medRxiv - Allergy and Immunology最新文献

{"title":"The extent and impact of vaccine status miscategorisation on covid-19 vaccine efficacy studies","authors":"Martin Neil, Scott McLachlan, Norman Fenton","doi":"10.1101/2024.03.09.24304015","DOIUrl":"https://doi.org/10.1101/2024.03.09.24304015","url":null,"abstract":"It is recognised that many studies reporting high efficacy for Covid-19 vaccines suffer from various selection biases. Systematic review identified thirty-nine studies that suffered from one particular and serious form of bias called miscategorisation bias, whereby study participants who have been vaccinated are categorised as unvaccinated up to and until some arbitrarily defined time after vaccination occurred. Simulation demonstrates that this miscategorisation bias artificially boosts vaccine efficacy and infection rates even when a vaccine has zero or negative efficacy. Furthermore, simulation demonstrates that repeated boosters, given every few months, are needed to maintain this misleading impression of efficacy. Given this, any claims of Covid-19 vaccine efficacy based on these studies are likely to be a statistical illusion.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140156005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical multi-omics reveals the role of Tuomin Zhiti Decoction Intervention in Allergic Rhinitis from the perspective of biological network","authors":"Weibo Zhao, Boyang Wang, Lingyao Kong, Qi Wang, Shao Li","doi":"10.1101/2024.03.10.24303911","DOIUrl":"https://doi.org/10.1101/2024.03.10.24303911","url":null,"abstract":"Background: Increasing evidence showed that seasonal allergic rhinitis (SAR), as an allergy disease, could be alleviated with traditional Chinese medicine (TCM) formula, one example being Tuomin Zhiti Decoction (TZD). However, as a complex composition of TCM herbs, the mechanism of TZD in the treatment of SAR remain unclear.\u0000Purpose: Uncover the mechanism of TZD for treating SAR based on computational analysis and clinical multi-omics experiments.\u0000Study design: Integrate computational analysis including network target analysis and machine learning algorithms with clinical multi-omics experiments and public omics data.\u0000Methods: By analyzing TZD's composition through a network-based method, we identified the biological effects of each compound, constructing a comprehensive biological network to elucidate TZD's molecular and pathway mechanisms against AR. Single-arm clinical trials on the gut microbiome and serum transcriptomics corroborated our computational insights. Further validation through public omics data highlighted key TZD compounds, paving the way for future research.\u0000Results: TZD was discovered to exert a regulatory effect on various modules associated with AR, as demonstrated by the constructed biological network. Insights from gut microbiome and serum transcriptomics in clinical trials, where immune-related microbiomes represented by Prevotella, as well as pathways and biological processes including antigen processing and presentation, activation and regulating immune cell surface receptor, were markedly enriched (P value < 0.05), indicated that TZD played a pivotal role in modulating immune processes and the immune cells against AR. With the verification of multi-omics, it was determined that TZD potentially influences immune responses and downstream immune cells like CD4+ T cells, through both direct mechanisms involving antigen and indirect mechanisms mediated by gut microbiomes in the treatment of AR. Conclusion: Through combination of computational prediction and analysis together with clinical multi-omics, a network target based framework provided a new insight for uncovering the mechanism of TZD for treating AR.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"88 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140128402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Analysis Over Decades Reveals the Development and Immune Implications of Type I Interferon Autoantibodies in an Aging Population","authors":"Sonja Fernbach, Nina K. Mair, Irene A. Abela, Kevin Groen, Roger Kuratli, Marie Lork, Christian W. Thorball, Enos Bernasconi, Paraskevas Filippidis, Karoline Leuzinger, Julia Notter, Andri Rauch, Hans H. Hirsch, Michael Huber, Huldrych F. Günthard, Jacques Fellay, Roger D. Kouyos, Benjamin G. Hale, The Swiss HIV Cohort Study","doi":"10.1101/2024.02.27.24303363","DOIUrl":"https://doi.org/10.1101/2024.02.27.24303363","url":null,"abstract":"Pre-existing autoantibodies (autoAbs) neutralizing type I interferons (IFN-Is: IFNα, IFNβ, IFNω) have recently been described as significant contributors to the severity of viral infectious diseases. Here, we explore the development and consequences of anti-IFN-I autoAbs at high-resolution using retrospective samples and data from 1876 well-treated individuals >65 years of age enrolled in the Swiss HIV Cohort Study, a nationwide, longitudinal cohort with up to 35 years of follow-up. Approximately 