ImmunoHorizons最新文献

{"title":"Anti-Inflammatory Role of TRPV4 in Human Macrophages.","authors":"Yukiko Atsumi,&nbsp;Manami Toriyama,&nbsp;Hiroko Kato,&nbsp;Motoki Nakamura,&nbsp;Akimichi Morita,&nbsp;Masayuki Takaishi,&nbsp;Kaori Saito,&nbsp;Miku Tanaka,&nbsp;Fumihiro Okada,&nbsp;Makoto Tominaga,&nbsp;Ken J Ishii,&nbsp;Fumitaka Fujita","doi":"10.4049/immunohorizons.2200100","DOIUrl":"10.4049/immunohorizons.2200100","url":null,"abstract":"<p><p>The pathology of skin immune diseases such as atopic dermatitis is closely related to the overproduction of cytokines by macrophages. Although the pathological functions of macrophages in skin are known, mechanisms of how they detect the tissue environment remain unknown. TRPV4, a nonselective cation channel with high Ca2+ permeability, is activated at physiological temperatures from 27 to 35°C and involved in the functional control of macrophages. However, the relationship between TRPV4 function in macrophages and skin immune disease is unclear. In this study, we demonstrate that TRPV4 activation inhibits NF-κB signaling, resulting in the suppression of IL-1β production in both human primary monocytes and macrophages derived from human primary monocytes. A TRPV4 activator also inhibited the differentiation of human primary monocytes into GM-CSF M1 macrophages but not M-CSF M2 macrophages. We also observed a significant increase in the number of inducible NO synthase-positive/TRPV4-negative dermal macrophages in atopic dermatitis compared with healthy human skin specimens. Our findings provide insight into the physiological relevance of TRPV4 to the regulation of macrophages during homeostasis maintenance and raise the potential for TRPV4 to be an anti-inflammatory target.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 1","pages":"81-96"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10563396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10704009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing Mucosal-Associated Invariant T Cell Function and Expansion with Human Selective Serum.","authors":"Daniel Labuz,&nbsp;Jackson Cacioppo,&nbsp;Kelin Li,&nbsp;Jeffrey Aubé,&nbsp;Daniel T Leung","doi":"10.4049/immunohorizons.2200082","DOIUrl":"https://doi.org/10.4049/immunohorizons.2200082","url":null,"abstract":"<p><p>Mucosal-associated invariant T (MAIT) cells are promising innate-like lymphocytes with potential for use in anti-tumor immunotherapy. Existing MAIT cell expansion protocols are associated with potentially decremental phenotypic changes, including increased frequency of CD4+ MAIT cells and higher inhibitory receptor expression. In this study, we compared the effect on expansion of human MAIT cells of a serum replacement, Physiologix XF SR (Phx), with traditional serum FBS for supplementing RPMI 1640 media. Using flow cytometry, we found that Phx supported a significantly higher proliferative capacity for MAIT cells and resulted in a lower frequency of CD4+ MAIT cells, which have been associated with reduced Th1 effector and cytolytic functions. We saw that culturing MAIT cells in Phx led to better survival of MAIT cells and lower frequency of PD-1+ MAIT cells than FBS-supplemented media. Functionally, we saw that Phx supplementation was associated with a higher frequency of IFN-γ+ MAIT cells after stimulation with Escherichia coli than FBS-supplemented RPMI. In conclusion, we show that MAIT cells cultured in Phx have higher proliferative capacity, lower expression of inhibitory receptors, and higher capacity to produce IFN-γ after E. coli stimulation than FBS-supplemented RPMI. This work shows that expanding MAIT cells with Phx compared with FBS-supplemented RPMI results in a more functionally desirable MAIT cell for future anti-tumor immunotherapy.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 1","pages":"116-124"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6e/7e/nihms-1877429.PMC10026854.