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Georg Kochs - One of the best experts on this subject based on the ideXlab platform.
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Article Structure of Myxovirus Resistance Protein A Reveals Intra-and Intermolecular Domain Interactions Required for the Antiviral Function
2020Co-Authors: Song Gao, Georg Kochs, Otto Haller, Alexander Von Der Malsburg, Alexej Dick, Katja Faelber, Gunnar F Schrö, Oliver DaumkeAbstract:SUMMARY Human Myxovirus Resistance Protein 1 (MxA) is an interferon-induced dynamin-like GTPase that acts as a cell-autonomous host restriction factor against many viral pathogens including influenza viruses. To study the molecular principles of its antiviral activity, we determined the crystal structure of nucleotide-free MxA, which showed an extended threedomain architecture. The central bundle signaling element (BSE) connected the amino-terminal GTPase domain with the stalk via two hinge regions. MxA oligomerized in the crystal via the stalk and the BSE, which in turn interacted with the stalk of the neighboring monomer. We demonstrated that the intra-and intermolecular domain interplay between the BSE and stalk was essential for oligomerization and the antiviral function of MxA. Based on these results, we propose a structural model for the mechano-chemical coupling in ring-like MxA oligomers as the principle mechanism for this unique antiviral effector Protein
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equine mx2 is a restriction factor of equine infectious anemia virus eiav
Virology, 2018Co-Authors: Kristina Meier, Ananda Ayyappan Jaguva Vasudevan, Zeli Zhang, Ariane Bahr, Georg Kochs, Dieter Haussinger, Carsten MunkAbstract:Abstract Human Myxovirus Resistance Protein B (hMXB) is a restriction factor of HIV-1 that also inhibits a variety of retroviruses. However, hMXB is not antiviral against equine infectious anemia virus (EIAV). We show here that equine MX2 (eMX2) potently restricts EIAV in vitro. Additionally, eMX2 inhibits HIV-1 and other lentiviruses, including murine leukemia virus. Previously, it was reported that hMXB repression is reduced in hMXB Δ1–25, but not in GTP-binding mutant K131A and GTP-hydrolysis mutant T151A. In contrast to this phenomenon, our study indicates that eMX2 restriction is not diminished in eMX2 Δ1–25, but is in eMX2 K127A and T147A, which correspond to hMXB K131A and T151A, respectively. Thus, eMX2 may inhibit retroviral replication by a novel mechanism that differs from that of hMXB.
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Effects of allelic variations in the human Myxovirus Resistance Protein A on its antiviral activity.
The Journal of biological chemistry, 2018Co-Authors: Laura Graf, Alexej Dick, Oliver Daumke, Franziska Sendker, Emanuel Barth, Manja Marz, Georg KochsAbstract:Only a minority of patients infected with seasonal influenza A viruses exhibit a severe or fatal outcome of infection, but the reasons for this inter-individual variability in influenza susceptibility are unclear. To gain further insights into the molecular mechanisms underlying this variability, we investigated naturally occurring allelic variations of the Myxovirus Resistance 1 (MX1) gene coding for the influenza restriction factor MxA. The interferon-induced dynamin-like GTPase consists of an N-terminal GTPase domain, a bundle signaling element, and a C-terminal stalk responsible for oligomerization and viral target recognition. We used online databases to search for variations in the MX1 gene. Deploying in vitro approaches, we found that non-synonymous variations in the GTPase domain cause the loss of antiviral and enzymatic activities. Furthermore, we showed that these amino acid substitutions disrupt the interface for GTPase domain dimerization required for the stimulation of GTP hydrolysis. Variations in the stalk were neutral or slightly enhanced or abolished MxA antiviral function. Remarkably, two other stalk variants altered MxA's antiviral specificity. Variations causing the loss of antiviral activity were found only in heterozygous carriers. Interestingly, the inactive stalk variants blocked the antiviral activity of WT MxA in a dominant-negative way, suggesting that heterozygotes are phenotypically MxA-negative. In contrast, the GTPase-deficient variants showed no dominant-negative effect, indicating that heterozygous carriers should remain unaffected. Our results demonstrate that naturally occurring mutations in the human MX1 gene can influence MxA function, which may explain individual variations in influenza virus susceptibility in the human population.
