Aman Damara , Joanna Wegner , Emily R. Trzeciak , Antonia Kolb , Mahsa Nastaranpour , Rahul Khatri , Andrea Tuettenberg , Daniela Kramer , Stephan Grabbe , Fatemeh Shahneh
{"title":"LL37/self-DNA complexes mediate monocyte reprogramming","authors":"Aman Damara , Joanna Wegner , Emily R. Trzeciak , Antonia Kolb , Mahsa Nastaranpour , Rahul Khatri , Andrea Tuettenberg , Daniela Kramer , Stephan Grabbe , Fatemeh Shahneh","doi":"10.1016/j.clim.2024.110287","DOIUrl":"10.1016/j.clim.2024.110287","url":null,"abstract":"<div><p>LL37 alone and in complex with self-DNA triggers inflammatory responses in myeloid cells and plays a crucial role in the development of systemic autoimmune diseases, like psoriasis and systemic lupus erythematosus. We demonstrated that LL37/self-DNA complexes induce long-term metabolic and epigenetic changes in monocytes, enhancing their responsiveness to subsequent stimuli. Monocytes trained with LL37/self-DNA complexes and those derived from psoriatic patients exhibited heightened glycolytic and oxidative phosphorylation rates, elevated release of proinflammatory cytokines, and affected naïve CD4<sup>+</sup> T cells. Additionally, KDM6A/B, a demethylase of lysine 27 on histone 3, was upregulated in psoriatic monocytes and monocytes treated with LL37/self-DNA complexes. Inhibition of KDM6A/B reversed the trained immune phenotype by reducing proinflammatory cytokine production, metabolic activity, and the induction of IL-17-producing T cells by LL37/self-DNA-treated monocytes. Our findings highlight the role of LL37/self-DNA-induced innate immune memory in psoriasis pathogenesis, uncovering its impact on monocyte and T cell dynamics.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"265 ","pages":"Article 110287"},"PeriodicalIF":4.5,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003966/pdfft?md5=b66157a1bc7693c17a0092840843e743&pid=1-s2.0-S1521661624003966-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442207","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}
Tianyu Wang , Lichen Li , Shan Cao , Lele Sun , Gongqi Yu , Qianqian Xia , Tingting Liu , Qing Zhao , Zhenzhen Wang , Chuan Wang , Baoqi Yang , Yongxia Liu , Xuechao Chen , Shengli Chen , Guizhi Zhou , Hong Liu , Yonghu Sun , Furen Zhang
{"title":"Targeted serum proteome profiling reveals nicotinamide adenine dinucleotide phosphate (NADPH)-related biomarkers to discriminate linear IgA bullous disorder from dermatitis herpetiformis","authors":"Tianyu Wang , Lichen Li , Shan Cao , Lele Sun , Gongqi Yu , Qianqian Xia , Tingting Liu , Qing Zhao , Zhenzhen Wang , Chuan Wang , Baoqi Yang , Yongxia Liu , Xuechao Chen , Shengli Chen , Guizhi Zhou , Hong Liu , Yonghu Sun , Furen Zhang","doi":"10.1016/j.clim.2024.110291","DOIUrl":"10.1016/j.clim.2024.110291","url":null,"abstract":"<div><p>Linear IgA bullous dermatosis (LABD) and dermatitis herpetiformis (DH) represent the major subtypes of IgA mediated autoimmune bullous disorders. We sought to understand the disease etiology by using serum proteomics. We assessed 92 organ damage biomarkers in LABD, DH, and healthy controls using the Olink high-throughput proteomics. The positive proteomic serum biomarkers were used to correlate with clinical features and HLA type. Targeted proteomic analysis of IgA deposition bullous disorders vs. controls showed elevated biomarkers. Further clustering and enrichment analyses identified distinct clusters between LABD and DH, highlighting the involvement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Comparative analysis revealed biomarkers with distinction between LABD and DH and validated in the skin lesion. Finally, qualitative correlation analysis with DEPs suggested six biomarkers (NBN, NCF2, CAPG, FES, BID, and PXN) have better prognosis in DH patients. These findings provide potential biomarkers to differentiate the disease subtype of IgA deposition bullous disease.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"265 ","pages":"Article 110291"},"PeriodicalIF":4.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624004005/pdfft?md5=72b7da4f3da32420f326b1adf790dfef&pid=1-s2.0-S1521661624004005-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440265","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}