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10478979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TET Proteins in the Spotlight: Emerging Concepts of Epigenetic Regulation in T Cell Biology.","authors":"Ageliki Tsagaratou","doi":"10.4049/immunohorizons.2200067","DOIUrl":"10.4049/immunohorizons.2200067","url":null,"abstract":"<p><p>Ten-eleven translocation (TET) proteins are dioxygenases that oxidize 5-methylcytosine to form 5-hydroxymethylcytosine and downstream oxidized modified cytosines. In the past decade, intensive research established that TET-mediated DNA demethylation is critical for immune cell development and function. In this study, we discuss major advances regarding the role of TET proteins in regulating gene expression in the context of T cell lineage specification, function, and proliferation. Then, we focus on open questions in the field. We discuss recent findings regarding the diverse roles of TET proteins in other systems, and we ask how these findings might relate to T cell biology. Finally, we ask how this tremendous progress on understanding the multifaceted roles of TET proteins in shaping T cell identity and function can be translated to improve outcomes of human disease, such as hematological malignancies and immune response to cancer.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 1","pages":"106-115"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10152628/pdf/nihms-1866747.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9766290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Augmenting Granzyme B-Expressing NK Cells by Invariant NKT Ligand-Loaded APCs in Patients with Postoperative Early Stage Non-Small Cell Lung Cancer: Results of a Randomized Phase II Study.","authors":"Tomonori Iyoda,&nbsp;Kanako Shimizu,&nbsp;Masami Kawamura,&nbsp;Jun Shinga,&nbsp;Takashi Watanabe,&nbsp;Koya Fukunaga,&nbsp;Taisei Mushiroda,&nbsp;Hideo Saka,&nbsp;Chiyoe Kitagawa,&nbsp;Shin-Ichiro Shimamatsu,&nbsp;Mitsuhiro Takenoyama,&nbsp;Youko Suehiro,&nbsp;Takumi Imai,&nbsp;Ayumi Shintani,&nbsp;Suminobu Ito,&nbsp;Shin-Ichiro Fujii","doi":"10.4049/immunohorizons.2200091","DOIUrl":"10.4049/immunohorizons.2200091","url":null,"abstract":"<p><p>NK cells are major effector cells involved in the elimination of early tumors and prevent metastasis. They often have an impaired function in patients with cancer. Preclinical studies have demonstrated NK cell activation as the adjunctive effect of invariant NKT (iNKT) cells. Activation of iNKT cells after administration of the glycolipid ligand α-galactosylceramide, loaded with CD1d-expressing human PBMC-derived APCs (APC/Gal), is an attractive cancer therapy to optimize the use of NK cells. However, the subsets of NK cells that are activated following iNKT cell activation as well as the period of NK cell activation remain unclear. In this study, we report that the granzyme B-expressing NK cell response in postoperative lung cancer patients was enhanced 49 d after administration of APC/Gal in a phase II study. We found maximum IFN-γ production on day 49 in 13 out of 27 APC/Gal-treated patients. On day 49, 14 out of 27 patients (51.9%) had higher IFN-γ production by iNKT cells (>6-fold higher than the baseline level). This increment significantly correlated with granzyme B-expressing NK cells. Although IFN-γ production was lower in patients in the nontreated group, we detected maximum IFN-γ production 12 mo after the resection of lung cancer (9 out of 29 patients [31%]). These findings suggest that elimination of cancer cells leads to increased NK cell function, which can be further enhanced by APC/Gal therapy.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 1","pages":"1-16"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/53/27/ih2200091.PMC10563390.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9266023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood-Borne Microparticles Are an Inflammatory Stimulus in Type 2 Diabetes Mellitus.","authors":"Stephen R Thom,&nbsp;Veena M Bhopale,&nbsp;Awadhesh K Arya,&nbsp;Deepa Ruhela,&nbsp;Abid R Bhat,&nbsp;Nandita Mitra,&nbsp;Ole Hoffstad,&nbsp;D Scot Malay,&nbsp;Ziad K Mirza,&nbsp;John C Lantis,&nbsp;Hadar A Lev-Tov,&nbsp;Robert S Kirsner,&nbsp;Ru-Ching Hsia,&nbsp;Susan L Levinson,&nbsp;Mark J DiNubile,&nbsp;David J Margolis","doi":"10.4049/immunohorizons.2200099","DOIUrl":"10.4049/immunohorizons.2200099","url":null,"abstract":"<p><p>The proinflammatory state associated with diabetes mellitus (DM) remains poorly understood. We found patients with DM have 3- to 14-fold elevations of blood-borne microparticles (MPs) that bind phalloidin (Ph; Ph positive [+] MPs), indicating the presence of F-actin on their surface. We hypothesized that F-actin-coated MPs were an unrecognized cause for DM-associated