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Role of Nucleotide Binding and GTPase Domain Dimerization in Dynamin-like Myxovirus Resistance Protein A for GTPase Activation and Antiviral Activity
The Journal of biological chemistry, 2015Co-Authors: Alexej Dick, Georg Kochs, Song Gao, Alexander Von Der Malsburg, Laura Graf, Daniel Olal, Oliver DaumkeAbstract:Myxovirus Resistance (Mx) GTPases are induced by interferon and inhibit multiple viruses, including influenza and human immunodeficiency viruses. They have the characteristic domain architecture of dynamin-related Proteins with an N-terminal GTPase (G) domain, a bundle signaling element, and a C-terminal stalk responsible for self-assembly and effector functions. Human MxA (also called MX1) is expressed in the cytoplasm and is partly associated with membranes of the smooth endoplasmic reticulum. It shows a Protein concentration-dependent increase in GTPase activity, indicating regulation of GTP hydrolysis via G domain dimerization. Here, we characterized a panel of G domain mutants in MxA to clarify the role of GTP binding and the importance of the G domain interface for the catalytic and antiviral function of MxA. Residues in the catalytic center of MxA and the nucleotide itself were essential for G domain dimerization and catalytic activation. In pulldown experiments, MxA recognized Thogoto virus nucleocapsid Proteins independently of nucleotide binding. However, both nucleotide binding and hydrolysis were required for the antiviral activity against Thogoto, influenza, and La Crosse viruses. We further demonstrate that GTP binding facilitates formation of stable MxA assemblies associated with endoplasmic reticulum membranes, whereas nucleotide hydrolysis promotes dynamic redistribution of MxA from cellular membranes to viral targets. Our study highlights the role of nucleotide binding and hydrolysis for the intracellular dynamics of MxA during its antiviral action.
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structure of Myxovirus Resistance Protein a reveals intra and intermolecular domain interactions required for the antiviral function
Immunity, 2011Co-Authors: Song Gao, Georg Kochs, Otto Haller, Alexander Von Der Malsburg, Alexej Dick, Katja Faelber, Gunnar F Schroder, Oliver DaumkeAbstract:Human Myxovirus Resistance Protein 1 (MxA) is an interferon-induced dynamin-like GTPase that acts as a cell-autonomous host restriction factor against many viral pathogens including influenza viruses. To study the molecular principles of its antiviral activity, we determined the crystal structure of nucleotide-free MxA, which showed an extended three-domain architecture. The central bundle signaling element (BSE) connected the amino-terminal GTPase domain with the stalk via two hinge regions. MxA oligomerized in the crystal via the stalk and the BSE, which in turn interacted with the stalk of the neighboring monomer. We demonstrated that the intra- and intermolecular domain interplay between the BSE and stalk was essential for oligomerization and the antiviral function of MxA. Based on these results, we propose a structural model for the mechano-chemical coupling in ring-like MxA oligomers as the principle mechanism for this unique antiviral effector Protein.
Oliver Daumke - One of the best experts on this subject based on the ideXlab platform.
