Pub Date : 2024-07-15DOI: 10.1016/j.clim.2024.110312
STAT3 gain-of-function (GOF) variants results in a heterogeneous clinical syndrome characterized by early onset immunodeficiency, multi-organ autoimmunity, and lymphoproliferation. While 191 documented cases with STAT3 GOF variants have been reported, the impact of individual variants on immune regulation and the broad clinical spectrum remains unclear. We developed a Stat3p.L387R mouse model, mirroring a variant identified in a family exhibiting common STAT3 GOF symptoms, and rare phenotypes including pulmonary hypertension and retinal vasculitis. In vitro experiments revealed increased STAT3 phosphorylation, nuclear migration, and DNA binding of the variant. Our Stat3p.L387R model displayed similar traits from previous Stat3GOF strains, such as splenomegaly and lymphadenopathy. Notably, Stat3p.L387R/+ mice exhibited heightened embryonic lethality compared to prior Stat3GOF/+ models and ocular abnormalities were observed. This research underscores the variant-specific pathology in Stat3p.L387R/+ mice, highlighting the ability to recapitulate human STAT3 GOF syndrome in patient-specific transgenic murine models. Additionally, such models could facilitate tailored treatment development.
{"title":"A patient-based murine model recapitulates human STAT3 gain-of-function syndrome","authors":"","doi":"10.1016/j.clim.2024.110312","DOIUrl":"10.1016/j.clim.2024.110312","url":null,"abstract":"<div><p>STAT3 gain-of-function (GOF) variants results in a heterogeneous clinical syndrome characterized by early onset immunodeficiency, multi-organ autoimmunity, and lymphoproliferation. While 191 documented cases with <em>STAT3</em> GOF variants have been reported, the impact of individual variants on immune regulation and the broad clinical spectrum remains unclear. We developed a <em>Stat3</em><sup>p.L387R</sup> mouse model, mirroring a variant identified in a family exhibiting common <em>STAT3</em> GOF symptoms, and rare phenotypes including pulmonary hypertension and retinal vasculitis. <em>In vitro</em> experiments revealed increased STAT3 phosphorylation, nuclear migration, and DNA binding of the variant. Our <em>Stat3</em><sup>p.L387R</sup> model displayed similar traits from previous <em>Stat3</em><sup>GOF</sup> strains, such as splenomegaly and lymphadenopathy. Notably, <em>Stat3</em><sup>p.L387R/+</sup> mice exhibited heightened embryonic lethality compared to prior <em>Stat3</em><sup>GOF/+</sup> models and ocular abnormalities were observed. This research underscores the variant-specific pathology in <em>Stat3</em><sup>p.L387R/+</sup> mice, highlighting the ability to recapitulate human <em>STAT3</em> GOF syndrome in patient-specific transgenic murine models. Additionally, such models could facilitate tailored treatment development.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-14DOI: 10.1016/j.clim.2024.110307
{"title":"Corrigendum to “Demyelinating strain of mouse hepatitis virus infection bridging innate and adaptive immune response in the induction of demyelination” [Clinical Immunology 170 (2016) 9–19]","authors":"","doi":"10.1016/j.clim.2024.110307","DOIUrl":"10.1016/j.clim.2024.110307","url":null,"abstract":"","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624004169/pdfft?md5=9216344411d05812a02ab0ea9de88334&pid=1-s2.0-S1521661624004169-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-14DOI: 10.1016/j.clim.2024.110310
Systemic lupus erythematosus (SLE or lupus) is a complex autoimmune disease that can affect multiple organs. While the exact disease etiology remains incompletely understood, there is a suggested influence of X-chromosome dosage in the pathogenesis of lupus. Here, we report a rare case of a female patient diagnosed with mosaic Turner syndrome and subsequently presenting with juvenile-onset SLE. DNA methylation patterns were analyzed in this patient and compared with age-matched female SLE controls, revealing higher methylation levels in interferon-regulated genes previously shown to be hypomethylated in SLE. These data provide a potential link between a gene-dose effect from the X-chromosome and the lupus-defining epigenotype. We hypothesize that the attenuated demethylation in interferon-regulated genes might provide a protective effect explaining the rarity of SLE in Turner syndrome.