proinflammatory status. Ph+MPs, but not Ph-negative MPs, activate human and murine (Mus musculus) neutrophils through biophysical attributes of F-actin and membrane expression of phosphatidylserine (PS). Neutrophils respond to Ph+MPs via a linked membrane array, including the receptor for advanced glycation end products and CD36, PS-binding membrane receptors. These proteins in conjunction with TLR4 are coupled to NO synthase 1 adaptor protein (NOS1AP). Neutrophil activation occurs because of Ph+MPs causing elevations of NF-κB and Src kinase (SrcK) via a concurrent increased association of NO synthase 2 and SrcK with NOS1AP, resulting in SrcK S-nitrosylation. We conclude that NOS1AP links PS-binding receptors with intracellular regulatory proteins. Ph+MPs are alarmins present in normal human plasma and are increased in those with DM and especially those with DM and a lower-extremity ulcer.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"7 1","pages":"71-80"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d7/e3/ih2200099.PMC10563440.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10703561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-6/STAT3 Signaling Axis Enhances and Prolongs Pdcd1 Expression in Murine CD8 T Cells.","authors":"Michael D Powell, Peiyuan Lu, Dennis K Neeld, Anna K Kania, Lou-Ella M M George-Alexander, Alexander P R Bally, Christopher D Scharer, Jeremy M Boss","doi":"10.4049/immunohorizons.2100112","DOIUrl":"10.4049/immunohorizons.2100112","url":null,"abstract":"<p><p>CD8 cytotoxic T cells are a potent line of defense against invading pathogens. To aid in curtailing aberrant immune responses, the activation status of CD8 T cells is highly regulated. One mechanism in which CD8 T cell responses are dampened is via signaling through the immune-inhibitory receptor Programmed Cell Death Protein-1, encoded by Pdcd1. Pdcd1 expression is regulated through engagement of the TCR, as well as by signaling from extracellular cytokines. Understanding such pathways has influenced the development of numerous clinical treatments. In this study, we showed that signals from the cytokine IL-6 enhanced Pdcd1 expression when paired with TCR stimulation in murine CD8 T cells. Mechanistically, signals from IL-6 were propagated through activation of the transcription factor STAT3, resulting in IL-6-dependent binding of STAT3 to Pdcd1 cis-regulatory elements. Intriguingly, IL-6 stimulation overcame B Lymphocyte Maturation Protein 1-mediated epigenetic repression of Pdcd1, which resulted in a transcriptionally permissive landscape marked by heightened histone acetylation. Furthermore, in vivo-activated CD8 T cells derived from lymphocytic choriomeningitis virus infection required STAT3 for optimal Programmed Cell Death Protein-1 surface expression. Importantly, STAT3 was the only member of the STAT family present at Pdcd1 regulatory elements in lymphocytic choriomeningitis virus Ag-specific CD8 T cells. Collectively, these data define mechanisms by which the IL-6/STAT3 signaling axis can enhance and prolong Pdcd1 expression in murine CD8 T cells.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"6 12","pages":"872-882"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103150/pdf/nihms-1868256.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9662818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acly Deficiency Enhances Myelopoiesis through Acetyl Coenzyme A and Metabolic-Epigenetic Cross-Talk.","authors":"Dalton L Greenwood, Haley E Ramsey, Phuong T T Nguyen, Andrew R Patterson, Kelsey Voss, Jackie E Bader, Ayaka Sugiura, Zachary A Bacigalupa, Samuel Schaefer, Xiang Ye, Debolanle O Dahunsi, Matthew Z Madden, Kathryn E Wellen, Michael R Savona, P Brent Ferrell, Jeffrey C Rathmell","doi":"10.4049/immunohorizons.2200086","DOIUrl":"10.4049/immunohorizons.2200086","url":null,"abstract":"<p><p>Hematopoiesis integrates cytokine signaling, metabolism, and epigenetic modifications to regulate blood cell generation. These processes are linked, as metabolites provide essential substrates for epigenetic marks. In this study, we demonstrate that ATP citrate lyase (Acly), which metabolizes citrate to generate cytosolic acetyl-CoA and is of clinical interest, can regulate chromatin accessibility to limit myeloid differentiation. Acly was tested for a role in murine hematopoiesis