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Article Structure of Myxovirus Resistance Protein A Reveals Intra-and Intermolecular Domain Interactions Required for the Antiviral Function
2020Co-Authors: Song Gao, Georg Kochs, Otto Haller, Alexander Von Der Malsburg, Alexej Dick, Katja Faelber, Gunnar F Schrö, Oliver DaumkeAbstract:SUMMARY Human Myxovirus Resistance Protein 1 (MxA) is an interferon-induced dynamin-like GTPase that acts as a cell-autonomous host restriction factor against many viral pathogens including influenza viruses. To study the molecular principles of its antiviral activity, we determined the crystal structure of nucleotide-free MxA, which showed an extended threedomain architecture. The central bundle signaling element (BSE) connected the amino-terminal GTPase domain with the stalk via two hinge regions. MxA oligomerized in the crystal via the stalk and the BSE, which in turn interacted with the stalk of the neighboring monomer. We demonstrated that the intra-and intermolecular domain interplay between the BSE and stalk was essential for oligomerization and the antiviral function of MxA. Based on these results, we propose a structural model for the mechano-chemical coupling in ring-like MxA oligomers as the principle mechanism for this unique antiviral effector Protein
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Effects of allelic variations in the human Myxovirus Resistance Protein A on its antiviral activity.
The Journal of biological chemistry, 2018Co-Authors: Laura Graf, Alexej Dick, Oliver Daumke, Franziska Sendker, Emanuel Barth, Manja Marz, Georg KochsAbstract:Only a minority of patients infected with seasonal influenza A viruses exhibit a severe or fatal outcome of infection, but the reasons for this inter-individual variability in influenza susceptibility are unclear. To gain further insights into the molecular mechanisms underlying this variability, we investigated naturally occurring allelic variations of the Myxovirus Resistance 1 (MX1) gene coding for the influenza restriction factor MxA. The interferon-induced dynamin-like GTPase consists of an N-terminal GTPase domain, a bundle signaling element, and a C-terminal stalk responsible for oligomerization and viral target recognition. We used online databases to search for variations in the MX1 gene. Deploying in vitro approaches, we found that non-synonymous variations in the GTPase domain cause the loss of antiviral and enzymatic activities. Furthermore, we showed that these amino acid substitutions disrupt the interface for GTPase domain dimerization required for the stimulation of GTP hydrolysis. Variations in the stalk were neutral or slightly enhanced or abolished MxA antiviral function. Remarkably, two other stalk variants altered MxA's antiviral specificity. Variations causing the loss of antiviral activity were found only in heterozygous carriers. Interestingly, the inactive stalk variants blocked the antiviral activity of WT MxA in a dominant-negative way, suggesting that heterozygotes are phenotypically MxA-negative. In contrast, the GTPase-deficient variants showed no dominant-negative effect, indicating that heterozygous carriers should remain unaffected. Our results demonstrate that naturally occurring mutations in the human MX1 gene can influence MxA function, which may explain individual variations in influenza virus susceptibility in the human population.
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Role of Nucleotide Binding and GTPase Domain Dimerization in Dynamin-like Myxovirus Resistance Protein A for GTPase Activation and Antiviral Activity
The Journal of biological chemistry, 2015Co-Authors: Alexej Dick, Georg Kochs, Song Gao, Alexander Von Der Malsburg, Laura Graf, Daniel Olal, Oliver DaumkeAbstract:Myxovirus Resistance (Mx) GTPases are induced by interferon and inhibit multiple viruses, including influenza and human immunodeficiency viruses. They have the characteristic domain architecture of dynamin-related Proteins with an N-terminal GTPase (G) domain, a bundle signaling element, and a C-terminal stalk responsible for self-assembly and effector functions. Human MxA (also called MX1) is expressed in the cytoplasm and is partly associated with membranes of the smooth endoplasmic reticulum. It shows a Protein concentration-dependent increase in GTPase activity, indicating regulation of GTP hydrolysis via G domain dimerization. Here, we characterized a panel of G domain mutants in MxA to clarify the role of GTP binding and the importance of the G domain interface for the catalytic and antiviral function of MxA. Residues in the catalytic center of MxA and the nucleotide itself were essential for G domain dimerization and catalytic activation. In pulldown experiments, MxA recognized Thogoto virus nucleocapsid Proteins independently of nucleotide binding. However, both nucleotide binding and hydrolysis were required for the antiviral activity against Thogoto, influenza, and La Crosse viruses. We further demonstrate that GTP binding facilitates formation of stable MxA assemblies associated with endoplasmic reticulum membranes, whereas nucleotide hydrolysis promotes dynamic redistribution of MxA from cellular membranes to viral targets. Our study highlights the role of nucleotide binding and hydrolysis for the intracellular dynamics of MxA during its antiviral action.