系统性红斑狼疮(SLE 或狼疮)是一种复杂的自身免疫性疾病,可影响多个器官。虽然人们对该病的确切病因尚不完全清楚,但有一种说法认为,X 染色体的剂量对狼疮的发病机制有影响。在此,我们报告了一例罕见的女性患者,她被诊断为马赛克特纳综合征,随后又出现了幼年型系统性红斑狼疮。我们对该患者的DNA甲基化模式进行了分析,并将其与年龄匹配的女性系统性红斑狼疮对照组进行了比较,结果发现干扰素调控基因的甲基化水平较高,而这些基因以前曾被证明在系统性红斑狼疮中甲基化水平较低。这些数据提供了 X 染色体基因剂量效应与狼疮定义表观遗传型之间的潜在联系。我们推测,干扰素调控基因的去甲基化减弱可能提供了一种保护作用,从而解释了特纳综合征中系统性红斑狼疮的罕见性。
{"title":"Rare Turner syndrome and lupus coexistence with insights from DNA methylation patterns","authors":"","doi":"10.1016/j.clim.2024.110310","DOIUrl":"10.1016/j.clim.2024.110310","url":null,"abstract":"<div><p>Systemic lupus erythematosus (SLE or lupus) is a complex autoimmune disease that can affect multiple organs. While the exact disease etiology remains incompletely understood, there is a suggested influence of X-chromosome dosage in the pathogenesis of lupus. Here, we report a rare case of a female patient diagnosed with mosaic Turner syndrome and subsequently presenting with juvenile-onset SLE. DNA methylation patterns were analyzed in this patient and compared with age-matched female SLE controls, revealing higher methylation levels in interferon-regulated genes previously shown to be hypomethylated in SLE. These data provide a potential link between a gene-dose effect from the X-chromosome and the lupus-defining epigenotype. We hypothesize that the attenuated demethylation in interferon-regulated genes might provide a protective effect explaining the rarity of SLE in Turner syndrome.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624004194/pdfft?md5=22bca384a0e1a66de9ab61fc2624456e&pid=1-s2.0-S1521661624004194-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-11DOI: 10.1016/j.clim.2024.110309
Psoriasis is a common inflammatory systemic disease characterized by pro-inflammatory macrophages activation (M1 macrophage) infiltrated in the dermal layer. How M1 macrophage contributes to psoriasis remains unknown. In this study, we found that adenosine A2A receptor (A2AR) agonist CGS 21680 HCl alleviated the imiquimod (IMQ) and mouse IL-23 Protein (rmIL-23)-induced psoriasis inflammation through reducing infiltration of M1. Conversely, Adora2a deletion in mice exacerbated psoriasis-like phenotype. Mechanistically, A2AR activation inhibited M1 macrophage activation via the NF-κB-KRT16 pathway to reduce the secretion of CXCL10/11 and inhibit Th1/17 differentiation. Notably, the KRT16 expression was first found in M1 macrophage in our study, not only in keratinocytes (KCs). CXCL10/11 are first identified as primarily derived from macrophages and dendritic cells (DCs) rather than KCs in psoriasis using single cell RNA sequencing (scRNA-Seq). In total, the study emphasizes the importance of M1 as an innate immune cell in pathogenesis of psoriasis.