Hyun Lee , Miseon Lee , Chae Lyul Lim , Hye Seon Park , In Hye Song , Byung-Kwan Jeong , Dong Kwan Kim , Yong-Hee Kim , Sehoon Choi , Geun Dong Lee , Sae Byul Lee , SungWook Jung , Gyungyub Gong , Sung-Bae Kim , Changhoon Yoo , Joo Young Kim , Hee Jin Lee
{"title":"Expansion of tumor-infiltrating lymphocytes in non-small cell lung cancer: Clinical potential and efficacy in EGFR mutation subsets","authors":"Hyun Lee , Miseon Lee , Chae Lyul Lim , Hye Seon Park , In Hye Song , Byung-Kwan Jeong , Dong Kwan Kim , Yong-Hee Kim , Sehoon Choi , Geun Dong Lee , Sae Byul Lee , SungWook Jung , Gyungyub Gong , Sung-Bae Kim , Changhoon Yoo , Joo Young Kim , Hee Jin Lee","doi":"10.1016/j.clim.2024.110289","DOIUrl":"10.1016/j.clim.2024.110289","url":null,"abstract":"<div><p>Our study aimed to expand tumor-infiltrating lymphocytes (TILs) from primary non-small cell lung cancers (NSCLCs) and evaluate their reactivity against tumor cells. We expanded TILs from 103 primary NSCLCs using histopathological analysis, flow cytometry, IFN-γ release assays, cell-mediated cytotoxicity assays, and <em>in vivo</em> efficacy tests. TIL expansion was observed in all cases, regardless of <em>EGFR</em> mutation status. There was also an increase in the median CD4<sup>+</sup>/CD8<sup>+</sup> ratio during expansion. In post-rapid expansion protocol (REP) TILs, 13 out of 16 cases, including all three cases with <em>EGFR</em> mutations, exhibited a two-fold or greater increase in IFN-γ secretion. The cytotoxicity assay revealed enhanced tumor cell death in three of the seven cases, two of which had <em>EGFR</em> mutations. <em>In vivo</em> functional testing in a patient-derived xenograft model showed a reduction in tumor volume. The anti-tumor activity of post-REP TILs underscores their potential as a therapeutic option for advanced NSCLC, irrespective of mutation status.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"265 ","pages":"Article 110289"},"PeriodicalIF":4.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440264","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}
Coziana Ciurtin , Ghada Adly Helmy , Alexia Correia Ferreira , Jessica J. Manson , Elizabeth C. Jury , Thomas McDonnell
{"title":"A tale of two functions: C-reactive protein complement-ary structures and their role in rheumatoid arthritis","authors":"Coziana Ciurtin , Ghada Adly Helmy , Alexia Correia Ferreira , Jessica J. Manson , Elizabeth C. Jury , Thomas McDonnell","doi":"10.1016/j.clim.2024.110281","DOIUrl":"10.1016/j.clim.2024.110281","url":null,"abstract":"<div><p>C-reactive protein (CRP) is an inflammatory biomarker with associated clinical utility in a wide number of inflammatory disorders, including rheumatoid arthritis (RA). The interaction of CRP with pro-inflammatory cytokines has been explored before, however its role in complement regulation is more subtle, where CRP is capable of both up and downregulating the complement cascade. CRP is produced in a pentameric form and can dissociate to a monomeric form in circulation which has significant implications for its ability to interact with receptors and binding partners. This dichotomy of CRP structure could have relevance in patients with RA who have significant dysfunction in their complement cascade and also widely varying CRP levels including at the time of flare. This review aims to bring together current knowledge of CRP in its various forms, its effects on complement function and how this could influence pathology in the context of RA.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"265 ","pages":"Article 110281"},"PeriodicalIF":4.5,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003905/pdfft?md5=397fe8084f3264b5b0b1b47588435ea0&pid=1-s2.0-S1521661624003905-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141398017","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}
J. Soul , E. Carlsson , S.R. Hofmann , S. Russ , J. Hawkes , F. Schulze , M. Sergon , J. Pablik , S. Abraham , C.M. Hedrich