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structure of Myxovirus Resistance Protein a reveals intra and intermolecular domain interactions required for the antiviral function
Immunity, 2011Co-Authors: Song Gao, Georg Kochs, Otto Haller, Alexander Von Der Malsburg, Alexej Dick, Katja Faelber, Gunnar F Schroder, Oliver DaumkeAbstract:Human Myxovirus Resistance Protein 1 (MxA) is an interferon-induced dynamin-like GTPase that acts as a cell-autonomous host restriction factor against many viral pathogens including influenza viruses. To study the molecular principles of its antiviral activity, we determined the crystal structure of nucleotide-free MxA, which showed an extended three-domain architecture. The central bundle signaling element (BSE) connected the amino-terminal GTPase domain with the stalk via two hinge regions. MxA oligomerized in the crystal via the stalk and the BSE, which in turn interacted with the stalk of the neighboring monomer. We demonstrated that the intra- and intermolecular domain interplay between the BSE and stalk was essential for oligomerization and the antiviral function of MxA. Based on these results, we propose a structural model for the mechano-chemical coupling in ring-like MxA oligomers as the principle mechanism for this unique antiviral effector Protein.
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Structural basis of oligomerization in the stalk region of dynamin-like MxA.
Nature, 2010Co-Authors: Song Gao, Georg Kochs, Otto Haller, Alexander Von Der Malsburg, Susann Paeschke, Joachim Behlke, Oliver DaumkeAbstract:The interferon-inducible dynamin-like Myxovirus Resistance Protein 1 (MxA; also called MX1) GTPase is a key mediator of cell-autonomous innate immunity against pathogens such as influenza viruses. MxA partially localizes to COPI-positive membranes of the smooth endoplasmic reticulum-Golgi intermediate compartment. At the point of infection, it redistributes to sites of viral replication and promotes missorting of essential viral constituents. It has been proposed that the middle domain and the GTPase effector domain of dynamin-like GTPases constitute a stalk that mediates oligomerization and transmits conformational changes from the G domain to the target structure; however, the molecular architecture of this stalk has remained elusive. Here we report the crystal structure of the stalk of human MxA, which folds into a four-helical bundle. This structure tightly oligomerizes in the crystal in a criss-cross pattern involving three distinct interfaces and one loop. Mutations in each of these interaction sites interfere with native assembly, oligomerization, membrane binding and antiviral activity of MxA. On the basis of these results, we propose a structural model for dynamin oligomerization and stimulated GTP hydrolysis that is consistent with previous structural predictions and has functional implications for all members of the dynamin family.
Johanna Westra - One of the best experts on this subject based on the ideXlab platform.
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P27 Myxovirus Resistance Protein A is a useful additional histological marker for cutaneous lupus erythematosus
Poster presentations, 2020Co-Authors: Wietske M Lambers, Gilles F. H. Diercks, Femke M Homan, Berber Doornbos-van Der Meer, Hendrika Bootsma, Johanna Westra, Karina De LeeuwAbstract:Background Cutaneous Lupus Erythematosus (CLE) is a heterogeneous auto-inflammatory skin disease, that is to a great extent driven by type I and III interferon (IFN). Histology of skin biopsies plays an important role in the diagnostic confirmation of CLE. Unfortunately, no specific histological marker for CLE is available. In this study, we tested the diagnostic potential of immunostaining with Myxovirus Resistance Protein A (MxA), which is tightly induced by type I and type III IFN, in CLE skin biopsies. Methods 178 skin biopsy specimens were collected from the local pathology database. Various skin conditions were selected, provided that clinical diagnosis matched with histological diagnosis. Skin sections were incubated with anti-MxA (R&D systems, AF7946). Consecutively, rabbit anti goat-HRP conjugate (Dako, 0449) was added and sections were stained with diaminobenzidine. The expression of MxA was scored semi-quantitatively. Results MxA staining was strongly positive in 90.3% of lesional CLE skin sections (except lupus tumidus) and had a negative predictive value of 94%. The same MxA expression pattern was found in dermatomyositis, which is also an IFN-driven autoimmune disease. In some conditions, like perniosis and graft versus host disease, high expression could be found, but this was less consistent compared to CLE. Most other inflammatory skin diseases did show no or a low expression of MxA. (See figure 1). Conclusion MxA is strongly expressed in CLE skin with a high negative predictive value and is thus useful as additional diagnostic histological marker, expectedly resulting in restriction of misdiagnosis and treatment delay.