{"title":"Adenosine A2A receptor activation regulates the M1 macrophages activation to initiate innate and adaptive immunity in psoriasis","authors":"","doi":"10.1016/j.clim.2024.110309","DOIUrl":"10.1016/j.clim.2024.110309","url":null,"abstract":"<div><p>Psoriasis is a common inflammatory systemic disease characterized by pro-inflammatory macrophages activation (M1 macrophage) infiltrated in the dermal layer. How M1 macrophage contributes to psoriasis remains unknown. In this study, we found that adenosine A2A receptor (A2AR) agonist CGS 21680 HCl alleviated the imiquimod (IMQ) and mouse IL-23 Protein (rmIL-23)-induced psoriasis inflammation through reducing infiltration of M1. Conversely, Adora2a deletion in mice exacerbated psoriasis-like phenotype. Mechanistically, A2AR activation inhibited M1 macrophage activation via the NF-κB-KRT16 pathway to reduce the secretion of CXCL10/11 and inhibit Th1/17 differentiation. Notably, the KRT16 expression was first found in M1 macrophage in our study, not only in keratinocytes (KCs). CXCL10/11 are first identified as primarily derived from macrophages and dendritic cells (DCs) rather than KCs in psoriasis using single cell RNA sequencing (scRNA-Seq). In total, the study emphasizes the importance of M1 as an innate immune cell in pathogenesis of psoriasis.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-11DOI: 10.1016/j.clim.2024.110308
Psoriasis is a chronic inflammatory skin disease connected with immune dysregulation. Macrophages are key inflammatory cells in psoriasis but the specific mechanism of their activation is not fully understood. Neutrophil extracellular traps (NETs) have been shown to regulate macrophage function. Here, we found that NET deposition was increased in psoriasis lesions. Peptidylarginine deaminase 4 (PAD4, a key enzyme for NET formation) deficiency attenuated skin lesions and inflammation in an imiquimod-induced psoriatic mouse model. Furthermore, the STING signaling pathway was markedly activated in psoriasis and abolished by PAD4 deficiency. PAD4-deficient mice treated with the STING agonist DMXAA exhibited more severe symptoms and inflammation than control mice. Mechanistically, the STING inhibitor C-176 inhibited NET-induced macrophage inflammation and further inhibited the proliferation of HaCaT cells. Our findings suggest an important role of NETs in the pathogenesis of psoriasis, and activation of macrophage STING/NF-κB signaling pathway might involve in NETs related psoriasis.
{"title":"Neutrophil extracellular traps promote macrophage inflammation in psoriasis","authors":"","doi":"10.1016/j.clim.2024.110308","DOIUrl":"10.1016/j.clim.2024.110308","url":null,"abstract":"<div><p>Psoriasis is a chronic inflammatory skin disease connected with immune dysregulation. Macrophages are key inflammatory cells in psoriasis but the specific mechanism of their activation is not fully understood. Neutrophil extracellular traps (NETs) have been shown to regulate macrophage function. Here, we found that NET deposition was increased in psoriasis lesions. Peptidylarginine deaminase 4 (PAD4, a key enzyme for NET formation) deficiency attenuated skin lesions and inflammation in an imiquimod-induced psoriatic mouse model. Furthermore, the STING signaling pathway was markedly activated in psoriasis and abolished by PAD4 deficiency. PAD4-deficient mice treated with the STING agonist DMXAA exhibited more severe symptoms and inflammation than control mice. Mechanistically, the STING inhibitor C-176 inhibited NET-induced macrophage inflammation and further inhibited the proliferation of HaCaT cells. Our findings suggest an important role of NETs in the pathogenesis of psoriasis, and activation of macrophage STING/NF-κB signaling pathway might involve in NETs related psoriasis.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-11DOI: 10.1016/j.clim.2024.110313
Autoimmunity is a normal physiological state that requires immunological homeostasis and surveillance, whereas necroptosis is a type of inflammatory cell death. When necroptosis occurs, various immune system cells must perform their appropriate duties to preserve immunological homeostasis, whether the consequence is expanding or limiting the inflammatory response and the pathological condition is cleared or progresses to the autoimmune disease stage. This article discusses necroptosis based on RIP homotypic interaction motif (RHIM) interaction under various physiological and pathological situations, with the RIPK1-RIPK3-MLKL necrosome serving as the regulatory core. In addition, the cell biology of necroptosis involved in autoimmunity and its application in autoimmune diseases were also reviewed.
{"title":"Necroptosis and autoimmunity","authors":"","doi":"10.1016/j.clim.2024.110313","DOIUrl":"10.1016/j.clim.2024.110313","url":null,"abstract":"<div><p>Autoimmunity is a normal physiological state that requires immunological homeostasis and surveillance, whereas necroptosis is a type of inflammatory cell death. When necroptosis occurs, various immune system cells must perform their appropriate duties to preserve immunological homeostasis, whether the consequence is expanding or limiting the inflammatory response and the pathological condition is cleared or progresses to the autoimmune disease stage. This article discusses necroptosis based on RIP homotypic interaction motif (RHIM) interaction under various physiological and pathological situations, with the RIPK1-RIPK3-MLKL necrosome serving as the regulatory core. In addition, the cell biology of necroptosis involved in autoimmunity and its application in autoimmune diseases were also reviewed.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1016/j.clim.2024.110311
Chimeric antigen receptor T cell (CAR-T) therapy is a promising treatment for hematologic tumors, and adverse events of acute kidney injury (AKI) have been reported. However, its incidence, clinical characteristics, and prognosis remained unclear. We searched PubMed, EMBASE, and Web of Science for study about AKI after CAR-T therapy, a total of 15 studies, comprising 694 patients, were included. Among the 694 patients, 154 (22%) developed AKI, of which 89 (57.8%) were in stage 1, 59 (38.3%) were in stage 2 or 3, and 6 (3.9%) were not reported. Cytokine release syndrome is considered to be the most common cause of AKI. Of the 154 AKI patients, only 16 (10.4%) received renal replacement therapy, most AKI recovered renal function after symptomatic treatment. Although the occurrence of AKI after CAR-T therapy is rare and mostly mild, active knowledge of its pathogenesis, timely diagnosis and treatment are necessary for clinicians.