{"title":"Tissue gene expression profiles and communication networks inform candidate blood biomarker identification in psoriasis and atopic dermatitis","authors":"J. Soul , E. Carlsson , S.R. Hofmann , S. Russ , J. Hawkes , F. Schulze , M. Sergon , J. Pablik , S. Abraham , C.M. Hedrich","doi":"10.1016/j.clim.2024.110283","DOIUrl":"10.1016/j.clim.2024.110283","url":null,"abstract":"<div><p>Overlapping clinical and pathomechanistic features can complicate the diagnosis and treatment of inflammatory skin diseases, including psoriasis and atopic dermatitis (AD). Spatial transcriptomics allows the identification of disease- and cell-specific molecular signatures that may advance biomarker development and future treatments.</p><p>This study identified transcriptional signatures in keratinocytes and sub-basal CD4<sup>+</sup> and CD8<sup>+</sup> T lymphocytes from patients with psoriasis and AD. <em>In silico</em> prediction of ligand:receptor interactions delivered key signalling pathways (interferon, effector T cells, stroma cell and matrix biology, neuronal development, <em>etc.</em>). Targeted validation of selected transcripts, including CCL22, RELB, and JUND, in peripheral blood T cells suggests the chosen approach as a promising tool also in other inflammatory diseases.</p><p>Psoriasis and AD are characterized by transcriptional dysregulation in T cells and keratinocytes that may be targeted therapeutically. Spatial transcriptomics is a valuable tool in the search for molecular signatures that can be used as biomarkers and/or therapeutic targets.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"265 ","pages":"Article 110283"},"PeriodicalIF":8.6,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003929/pdfft?md5=cd23fd33b393b9c213d5242c41baf828&pid=1-s2.0-S1521661624003929-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330521","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}
Jenn-Haung Lai , De-Wei Wu , Chuan-Yueh Huang , Li-Feng Hung , Chien-Hsiang Wu , Ling-Jun Ho
{"title":"USP18 induction regulates immunometabolism to attenuate M1 signal-polarized macrophages and enhance IL-4-polarized macrophages in systemic lupus erythematosus","authors":"Jenn-Haung Lai , De-Wei Wu , Chuan-Yueh Huang , Li-Feng Hung , Chien-Hsiang Wu , Ling-Jun Ho","doi":"10.1016/j.clim.2024.110285","DOIUrl":"10.1016/j.clim.2024.110285","url":null,"abstract":"<div><p>Effective treatment of systemic lupus erythematosus (SLE) remains an unmet need. Different subsets of macrophages play differential roles in SLE and the modulation of macrophage polarization away from M1 status is beneficial for SLE therapeutics. Given the pathogenic roles of type I interferons (IFN-I) in SLE, this study investigated the effects and mechanisms of a mitochondria localization molecule ubiquitin specific peptidase 18 (USP18) preserving anti-IFN effects and isopeptidase activity on macrophage polarization. After observing USP18 induction in monocytes from SLE patients, we studied mouse bone marrow-derived macrophages and showed that USP18 deficiency increased M1signal (LPS + IFN-γ treatment)-induced macrophage polarization, and the effects involved the induction of glycolysis and mitochondrial respiration and the expression of several glycolysis-associated enzymes and molecules, such as hypoxia-inducible factor-1α. Moreover, the effects on mitochondrial activities, such as mitochondrial DNA release and mitochondrial reactive oxygen species production were observed. In contrast, the overexpression of USP18 inhibited M1signal-mediated and enhanced interleukin-4 (IL-4)-mediated polarization of macrophages and the related cellular events. Moreover, the levels of <em>USP18</em> mRNA expression showed tendency of correlation with the expression of metabolic enzymes in monocytes from patients with SLE. We thus concluded that by preserving anti-IFN effect and downregulating M1 signaling, promoting USP18 activity may serve as a useful approach for SLE therapeutics.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"265 ","pages":"Article 110285"},"PeriodicalIF":8.6,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330522","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}
Alexandru Tatomir , Sonia Vlaicu , Vinh Nguyen , Irina G. Luzina , Sergei P. Atamas , Cinthia Drachenberg , John Papadimitriou , Tudor C. Badea , Horea G. Rus , Violeta Rus