1.9% of individuals developed anti-IFN-I autoAbs, with a median onset age of ~63 years (range 45-80). Once developed, anti-IFN-I autoAbs persisted for life, and generally increased in titer over years. Most individuals developed distinct neutralizing and non-neutralizing anti-IFN-I autoAb repertoires at discrete times that selectively targeted various combinations of IFNα, IFNβ, and IFNω. Longitudinal analyses further revealed that emergence of neutralizing anti-IFNα autoAbs correlated with reduced IFN-stimulated gene (ISG) levels, indicating impairment of innate immunity. Patient data review suggested that prior recorded viral infections and autoimmune history influence the likelihood of mounting anti-IFN-I autoAbs. Indeed, systematic measurements in biobanked samples revealed significant enrichment of pre-existing autoreactivity against clinically relevant autoantigens in individuals who later developed anti-IFN-I autoAbs. In this context, we describe lifelong neutralizing anti-IFNα autoAbs (and impaired innate immunity), that manifested in an individual following IFNα therapy, and who was retrospectively found to have had pre-existing autoreactivity to β2-glycoprotein-I before IFNα treatment. Our decades-spanning longitudinal analyses illuminate the development and immune implications of anti-IFN-I autoAbs in an aging population, and support a 'two-hit' hypothesis whereby loss of self-tolerance prior to immune-triggering with endogenous or exogenous IFN-I may pose a risk for developing late-onset, lifelong IFN-I functional deficiency.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140045998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Majority of SARS-CoV-2 Plasma Cells are Excluded from the Bone Marrow Long-Lived Compartment 33 Months after mRNA Vaccination","authors":"Doan C Nguyen, Ian T Hentenaar, Andrea Morrison-Porter, David Solano, Natalie S. Haddad, Carlos Castrillon, Pedro A Lamothe, Joel Andrews, Danielle Roberts, Sagar Lonial, Ignacio Sanz, Frances Eun-Hyung Lee","doi":"10.1101/2024.03.02.24303242","DOIUrl":"https://doi.org/10.1101/2024.03.02.24303242","url":null,"abstract":"The goal of any vaccine is to induce long-lived plasma cells (LLPC) to provide life-long protection. Natural infection by influenza, measles, or mumps viruses generates bone marrow (BM) LLPC similar to tetanus vaccination which affords safeguards for decades. Although the SARS-CoV-2 mRNA vaccines protect from severe disease, the serologic half-life is short-lived even though SARS-CoV-2-specific plasma cells can be found in the BM. To better understand this paradox, we enrolled 19 healthy adults at 1.5-33 months after SARS-CoV-2 mRNA vaccine and measured influenza-, tetanus-, or SARS-CoV-2-specific antibody secreting cells (ASC) in LLPC (CD19-) and non-LLPC (CD19+) subsets within the BM. All individuals had IgG ASC specific for influenza, tetanus, and SARS-CoV-2 in at least one BM ASC compartment. However, only influenza- and tetanus-specific ASC were readily detected in the LLPC whereas SARS-CoV-2 specificities were mostly excluded. The ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.61, 0.44, and 29.07, respectively. Even in five patients with known PCR-proven history of infection and vaccination, SARS-CoV-2-specific ASC were mostly excluded from the LLPC. These specificities were further validated by using multiplex bead binding assays of secreted antibodies in the supernatants of cultured ASC. Similarly, the IgG ratios of non-LLPC:LLPC for influenza, tetanus, and SARS-CoV-2 were 0.66, 0.44, and 23.26, respectively. In all, our studies demonstrate that rapid waning of serum antibodies is accounted for by the inability of mRNA vaccines to induce BM LLPC.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140037673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of physical activity in obese children and adolescents and serum interleukin-10 levels: A protocol for systematic review","authors":"Andreza Gomes Pascoal, Paula de Souza Mendes, Luiz Eduardo Rodrigues Lima, Bruno Mori","doi":"10.1101/2024.02.29.24303561","DOIUrl":"https://doi.org/10.1101/2024.02.29.24303561","url":null,"abstract":"<strong>Background</strong> Obesity is a global health problem that affects millions of people around the world, especially children and adolescents. The main causes of obesity are a sedentary lifestyle, unhealthy diet, and lack of reduction in the level of physical activity with negative consequences for physical and mental health, such as increased risk of cardiovascular diseases, diabetes, hypertension, dyslipidemia, and inflammation. Therefore, we will carry out a perform a systematic review to evaluate the effectiveness of physical activity in obese children and adolescents and serum interleukin-10 levels.