by small-molecule inhibition or genetic deletion in lineage-depleted, c-Kit-enriched hematopoietic stem and progenitor cells from Mus musculus. Treatments increased the abundance of cell populations that expressed the myeloid integrin CD11b and other markers of myeloid differentiation. When single-cell RNA sequencing was performed, we found that Acly inhibitor-treated hematopoietic stem and progenitor cells exhibited greater gene expression signatures for macrophages and enrichment of these populations. Similarly, the single-cell assay for transposase-accessible chromatin sequencing showed increased chromatin accessibility at genes associated with myeloid differentiation, including CD11b, CD11c, and IRF8. Mechanistically, Acly deficiency altered chromatin accessibility and expression of multiple C/EBP family transcription factors known to regulate myeloid differentiation and cell metabolism, with increased Cebpe and decreased Cebpa and Cebpb. This effect of Acly deficiency was accompanied by altered mitochondrial metabolism with decreased mitochondrial polarization but increased mitochondrial content and production of reactive oxygen species. The bias to myeloid differentiation appeared due to insufficient generation of acetyl-CoA, as exogenous acetate to support alternate compensatory pathways to produce acetyl-CoA reversed this phenotype. Acly inhibition thus can promote myelopoiesis through deprivation of acetyl-CoA and altered histone acetylome to regulate C/EBP transcription factor family activity for myeloid differentiation.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"6 12","pages":"837-850"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9935084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9102127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monocytic Myeloid-Derived Suppressor Cells from Tumor Tissue Are a Differentiated Cell with Limited Fate Plasticity.","authors":"Ryan D Calvert, James C Fleet, Pierrick G J Fournier, Patricia Juarez, Grant N Burcham, Jessica M Haverkamp, Theresa A Guise, Timothy L Ratliff, Bennett D Elzey","doi":"10.4049/immunohorizons.2200079","DOIUrl":"10.4049/immunohorizons.2200079","url":null,"abstract":"<p><p>Owing to ease of access and high yield, most murine myeloid-derived suppressor cell (MDSC) knowledge comes from the study of spleen-derived MDSCs rather than those isolated from the tumor. Although several studies have identified subtle differences in suppressive function between these MDSCs, a recent report demonstrated that the whole peripheral myeloid compartment poorly reflects myeloid populations found at the tumor. We confirm and extend these observations by presenting data that indicate extensive differences exist between peripheral and tumor MDSCs, suggesting that it may be inappropriate to use spleen MDSCs as surrogates for studying tumor MDSCs. Using cytospins, we observed that tumor MDSCs have undergone a morphologic shift from immature myeloid cell forms commonly seen in bone marrow (BM) and spleen MDSCs and acquired mature myeloid cell characteristics. Spleen and BM monocyte-like MDSCs (M-MDSCs) readily responded to differentiation signals for multiple myeloid cell types whereas tumor M-MDSCs had remarkably reduced cellular plasticity. At the time of isolation, M-MDSCs from BM or spleen have little to no T cell suppressive activity whereas those from the tumor possess immediate and efficient T cell suppressive function. Finally, microarray analysis revealed that the transcriptomes of tumor and spleen M-MDSCs possessed >4500 differentially expressed transcripts. We conclude that tumor M-MDSCs are more differentiated and mature, and that they are morphologically, genetically, and functionally distinct from spleen and BM M-MDSCs. These observations have important implications for the design of anti-MDSC therapies and suggest that preclinical studies using nontumor MDSCs could lead to results not applicable to tumor MDSCs.