{"title":"RGC-32 mediates proinflammatory and profibrotic pathways in immune-mediated kidney disease","authors":"Alexandru Tatomir , Sonia Vlaicu , Vinh Nguyen , Irina G. Luzina , Sergei P. Atamas , Cinthia Drachenberg , John Papadimitriou , Tudor C. Badea , Horea G. Rus , Violeta Rus","doi":"10.1016/j.clim.2024.110279","DOIUrl":"10.1016/j.clim.2024.110279","url":null,"abstract":"<div><p>Systemic lupus erythematosus is an autoimmune disease that results in immune-mediated damage to kidneys and other organs. We investigated the role of response gene to complement-32 (RGC-32), a proinflammatory and profibrotic mediator induced by TGFβ and C5b-9, in nephrotoxic nephritis (NTN), an experimental model that mimics human lupus nephritis. Proteinuria, loss of renal function and kidney histopathology were attenuated in RGC-32 KO NTN mice. RGC-32 KO NTN mice displayed downregulation of the CCL20/CCR6 and CXCL9/CXCR3 ligand/receptor pairs resulting in decreased renal recruitment of IL-17<sup>+</sup> and IFNγ<sup>+</sup> cells and subsequent decrease in the influx of innate immune cells. RGC-32 deficiency attenuated renal fibrosis as demonstrated by decreased deposition of collagen I, III and fibronectin. Thus, RGC-32 is a unique mediator shared by the Th17 and Th1 dependent proinflammatory and profibrotic pathways and a potential novel therapeutic target in the treatment of immune complex mediated glomerulonephritis such as lupus nephritis.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"265 ","pages":"Article 110279"},"PeriodicalIF":8.6,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327296","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}
Litong Zhu , Yick Hei Wong , Sunny S.H. Wong , Simon C.Y. Cheung , Jason K.H. Sher , Irene Y.L. Yam , Susan Yung , Tak Mao Chan , Desmond Y.H. Yap
{"title":"Alterations in exhausted and classical memory B cells in lupus nephritis – Relationship with disease relapse","authors":"Litong Zhu , Yick Hei Wong , Sunny S.H. Wong , Simon C.Y. Cheung , Jason K.H. Sher , Irene Y.L. Yam , Susan Yung , Tak Mao Chan , Desmond Y.H. Yap","doi":"10.1016/j.clim.2024.110284","DOIUrl":"10.1016/j.clim.2024.110284","url":null,"abstract":"<div><h3>Introduction</h3><p>B cell exhaustion is a functional abnormality of B lymphocytes observed in chronic infections and shows association with autoreactivity. The role of exhausted and classical memory B cells in maintaining disease stability of lupus nephritis (LN) remains unclear.</p></div><div><h3>Methods</h3><p>We measured classical memory (CD19<sup>+</sup>CD21<sup>+</sup>CD27<sup>+</sup>), exhausted B cells (CD19<sup>+</sup>CD21<sup>−</sup>CD27<sup>−</sup>), and related cytokines in LN patients with multiple relapses (MR) (<em>n</em> = 15) and no relapse (NR) (n = 15) during disease remission. The expression of inhibitory/adhesion molecules, cell proliferation and calcium mobilization in classical memory and exhausted B cells were also assessed.</p></div><div><h3>Results</h3><p>The MR group had higher proportion of circulating exhausted and classical memory B cells compared to the NR group and healthy controls (HC) (p all <0.05 for MR vs. NR or HC). Blood levels of IL-6, BAFF, IL-21, CD62L, CXCR3 and Siglec-6 were all higher in the MR group (<em>p</em> < 0.05, for all). Exhausted B cells from the MR group showed higher FcRL4, CD22, CD85j and CD183 but lower CD62L expression than NR and HC groups. Exhausted B cells from MR patients exhibited reduced proliferation compared to NR patients and HC, while classical memory B cell proliferation in MR group was higher than the other two groups. Exhausted B cells from both MR and NR patients showed impaired calcium mobilization.</p></div><div><h3>Conclusion</h3><p>Alterations in exhausted and classical memory B cells are related to disease relapse in LN. These findings may help devise new strategies for monitoring disease activity and preventing relapse in LN.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":"265 ","pages":"Article 110284"},"PeriodicalIF":4.5,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003930/pdfft?md5=11b0e15f4ee4915608200ebb30e145ec&pid=1-s2.0-S1521661624003930-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327295","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}