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interferon score is increased in incomplete systemic lupus erythematosus and correlates with Myxovirus Resistance Protein a in blood and skin
Arthritis Research & Therapy, 2019Co-Authors: Wietske M Lambers, Gilles F. H. Diercks, Hendrika Bootsma, Karina De Leeuw, Berber Doornbosvan Der Meer, Johanna WestraAbstract:OBJECTIVES: Patients with incomplete systemic lupus erythematosus (iSLE) have lupus features, but do not meet classification criteria for SLE. Type I interferons (IFN) are important early mediators in SLE, and IFN upregulation in incomplete SLE may be associated with progression to SLE. Since many patients present with skin symptoms, the aim of this study is to investigate IFN type I expression and IFN-related mediators in the blood and skin of iSLE patients. METHODS: Twenty-nine iSLE patients (ANA titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical criterion), 39 SLE patients with quiescent disease (fulfilling ACR or SLICC criteria, SLEDAI ≤4), and 22 healthy controls were included. IFN signature was measured in whole blood, based on 12 IFN-related genes, using RT-PCR, and IFN-score was calculated. IFN-related mediators Myxovirus-Resistance Protein A (MxA), IFN-γ-induced Protein 10 (IP-10), and monocyte chemoattractant Protein (MCP-1) were measured using ELISA. IFN type I expression in the unaffected skin was analyzed by immunostaining with MxA. RESULTS: IFN-score was increased in 50% of iSLE patients and 46% of SLE patients and correlated positively with the number of autoantibodies, anti-SSA titer, ESR, and IgG and negatively with C4 in iSLE. Levels of MxA correlated strongly with IFN-score (r = 0.78, p < 0.0001). Furthermore, MxA expression was found in 29% of unaffected skin biopsies of iSLE and 31% of SLE patients and also correlated with IFN-score (r = 0.54, p < 0.0001). CONCLUSIONS: IFN-score was increased in half of the iSLE patients, and given the correlation with complement and autoantibody diversity, this suggests a higher risk for disease progression. MxA in the blood and unaffected skin correlated strongly with the IFN-score and is possibly an easily applicable marker for IFN upregulation.