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"6 12","pages":"790-806"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11955908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10465531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Status of Immunology Education in U.S. Medical Schools.","authors":"Austin B Reynolds,&nbsp;Ritvik Bhattacharjee,&nbsp;Yuan Zhao","doi":"10.4049/immunohorizons.2200076","DOIUrl":"https://doi.org/10.4049/immunohorizons.2200076","url":null,"abstract":"<p><p>Immunology is an integral component of undergraduate medical education because of its critical role in many disease processes. Due to the complexity of the subject, the best practice of immunology education in the undergraduate medical curriculum has not been extensively discussed. This study intended to determine the current status of immunology education in U.S. medical schools with the hope of providing insight into curriculum design pertaining to this subject. Immunology curriculum information was collected from the curriculum Web pages of 199 U.S. medical schools, including multiple campuses. Data pertaining to the setting of immunology education such as subjects that are co-taught with immunology, timing of courses, credit hours, and integration level were recorded in Microsoft Excel for analysis. Of 199 U.S. medical schools studied, 174 posted curriculum information related to immunology online. For course settings, 59 (33.9%) offer immunology with microbiology, 42 (24.1%) offer immunology as part of a foundational sciences course, and 18 (10.3%) offer immunology as a stand-alone course. Ten programs (5.7%) have immunology fully integrated in system-based curriculum. Of 119 medical schools that provide information regarding timing, 94 (71.9%) provide immunology education in year 1 of the curriculum, 16 (9.2%) in year 2, and 9 (5.2%) in both years 1 and 2. Differences exist in allopathic versus osteopathic programs in the immunology curriculum setting. Credit hour data were not complete due to inconsistent availability. Our data suggest that immunology education in U.S. medical schools lacks consensus. Continued discussion on best practices of immunology education across U.S. medical schools is recommended.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"6 12","pages":"864-871"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10825257","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 Lack of Natural IgM Increases Susceptibility and Impairs Anti-Vi Polysaccharide IgG Responses in a Mouse Model of Typhoid.","authors":"Akhil S Alugupalli,&nbsp;Matthew P Cravens,&nbsp;Justin A Walker,&nbsp;Dania Gulandijany,&nbsp;Gregory S Dickinson,&nbsp;Genevieve Lewis,&nbsp;Gudrun F Debes,&nbsp;Dieter M Schifferli,&nbsp;Andreas J Bäumler,&nbsp;Kishore R Alugupalli","doi":"10.4049/immunohorizons.2200088","DOIUrl":"https://doi.org/10.4049/immunohorizons.2200088","url":null,"abstract":"<p><p>Circulating IgM present in the body prior to any apparent Ag exposure is referred to as natural IgM. Natural IgM provides protective immunity against a variety of pathogens. Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever in humans. Because mice are not permissive to S. Typhi infection, we employed a murine model of typhoid using S. enterica serovar Typhimurium expressing the Vi polysaccharide (ViPS) of S. Typhi (S. Typhimurium strain RC60) to evaluate the role of natural IgM in pathogenesis. We found that natural mouse IgM binds to S. Typhi and S. Typhimurium. The severity of S. Typhimurium infection in mice is dependent on presence of the natural resistance-associated macrophage protein 1 (Nramp1) allele; therefore, we infected mice deficient in secreted form of IgM (sIgM) on either a Nramp1-resistant (129S) or -susceptible (C57BL/6J) background. We found that the lack of natural IgM results in a significantly increased susceptibility and an exaggerated liver pathology regardless of the route of infection or the Nramp1 allele. Reconstitution of sIgM-/- mice with normal mouse serum or purified polyclonal IgM restored the resistance to that of sIgM+/+ mice. Furthermore, immunization of sIgM-/- mice with heat-killed S. Typhi induced a significantly reduced anti-ViPS IgG and complement-dependent bactericidal activity against S. Typhi in vitro, compared with that of sIgM+/+ mice. These findings indicate that natural IgM is an important factor in reducing the typhoid severity and inducing an optimal anti-ViPS IgG response to vaccination.</p>","PeriodicalId":13448,"journal":{"name":"ImmunoHorizons","volume":"6 12","pages":"807-816"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10205010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9507304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}