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140037858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Systematic Review on Malaria and Tuberculosis (TB) Vaccine Challenges in Sub-Saharan African Clinical Trials","authors":"Maonezi Abas Hamisi, Nur Ain Mohd Asri, Aini Syahida Mat Yassim, Rapeah Suppian","doi":"10.1101/2024.02.28.24302787","DOIUrl":"https://doi.org/10.1101/2024.02.28.24302787","url":null,"abstract":"<strong>Objective</strong> For more than a century, developing novel and effective vaccines against malaria and tuberculosis (TB) infections has been a challenge. This review sought to investigate the reasons for the slow progress of malaria and TB vaccine candidates in sub-Saharan African clinical trials.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140037773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating circulating T follicular memory cells and autoantibody repertoires for characterization of autoimmune disorders","authors":"Emily M. Harris, Sarah Chamseddine, Anne Chu, Leetah Senkpeil, Matthew Nikiciuk, Amer Al-Musa, Brian Woods, Elif Ozdogan, Sarife Saker, David P Hoytema van Konijnenburg, Christina S.K. Yee, Ryan Nelson, Pui Y Lee, Olha Halyabar, Rebecca C Hale, Megan Day-Lewis, Lauren A Henderson, Alan A Nguyen, Megan Elkins, Toshiro K. Ohsumi, Maria Gutierrez-Arcelus, Janique M. Peyper, Craig D. Platt, Rachael F. Grace, Brenna LaBere, Janet Chou","doi":"10.1101/2024.02.25.24303331","DOIUrl":"https://doi.org/10.1101/2024.02.25.24303331","url":null,"abstract":"Introduction. Autoimmune diseases are heterogeneous and often lack specific or sensitive diagnostic tests. Increased percentages of CD4+CXCR5+PD1+ circulating T follicular helper (cTfh) cells and skewed distributions of cTfh subtypes have been associated with autoimmunity. However, cTfh cell percentages can normalize with immunomodulatory treatment despite persistent disease activity, indicating the need for identifying additional cellular and/or serologic features correlating with autoimmunity. Methods. The cohort included 50 controls and 56 patients with autoimmune cytopenias, gastrointestinal, pulmonary, and/or neurologic autoimmune disease. Flow cytometry was used to measure CD4+CXCR5+ T cell subsets expressing the chemokine receptors CXCR3 and/or CCR6: CXCR3+CCR6- Type 1, CXCR3-CCR6- Type 2, CXCR3+CCR6+ Type 1/17, and CXCR3-CCR6+ Type 17 T cells. IgG and IgA autoantibodies were quantified using a microarray featuring 1616 full-length, conformationally intact protein antigens. The 97.5th percentile in the control cohort defined normal limits for T cell subset percentages and total number (burden) of autoantibodies. Results. This study focused on CD4+CXCR5+ T cells because CXCR5 upregulation occurs after cognate T-B cell interactions characteristic of autoimmune diseases. We refer to these cells as circulating T follicular memory (cTfm) cells to acknowledge the dynamic nature of antigen-experienced CXCR5+ T cells, which encompass early progenitors of cTfh or Tfh cells as well as effector memory T cells that eventually lose CXCR5. Compared to controls, 57.1% of patients had increased CXCR5+CXCR3+CCR6+ cTfm1/17 and 25% had increased CXCR5+CXCR3-CCR6+ cTfm17 cell percentages. Patients had significantly more diverse IgG and IgA autoantibodies than controls and 44.6% had an increased burden of autoantibodies. Unsupervised autoantibody clustering identified three clusters of patients with IgG autoantibody profiles distinct from those of controls, enriched for patients with active autoimmunity and monogenic diseases. An increased percentage of cTfm17 cells was most closely associated with an increased burden of high-titer IgG and IgA autoantibodies. A composite measure integrating increased cTfm1/17, cTfm17, and high-titer IgG and/or IgA autoantibodies had 91.1% sensitivity and 90.9% specificity for identifying patients with autoimmunity. Percentages of cTfm1/17 and cTfm17 percentages and numbers of high-titer autoantibodies in patients receiving immunomodulatory treatment did not differ from those in untreated patients, thus suggesting that measurements of cTfm can complement measurements of other cellular markers affected by treatment. Conclusions. This study highlights two new approaches for assessing autoimmunity: measuring CD4+CXCR5+ cTfm subsets as well as total burden of autoantibodies. Our findings suggest that these approaches are particularly relevant to patients with rare autoimmune disorders for whom target antigens and prognosis are ofte","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139981196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing the skeletal muscle immune microenvironment for sarcopenia using transcriptome analysis and histological validation","authors":"Liting Jiang, Linhui Shen, Yuan Zong, Jiawen Zhao, Yi Yang, Lei Li, Ning Li, Yiming Gao, Xianfei Xie, Qiyuan Bao, Weiguo Hu","doi":"10.1101/2024.02.23.24303270","DOIUrl":"https://doi.org/10.1101/2024.02.23.24303270","url":null,"abstract":"Sarcopenia is a condition characterized by the age-related loss of skeletal muscle mass and function. The pathogenesis of the disease is influenced by chronic low-grade inflammation. However, the specific changes in the immune landscape changes of