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interferon score is increased in incomplete systemic lupus erythematosus and correlates with Myxovirus Resistance Protein a in blood and skin
Arthritis Research & Therapy, 2019Co-Authors: Wietske M Lambers, Gilles F. H. Diercks, Hendrika Bootsma, Karina De Leeuw, Berber Doornbosvan Der Meer, Johanna WestraAbstract:Patients with incomplete systemic lupus erythematosus (iSLE) have lupus features, but do not meet classification criteria for SLE. Type I interferons (IFN) are important early mediators in SLE, and IFN upregulation in incomplete SLE may be associated with progression to SLE. Since many patients present with skin symptoms, the aim of this study is to investigate IFN type I expression and IFN-related mediators in the blood and skin of iSLE patients. Twenty-nine iSLE patients (ANA titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical criterion), 39 SLE patients with quiescent disease (fulfilling ACR or SLICC criteria, SLEDAI ≤4), and 22 healthy controls were included. IFN signature was measured in whole blood, based on 12 IFN-related genes, using RT-PCR, and IFN-score was calculated. IFN-related mediators Myxovirus-Resistance Protein A (MxA), IFN-γ-induced Protein 10 (IP-10), and monocyte chemoattractant Protein (MCP-1) were measured using ELISA. IFN type I expression in the unaffected skin was analyzed by immunostaining with MxA. IFN-score was increased in 50% of iSLE patients and 46% of SLE patients and correlated positively with the number of autoantibodies, anti-SSA titer, ESR, and IgG and negatively with C4 in iSLE. Levels of MxA correlated strongly with IFN-score (r = 0.78, p < 0.0001). Furthermore, MxA expression was found in 29% of unaffected skin biopsies of iSLE and 31% of SLE patients and also correlated with IFN-score (r = 0.54, p < 0.0001). IFN-score was increased in half of the iSLE patients, and given the correlation with complement and autoantibody diversity, this suggests a higher risk for disease progression. MxA in the blood and unaffected skin correlated strongly with the IFN-score and is possibly an easily applicable marker for IFN upregulation.
Wietske M Lambers - One of the best experts on this subject based on the ideXlab platform.
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P27 Myxovirus Resistance Protein A is a useful additional histological marker for cutaneous lupus erythematosus
Poster presentations, 2020Co-Authors: Wietske M Lambers, Gilles F. H. Diercks, Femke M Homan, Berber Doornbos-van Der Meer, Hendrika Bootsma, Johanna Westra, Karina De LeeuwAbstract:Background Cutaneous Lupus Erythematosus (CLE) is a heterogeneous auto-inflammatory skin disease, that is to a great extent driven by type I and III interferon (IFN). Histology of skin biopsies plays an important role in the diagnostic confirmation of CLE. Unfortunately, no specific histological marker for CLE is available. In this study, we tested the diagnostic potential of immunostaining with Myxovirus Resistance Protein A (MxA), which is tightly induced by type I and type III IFN, in CLE skin biopsies. Methods 178 skin biopsy specimens were collected from the local pathology database. Various skin conditions were selected, provided that clinical diagnosis matched with histological diagnosis. Skin sections were incubated with anti-MxA (R&D systems, AF7946). Consecutively, rabbit anti goat-HRP conjugate (Dako, 0449) was added and sections were stained with diaminobenzidine. The expression of MxA was scored semi-quantitatively. Results MxA staining was strongly positive in 90.3% of lesional CLE skin sections (except lupus tumidus) and had a negative predictive value of 94%. The same MxA expression pattern was found in dermatomyositis, which is also an IFN-driven autoimmune disease. In some conditions, like perniosis and graft versus host disease, high expression could be found, but this was less consistent compared to CLE. Most other inflammatory skin diseases did show no or a low expression of MxA. (See figure 1). Conclusion MxA is strongly expressed in CLE skin with a high negative predictive value and is thus useful as additional diagnostic histological marker, expectedly resulting in restriction of misdiagnosis and treatment delay.
