibodies against the first component of the classical pathway of complement (C1q) offers the exceptional opportunity to elucidate the interplay of some of them, i.e. complement, apoptosis, Ebstein-Barr-Virus (EBV) and the coagulation system. A major hypothesis of the pathogenesis of SLE assumes that the disease is driven by a defective clearance of dead and dying cells. In the context of an altered clearance, dying cells could become antigenic and initiate an autoimmune response. Complement has been shown to play an important role in the clearance of apoptotic cells and the deficiency of one of the early components of the classical pathway of complement is strongly associated with the development of SLE. However, most SLE patients have no primary complement deficiency. In contrast, hypocomplementemia in SLE patients is a secondary event and most often associated with autoantibodies against C1q (anti-C1q). As we could show, anti-C1q strongly correlate with severe lupus nephritis suggesting that the occurrence of anti-C1q is necessary for the development of proliferative lupus nephritis. 1) Recently, we identified a major linear epitope targeted by anti-C1q. The dissection of its core amino acid sequence revealed a striking sequence homology with EBV suggesting cross-reactivity through molecular mimicry. This is a particularly interesting observation since EBV infection is considered to be essential for the occurrence of SLE and might be an important driver for the development of anti-C1q. 2) We could also demonstrate that binding of anti-C1q to C1q leads to complement activation via the classical pathway. However, since our previous studies showed that bone marrow-derived, affinity matured anti-C1q specifically bind to C1q bound on early apoptotic cells, it is likely that they interfere not only with the activation but also with other important functions of complement, e.g. the clearance of apoptotic cells. 3) Independently, our analyses of bone marrow-derived anti-C1q identified sequence homologies with von Willebrand Factor (vWF) suggesting that, at least in specific situations, vWF might also bind to C1q. In fact, we could demonstrate binding of vWF to bound C1q. Considering the binding characteristics of anti-C1q, C1q bound to apoptotic cells might allow the binding of vWF and consequently trigger platelet aggregation. Such a finding would for the first time demonstrate a direct link between an activating molecule of the complement cascade and a component of primary hemostasis. As a consequence, in this proposal we aim to examine 1) whether EBV-derived peptides can induce antibodies cross-reacting with C1q through molecular mimicry in vivo and to compare phage display derived anti-C1q and anti-EBV from SLE patients on a molecular level. 2) We will study the consequences of the binding of anti-C1q to C1q for phagocytic cells by the analysis of characteristics of macrophages and immature dendritic cells exposed to C1q-coated apoptotic cell material in the presence or absence of anti-C1q. 3) We will investigate the binding characteristics of vWF to C1q and its functional relevance. Taken together, the proposed projects based on the analysis of anti-C1q will help to understand the role of complement C1q, apoptosis, EBV and primary hemostasis in SLE. Considering the important role of these factors in SLE, data generated in this project will significantly improve the understanding of pathogenic mechanisms of the disease, including the understanding of driving factors and alterations in coagulation as frequently observed in SLE patients.
Waste disposal in the pathogenesis of Systemic Lupus Erythematosus (SLE): The role of anti-C1q antibodies Research Project | 1 Project MembersNo Description available
SHCS #637 Evaluation of the role of Mannose binding lectin (MBL) in HIV infected patients with and without CMV disease Research Project | 2 Project MembersNo Description available
The Swiss SLE cohort study Research Project | 1 Project MembersThe aim of the project is to establish a Swiss cohort of patients with Systemic lupus erythemaosus (SLE) providing clinical data and biological samples for research on the pathogenesis, diagnostic procedures and treatment of SLE. The proposed structure of SSCS aims to reflect the particular interdisciplinary character of the disease as well as the federal structure of the health system. All patients with definitive or probable SLE according to the criteria of the American College of Rheumatology (ACR) will be included upon informed consent. Collected data consist of an essential dataset containing basic data on current and former disease manifestations, an extended dataset on disease activity and biological parameters, supplementary datasets on diagnostic procedures and treatment, and a quality-of-life questionnaire. Patient data is anonymised and then transferred to a central database. Serum, plasma, peripheral blood mononuclear cells (PBMC) and genomic nucleic acids are collected and stored at the recruiting centres until a central biobank will be established. Collection of follow-up data and blood samples will take place routinely every twelve months or earlier in case of flares. A cohort of well characterised SLE patients is likely to become an important investigational and long-term tool for clinical as well as experimental research on mechanisms of disease, disease manifestations, clinical outcomes and new therapeutic approaches. All Swiss medical institutions taking care of SLE patients are invited to participate. SSCS will serve as an interdisciplinary network between experimental and clinically oriented scientists, between different departments, between university and non-university hospitals, and between hospitals and practitioners. Existing or evolving scientific questions on SLE and on systemic autoimmunity in general may be addressed by separate research projects using SSCS' resources.