嵌合抗原受体 T 细胞(CAR-T)疗法是一种很有前景的血液肿瘤治疗方法,但也有急性肾损伤(AKI)不良事件的报道。然而,其发病率、临床特征和预后仍不清楚。我们在PubMed、EMBASE和Web of Science上检索了有关CAR-T治疗后AKI的研究,共纳入15项研究,包括694名患者。在 694 例患者中,154 例(22%)发生了 AKI,其中 88 例(57.1%)为 1 期,60 例(39.0%)为 2/3 期,6 例(3.9%)未报告。细胞因子释放综合征被认为是导致 AKI 的最常见原因,其次是肿瘤溶解综合征。在154例AKI患者中,只有15例接受了肾脏替代治疗,大多数AKI患者在对症治疗后恢复了肾功能。虽然CAR-T治疗后发生AKI的情况很少见,而且大多较轻,但临床医生有必要积极了解其发病机制,及时诊断和治疗。
{"title":"Acute kidney injury following chimeric antigen receptor T-cell therapy: Epidemiology, mechanism and prognosis","authors":"","doi":"10.1016/j.clim.2024.110311","DOIUrl":"10.1016/j.clim.2024.110311","url":null,"abstract":"<div><p>Chimeric antigen receptor T cell (CAR-T) therapy is a promising treatment for hematologic tumors, and adverse events of acute kidney injury (AKI) have been reported. However, its incidence, clinical characteristics, and prognosis remained unclear. We searched PubMed, EMBASE, and Web of Science for study about AKI after CAR-T therapy, a total of 15 studies, comprising 694 patients, were included. Among the 694 patients, 154 (22%) developed AKI, of which 89 (57.8%) were in stage 1, 59 (38.3%) were in stage 2 or 3, and 6 (3.9%) were not reported. Cytokine release syndrome is considered to be the most common cause of AKI. Of the 154 AKI patients, only 16 (10.4%) received renal replacement therapy, most AKI recovered renal function after symptomatic treatment. Although the occurrence of AKI after CAR-T therapy is rare and mostly mild, active knowledge of its pathogenesis, timely diagnosis and treatment are necessary for clinicians.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-06DOI: 10.1016/j.clim.2024.110306
Benedicte Alary , Pascal Cintas , Corentin Claude , Olivier Dellis , Corinne Thèze , Charles Van Goethem , Mireille Cossée , Martin Krahn , Valérie Delague , Marc Bartoli
Store-operated calcium entry (SOCE) plays a crucial role in maintaining cellular calcium homeostasis. This mechanism involves proteins, such as stromal interaction molecule 1 (STIM1) and ORAI1. Mutations in the genes encoding these proteins, especially STIM1, can lead to various diseases, including CRAC channelopathies associated with severe combined immunodeficiency. Herein, we describe a novel homozygous mutation, NM_003156 c.792-3C > G, in STIM1 in a patient with a clinical profile of CRAC channelopathy, including immune system deficiencies and muscle weakness. Functional analyses revealed three distinct spliced forms in the patient cells: wild-type, exon 7 skipping, and intronic retention. Calcium influx analysis revealed impaired SOCE in the patient cells, indicating a loss of STIM1 function. We developed an antisense oligonucleotide treatment that improves STIM1 splicing and highlighted its potential as a therapeutic approach. Our findings provide insights into the complex effects of STIM1 mutations and shed light on the multifaceted clinical presentation of the patient.