sarcopenic muscle are not yet fully understood. To gain insights into the immune cell composition and interactions, we combined single-nuclei RNA sequencing data, bulk RNA sequencing datasets, and comprehensive bioinformatic analyses on skeletal muscle samples from young, aged, and sarcopenic individuals. Histological staining was then performed on skeletal muscles to validate the distribution of immune cells in clinical samples. Overall, we analyzed the transcriptomes of 101,862 single nuclei, revealing a total of 10 major cell types and 6 subclusters of immune cell types within the human skeletal muscle tissues. Among the immune cells, macrophages constituted the largest immune fraction. A specific marker gene LYVE1 for skeletal muscle macrophages was further identified. Cellular subclasses included four distinct groups of resident macrophages, which play a different role in physiological or non-physiological conditions. Using bulk RNA sequencing data, we identified strong enrichment for a macrophage- rich inflammation in sarcopenia. Our findings demonstrate age-related changes in the composition and cross-talk of immune cells, which contribute to chronic inflammation. Furthermore, macrophages emerge as a potential therapeutic target, thus advancing our understanding of the pathogenesis of sarcopenia.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139948389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of DOCK8 in Hyper-inflammatory Syndromes","authors":"Mingce Zhang, Remy R Cron, Niansheng Chu, Junior Nguyen, Scott M Gordon, Esraa M Eloseily, Thomas Prescott Atkinson, Peter Weiser, Mark R Walter, Portia A Kreiger, Scott W Canna, Edward M Behrens, Randy Q Cron","doi":"10.1101/2024.02.20.24303049","DOIUrl":"https://doi.org/10.1101/2024.02.20.24303049","url":null,"abstract":"Background: Cytokine storm syndromes (CSS), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyper-inflammatory states leading to multi-organ failure and death. Familial HLH (FHL) in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T-lymphocytes and natural killer (NK) cells. Later onset CSS are frequently associated with heterozygous defects in FHL genes, but genetic etiologies for most are unknown. We identified rare <em>DOCK8</em> variants in CSS patients. Objective: We explore the role of CSS patient derived <em>DOCK8</em> mutations on cytolytic activity in NK cells. We further study effects of <em>Dock8^-/-</em> in murine models of CSS. Methods: <em>DOCK8</em> cDNA from 2 unrelated CSS patients with different missense mutations were introduced into human NK-92 NK cells by foamy virus transduction. NK cell degranulation (CD107a), cytolytic activity against K562 target cells, and interferon-gamma (IFNlower case Greek gamma) production were explored by flow cytometry (FCM). A third CSS patient <em>DOCK8</em> mRNA splice acceptor site variant was explored by exon trapping. <em>Dock8^-/-</em> mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFNlower case Greek gamma levels) upon challenge with lymphochoriomeningitic virus (LCMV) and excess IL-18. Results: Both patient <em>DOCK8</em> missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion <em>in vitro</em>. The patient <em>DOCK8</em> splice variant disrupted mRNA splicing <em>in vitro</em>. <em>Dock8^-/-</em> mice tolerated excess IL-18 but developed features of CSS upon LCMV infection. Conclusion: Mutations in <em>DOCK8</em> may contribute to CSS-like hyper-inflammatory states by altering cytolytic function in a threshold model of disease.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"284 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139956529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis","authors":"Stephanie Guillet, Tomi Lazarov, Natasha Jordan, Bertrand Boisson, Maria Tello, Barbara Craddock, Ting Zhou, Chihiro Nishi, Rohan Bareja, Hairu Yang, Frederic Rieux-Laucat, Rosa Irene Fregel Lorenzo, Sabrina D. Dyall, David Isenberg, David D'Cruz, Nico Lachmann, Olivier Elemento, Agnes Viale, Nicholas D. Socci, Laurent Abel, Shigekazu Nagata, Morgan Huse, W Todd Miller, Jean-Laurent Casanova, Frédéric Geissmann","doi":"10.1101/2024.02.15.24302255","DOIUrl":"https://doi.org/10.1101/2024.02.15.24302255","url":null,"abstract":"Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We report compound heterozygous deleterious variants in the kinase domains of the non-receptor tyrosine kinases (NRTK) TNK2/ACK1 in one multiplex family and PTK6/BRK in another. Experimental blockade of mouse ACK1 or BRK increases glomerular IgG deposits and circulating autoantibodies in an <em>in vivo</em> SLE model. In addition, we found that the patients’ ACK and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cells (hiPSC)-derived macrophages. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis.","PeriodicalId":501527,"journal":{"name":"medRxiv - Allergy and Immunology","volume":"254 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139902703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}