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interferon score is increased in incomplete systemic lupus erythematosus and correlates with Myxovirus Resistance Protein a in blood and skin
Arthritis Research & Therapy, 2019Co-Authors: Wietske M Lambers, Gilles F. H. Diercks, Hendrika Bootsma, Karina De Leeuw, Berber Doornbosvan Der Meer, Johanna WestraAbstract:OBJECTIVES: Patients with incomplete systemic lupus erythematosus (iSLE) have lupus features, but do not meet classification criteria for SLE. Type I interferons (IFN) are important early mediators in SLE, and IFN upregulation in incomplete SLE may be associated with progression to SLE. Since many patients present with skin symptoms, the aim of this study is to investigate IFN type I expression and IFN-related mediators in the blood and skin of iSLE patients. METHODS: Twenty-nine iSLE patients (ANA titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical criterion), 39 SLE patients with quiescent disease (fulfilling ACR or SLICC criteria, SLEDAI ≤4), and 22 healthy controls were included. IFN signature was measured in whole blood, based on 12 IFN-related genes, using RT-PCR, and IFN-score was calculated. IFN-related mediators Myxovirus-Resistance Protein A (MxA), IFN-γ-induced Protein 10 (IP-10), and monocyte chemoattractant Protein (MCP-1) were measured using ELISA. IFN type I expression in the unaffected skin was analyzed by immunostaining with MxA. RESULTS: IFN-score was increased in 50% of iSLE patients and 46% of SLE patients and correlated positively with the number of autoantibodies, anti-SSA titer, ESR, and IgG and negatively with C4 in iSLE. Levels of MxA correlated strongly with IFN-score (r = 0.78, p < 0.0001). Furthermore, MxA expression was found in 29% of unaffected skin biopsies of iSLE and 31% of SLE patients and also correlated with IFN-score (r = 0.54, p < 0.0001). CONCLUSIONS: IFN-score was increased in half of the iSLE patients, and given the correlation with complement and autoantibody diversity, this suggests a higher risk for disease progression. MxA in the blood and unaffected skin correlated strongly with the IFN-score and is possibly an easily applicable marker for IFN upregulation.
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interferon score is increased in incomplete systemic lupus erythematosus and correlates with Myxovirus Resistance Protein a in blood and skin
Arthritis Research & Therapy, 2019Co-Authors: Wietske M Lambers, Gilles F. H. Diercks, Hendrika Bootsma, Karina De Leeuw, Berber Doornbosvan Der Meer, Johanna WestraAbstract:Patients with incomplete systemic lupus erythematosus (iSLE) have lupus features, but do not meet classification criteria for SLE. Type I interferons (IFN) are important early mediators in SLE, and IFN upregulation in incomplete SLE may be associated with progression to SLE. Since many patients present with skin symptoms, the aim of this study is to investigate IFN type I expression and IFN-related mediators in the blood and skin of iSLE patients. Twenty-nine iSLE patients (ANA titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical criterion), 39 SLE patients with quiescent disease (fulfilling ACR or SLICC criteria, SLEDAI ≤4), and 22 healthy controls were included. IFN signature was measured in whole blood, based on 12 IFN-related genes, using RT-PCR, and IFN-score was calculated. IFN-related mediators Myxovirus-Resistance Protein A (MxA), IFN-γ-induced Protein 10 (IP-10), and monocyte chemoattractant Protein (MCP-1) were measured using ELISA. IFN type I expression in the unaffected skin was analyzed by immunostaining with MxA. IFN-score was increased in 50% of iSLE patients and 46% of SLE patients and correlated positively with the number of autoantibodies, anti-SSA titer, ESR, and IgG and negatively with C4 in iSLE. Levels of MxA correlated strongly with IFN-score (r = 0.78, p < 0.0001). Furthermore, MxA expression was found in 29% of unaffected skin biopsies of iSLE and 31% of SLE patients and also correlated with IFN-score (r = 0.54, p < 0.0001). IFN-score was increased in half of the iSLE patients, and given the correlation with complement and autoantibody diversity, this suggests a higher risk for disease progression. MxA in the blood and unaffected skin correlated strongly with the IFN-score and is possibly an easily applicable marker for IFN upregulation.