{"title":"Store-operated calcium entry dysfunction in CRAC channelopathy: Insights from a novel STIM1 mutation","authors":"Benedicte Alary , Pascal Cintas , Corentin Claude , Olivier Dellis , Corinne Thèze , Charles Van Goethem , Mireille Cossée , Martin Krahn , Valérie Delague , Marc Bartoli","doi":"10.1016/j.clim.2024.110306","DOIUrl":"10.1016/j.clim.2024.110306","url":null,"abstract":"<div><p>Store-operated calcium entry (SOCE) plays a crucial role in maintaining cellular calcium homeostasis. This mechanism involves proteins, such as stromal interaction molecule 1 (STIM1) and ORAI1. Mutations in the genes encoding these proteins, especially STIM1, can lead to various diseases, including CRAC channelopathies associated with severe combined immunodeficiency. Herein, we describe a novel homozygous mutation, NM_003156 c.792-3C > G, in <em>STIM1</em> in a patient with a clinical profile of CRAC channelopathy, including immune system deficiencies and muscle weakness. Functional analyses revealed three distinct spliced forms in the patient cells: wild-type, exon 7 skipping, and intronic retention. Calcium influx analysis revealed impaired SOCE in the patient cells, indicating a loss of STIM1 function. We developed an antisense oligonucleotide treatment that improves <em>STIM1</em> splicing and highlighted its potential as a therapeutic approach. Our findings provide insights into the complex effects of <em>STIM1</em> mutations and shed light on the multifaceted clinical presentation of the patient.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624004157/pdfft?md5=598d2d3cc8fdad3fd207d9ab0d1e7045&pid=1-s2.0-S1521661624004157-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05DOI: 10.1016/j.clim.2024.110305
S. Rischke , S.M.G. Schäfer , A. König , T. Ickelsheimer , M. Köhm , L. Hahnefeld , A. Zaliani , K. Scholich , A. Pinter , G. Geisslinger , F. Behrens , R. Gurke
Auto-inflammatory skin diseases place considerable symptomatic and emotional burden on the affected and put pressure on healthcare expenditures. Although most apparent symptoms manifest on the skin, the systemic inflammation merits a deeper analysis beyond the surface. We set out to identify systemic commonalities, as well as differences in the metabolome and lipidome when comparing between diseases and healthy controls. Lipidomic and metabolomic LC-MS profiling was applied, using plasma samples collected from patients suffering from atopic dermatitis, plaque-type psoriasis or hidradenitis suppurativa or healthy controls. Plasma profiles revealed a notable shift in the non-enzymatic anti-oxidant defense in all three inflammatory disorders, placing cysteine metabolism at the center of potential dysregulation. Lipid network enrichment additionally indicated the disease-specific provision of lipid mediators associated with key roles in inflammation signaling. These findings will help to disentangle the systemic components of autoimmune dermatological diseases, paving the way to individualized therapy and improved prognosis.
{"title":"Metabolomic and lipidomic fingerprints in inflammatory skin diseases – Systemic illumination of atopic dermatitis, hidradenitis suppurativa and plaque psoriasis","authors":"S. Rischke , S.M.G. Schäfer , A. König , T. Ickelsheimer , M. Köhm , L. Hahnefeld , A. Zaliani , K. Scholich , A. Pinter , G. Geisslinger , F. Behrens , R. Gurke","doi":"10.1016/j.clim.2024.110305","DOIUrl":"10.1016/j.clim.2024.110305","url":null,"abstract":"<div><p>Auto-inflammatory skin diseases place considerable symptomatic and emotional burden on the affected and put pressure on healthcare expenditures. Although most apparent symptoms manifest on the skin, the systemic inflammation merits a deeper analysis beyond the surface. We set out to identify systemic commonalities, as well as differences in the metabolome and lipidome when comparing between diseases and healthy controls. Lipidomic and metabolomic LC-MS profiling was applied, using plasma samples collected from patients suffering from atopic dermatitis, plaque-type psoriasis or hidradenitis suppurativa or healthy controls. Plasma profiles revealed a notable shift in the non-enzymatic anti-oxidant defense in all three inflammatory disorders, placing cysteine metabolism at the center of potential dysregulation. Lipid network enrichment additionally indicated the disease-specific provision of lipid mediators associated with key roles in inflammation signaling. These findings will help to disentangle the systemic components of autoimmune dermatological diseases, paving the way to individualized therapy and improved prognosis.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624004145/pdfft?md5=72255d2f3023b416d5ed14820582bb3f&pid=1-s2.0-S1521661624004145-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-03DOI: 10.1016/j.clim.2024.110303
Marcelo Afonso , Jitong Sun , Koji Sakuraba , Alexandra Cîrciumaru , Denis Lagutkin , Maša Filipović , Anca I. Catrina , Caroline Grönwall , Aase Hensvold , Bence Réthi
We studied the effects of rheumatoid arthritis (RA) autoantibodies that target malondialdehyde-acetaldehyde protein adducts (anti-MAA) on inflammation and macrophage functions. We detected a profound reprogramming of gene expressions and the production of chemokines, such as CCL22 and CCL24, in anti-MAA exposed macrophages. Moreover, anti-MAA pretreatment promoted a more inflammatory cytokine profile upon TLR activation. Although anti-MAA are typically multi-reactive, we observed a prominent clonal diversity in inducing macrophage activation. Anti-MAA antibodies were not arthritogenic in mice, but altered a set of cytokine and growth factor encoding genes in the joints. In individuals at risk of RA anti-MAA IgG levels correlated with circulating inflammatory mediators prior to and at arthritis onset. Certain IgG anti-MAA clones may thus contribute to an inflammatory priming of the joint prior to the onset of systemic inflammation via inducing FcγR-mediated macrophage pre-activation and setting the stage for augmented responses to subsequent inflammatory stimuli.
我们研究了以丙二醛-乙醛蛋白加合物为靶点的类风湿性关节炎(RA)自身抗体(抗MAA)对炎症和巨噬细胞功能的影响。我们检测到抗-MAA暴露的巨噬细胞的基因表达和趋化因子(如CCL22和CCL24)的产生发生了深刻的重编程。此外,在 TLR 激活时,抗-MAA 预处理促进了炎性细胞因子谱的形成。虽然抗MAA通常具有多重反应性,但我们观察到诱导巨噬细胞活化的克隆具有显著的多样性。抗MAA抗体不会导致小鼠关节炎,但会改变关节中的一系列细胞因子和生长因子编码基因。在有患 RA 风险的个体中,抗 MAA IgG 水平与关节炎发病前和发病时的循环炎症介质相关。因此,某些 IgG 抗MAA 克隆可能通过诱导 FcγR 介导的巨噬细胞预激活,并为增强对后续炎症刺激的反应创造条件,从而在全身性炎症开始之前对关节的炎症启动做出贡献。
{"title":"Macrophage activation and inflammatory priming by anti-MAA antibodies in rheumatoid arthritis","authors":"Marcelo Afonso , Jitong Sun , Koji Sakuraba , Alexandra Cîrciumaru , Denis Lagutkin , Maša Filipović , Anca I. Catrina , Caroline Grönwall , Aase Hensvold , Bence Réthi","doi":"10.1016/j.clim.2024.110303","DOIUrl":"10.1016/j.clim.2024.110303","url":null,"abstract":"<div><p>We studied the effects of rheumatoid arthritis (RA) autoantibodies that target malondialdehyde-acetaldehyde protein adducts (anti-MAA) on inflammation and macrophage functions. We detected a profound reprogramming of gene expressions and the production of chemokines, such as CCL22 and CCL24, in anti-MAA exposed macrophages. Moreover, anti-MAA pretreatment promoted a more inflammatory cytokine profile upon TLR activation. Although anti-MAA are typically multi-reactive, we observed a prominent clonal diversity in inducing macrophage activation. Anti-MAA antibodies were not arthritogenic in mice, but altered a set of cytokine and growth factor encoding genes in the joints. In individuals at risk of RA anti-MAA IgG levels correlated with circulating inflammatory mediators prior to and at arthritis onset. Certain IgG anti-MAA clones may thus contribute to an inflammatory priming of the joint prior to the onset of systemic inflammation via inducing FcγR-mediated macrophage pre-activation and setting the stage for augmented responses to subsequent inflammatory stimuli.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624004121/pdfft?md5=c455424ea332b91cc0df91c01f59f5fc&pid=1-s2.0-S1521661624004121-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}