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op0175 interferon signature might serve as early biomarker for development of lupus and correlates strongly with Myxovirus Resistance Protein a
Annals of the Rheumatic Diseases, 2018Co-Authors: Wietske M Lambers, Hendrika Bootsma, H Westra, Doornbosvan Der B Meer, Marcel F Jonkman, K De LeeuwAbstract:Background Incomplete systemic lupus erythematosus (iSLE) marks a group of patients with typical features of SLE, who do not meet classification criteria. Up to 55% progress to SLE, but there are no predictive markers available. Interferon (IFN) type-I is an important early mediator in SLE. The majority of SLE patients show upregulation of interferon-inducible genes. Levels of IFN-related soluble markers, which are more easily applicable, are also increased in SLE. Objectives To measure IFN signature and IFN-related soluble markers in iSLE patients to determine if these can serve as predictors of SLE. Methods Thirty iSLE patients (ANA titer ≥1:80, disease duration RNA was isolated from whole blood using PAXgene tubes, reversely transcribed to cDNA and quantitatively analysed by Real time PCR. IFN score was calculated based on cumulative expression of 12 IFN-related transcripts (IP-10, IFI44L, IFIT3, LY6E, MX1, SERPING1, IFITM1, IRF7, STAT1, C1QA, IFI16 and IRF9). A positive IFN-score was defined as >2 SD of the mean of the control group. Levels of IFN-related mediators, including IFN-γ induced Protein 10 (IP-10) and Myxovirus-Resistance Protein A (MxA) were measured using ELISA. Statistical significance between groups was tested with Mann-Whitney U tests. Correlations of continuous data were calculated using Spearman’s r test. Results Baseline characteristics are shown in table 1. An increased IFN score was present in 55% of iSLE patients (p=0.05) and 46% of SLE patients (p=0.07) (figure 1a).In iSLE, IFN score correlated positively with ESR (r=0.52, p=0.004), SSA titer (r=0.64, p=0.02) and cumulative number of ENA (r=0.57, p=0.001), and negatively with leukocyte count (r=-0.38, p=0.04), Hb (r=-0.39, p=0.04), and C4 (r=-0.47, p=0.01). SLEDAI, clinical symptoms, nor use of hydroxychloroquine were correlated with IFN score. Levels of MxA correlated strongly with IFN score in both iSLE (r=0.78, p Conclusions IFN-signature is present in 55% of patients with iSLE and correlates with ESR, autoantibody number, leukopenia, anaemia and hypocomplementemia. Interestingly, MxA levels correlated strongly with IFN-gene upregulation and thus might be a suitable and easily applicable surrogate marker for IFN type-I activity. iSLE patients with IFN upregulation might be those at most risk for disease progression; longitudinal data however should be awaited. Disclosure of Interest None declared
Petra Liskova - One of the best experts on this subject based on the ideXlab platform.
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Myxovirus Resistance Protein A mRNA Expression Kinetics in Multiple Sclerosis Patients Treated with IFNβ.
PloS one, 2017Co-Authors: Jana Libertínová, Eva Meluzínová, Aleš Tomek, Dana Horakova, Ivana Kovarova, Vaclav Matoska, Simona Kumstyrova, Miroslav Zajac, Eva Hyncicova, Petra LiskovaAbstract:INTRODUCTION Interferon-β (IFNs) is the first-line treatment for relapsing-remitting multiple sclerosis. Myxovirus Resistance Protein A (MxA) is a marker of IFNs bioactivity, which may be reduced by neutralizing antibodies (NAbs) against IFNs. The aim of the study was to analyze the kinetics of MxA mRNA expression during long-term IFNβ treatment and assess its predictive value. METHODS A prospective, observational, open-label, non-randomized study was designed in multiple sclerosis patients starting IFNs treatment. MxA mRNA was assessed prior to initiation of IFNs therapy and every three months subsequently. NAbs were assessed every six months. Assessment of relapses was scheduled every three months during 24 months of follow up. The disease activity was correlated to the pretreatment baseline MxA mRNA value. In NAb negative patients, clinical status was correlated to MxA mRNA values. RESULTS 119 patients were consecutively enrolled and 107 were included in the final analysis. There was no correlation of MxA mRNA expression levels between baseline and month three. Using survival analysis, none of the selected baseline MxA mRNA cut off points allowed prediction of time to first relapse on the treatment. In NAb negative patients, mean MxA mRNA levels did not significantly differ in patients irrespective of relapse status. CONCLUSION Baseline MxA mRNA does not predict the response to IFNs treatment or the clinical status of the disease and the level of MxA mRNA does not correlate with disease activity in NAb negative patients.
