73 results on '"Jessica A. Hamerman"'
Search Results
2. Tracing Conidial Fate and Measuring Host Cell Antifungal Activity Using a Reporter of Microbial Viability in the Lung
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Anupam Jhingran, Katrina B. Mar, Debra K. Kumasaka, Sue E. Knoblaugh, Lisa Y. Ngo, Brahm H. Segal, Yoichiro Iwakura, Clifford A. Lowell, Jessica A. Hamerman, Xin Lin, and Tobias M. Hohl
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Biology (General) ,QH301-705.5 - Abstract
Fluorescence can be harnessed to monitor microbial fate and to investigate functional outcomes of individual microbial cell-host cell encounters at portals of entry in native tissue environments. We illustrate this concept by introducing fluorescent Aspergillus reporter (FLARE) conidia that simultaneously report phagocytic uptake and fungal viability during cellular interactions with the murine respiratory innate immune system. Our studies using FLARE conidia reveal stepwise and cell-type-specific requirements for CARD9 and Syk, transducers of C-type lectin receptor and integrin signals, in neutrophil recruitment, conidial uptake, and conidial killing in the lung. By achieving single-event resolution in defined leukocyte populations, the FLARE method enables host cell profiling on the basis of pathogen uptake and killing and may be extended to other pathogens in diverse model host organisms to query molecular, cellular, and pharmacologic mechanisms that shape host-microbe interactions. more...
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- 2012
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Catalog
3. Mediators of monocyte chemotaxis and matrix remodeling are associated with mortality and pulmonary fibroproliferation in patients with severe COVID-19.
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Sarah E Holton, Mallorie Mitchem, Hamid Chalian, Sudhakar Pipavath, Eric D Morrell, Pavan K Bhatraju, Jessica A Hamerman, Cate Speake, Uma Malhotra, Mark M Wurfel, Steven E Ziegler, and Carmen Mikacenic more...
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Medicine ,Science - Abstract
Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. Pulmonary fibrosis following COVID-19 pneumonia has been described at autopsy and following lung transplantation. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop features of pulmonary fibroproliferation. We enrolled COVID-19 patients admitted to the ICU with hypoxemic respiratory failure. (n = 195). Plasma was collected within 24h of ICU admission and at 7d. In mechanically ventilated patients, endotracheal aspirates (ETA) were collected. Protein concentrations were measured by immunoassay. We tested for associations between protein concentrations and respiratory outcomes using logistic regression adjusting for age, sex, treatment with steroids, and APACHE III score. In a subset of patients who had CT scans during hospitalization (n = 75), we tested for associations between protein concentrations and radiographic features of fibroproliferation. Among the entire cohort, plasma IL-6, TNF-α, CCL2, and Amphiregulin levels were significantly associated with in-hospital mortality. In addition, higher plasma concentrations of CCL2, IL-6, TNF-α, Amphiregulin, and CXCL12 were associated with fewer ventilator-free days. We identified 20/75 patients (26%) with features of fibroproliferation. Within 24h of ICU admission, no measured plasma proteins were associated with a fibroproliferative response. However, when measured 96h-128h after admission, Amphiregulin was elevated in those that developed fibroproliferation. ETAs were not correlated with plasma measurements and did not show any association with mortality, ventilator-free days (VFDs), or fibroproliferative response. This cohort study identifies proteins of tissue remodeling and monocyte recruitment are associated with in-hospital mortality, fewer VFDs, and radiographic fibroproliferative response. Measuring changes in these proteins over time may allow for early identification of patients with severe COVID-19 at risk for fibroproliferation. more...
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- 2024
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4. Immune Mechanisms in Inflammatory Anemia
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Susan P. Canny, Susana L. Orozco, Natalie K. Thulin, and Jessica A. Hamerman
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Immunology ,Immunology and Allergy - Abstract
Maintaining the correct number of healthy red blood cells (RBCs) is critical for proper oxygenation of tissues throughout the body. Therefore, RBC homeostasis is a tightly controlled balance between RBC production and RBC clearance, through the processes of erythropoiesis and macrophage hemophagocytosis, respectively. However, during the inflammation associated with infectious, autoimmune, or inflammatory diseases this homeostatic process is often dysregulated, leading to acute or chronic anemia. In each disease setting, multiple mechanisms typically contribute to the development of inflammatory anemia, impinging on both sides of the RBC production and RBC clearance equation. These mechanisms include both direct and indirect effects of inflammatory cytokines and innate sensing. Here, we focus on common innate and adaptive immune mechanisms that contribute to inflammatory anemias using examples from several diseases, including hemophagocytic lymphohistiocytosis/macrophage activation syndrome, severe malarial anemia during Plasmodium infection, and systemic lupus erythematosus, among others. more...
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- 2023
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5. Mediators of monocyte chemotaxis and matrix remodeling are associated with the development of fibrosis in patients with COVID-19
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Sarah E. Holton, Mallorie Mitchem, Sudhakar Pipavath, Eric D. Morrell, Pavan K. Bhatraju, Jessica A. Hamerman, Cate Speake, Uma Malhotra, Mark M. Wurfel, Steven Ziegler, and Carmen Mikacenic
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Article - Abstract
Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. This has been described in patients with COVID-19 pneumonia, but the underlying mechanisms have not been completely defined. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop radiographic fibrosis.We enrolled COVID-19 patients admitted to the ICU who had hypoxemic respiratory failure, were hospitalized and alive for at least 10 days, and had chest imaging done during hospitalization (n= 119). Plasma was collected within 24h of ICU admission and at 7d. In mechanically ventilated patients, endotracheal aspirates (ETA) were collected at 24h and 48-96h. Protein concentrations were measured by immunoassay. We tested for associations between protein concentrations and radiographic evidence of fibrosis using logistic regression adjusting for age, sex, and APACHE score.We identified 39 patients (33%) with features of fibrosis. Within 24h of ICU admission, plasma proteins related to tissue remodeling (MMP-9, Amphiregulin) and monocyte chemotaxis (CCL-2/MCP-1, CCL-13/MCP-4) were associated with the subsequent development of fibrosis whereas markers of inflammation (IL-6, TNF-α) were not. After 1 week, plasma MMP-9 increased in patients without fibrosis. In ETAs, only CCL-2/MCP-1 was associated with fibrosis at the later timepoint.This cohort study identifies proteins of tissue remodeling and monocyte recruitment that may identify early fibrotic remodeling following COVID-19. Measuring changes in these proteins over time may allow for early detection of fibrosis in patients with COVID-19. more...
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- 2023
6. Supplementary Figure Legends 1-4 from Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T Cells
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Shannon J. Turley, Ananda W. Goldrath, Jessica A. Hamerman, Roderick Bronson, Angelique Bellemare-Pelletier, Ai-ris Yonekura, Mark P. Rubinstein, Kutlu G. Elpek, and Mathieu Epardaud
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Supplementary Figure Legends 1-4 from Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T Cells
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- 2023
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7. Supplementary Figure 3 from Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T Cells
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Shannon J. Turley, Ananda W. Goldrath, Jessica A. Hamerman, Roderick Bronson, Angelique Bellemare-Pelletier, Ai-ris Yonekura, Mark P. Rubinstein, Kutlu G. Elpek, and Mathieu Epardaud
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Supplementary Figure 3 from Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T Cells
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- 2023
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8. Supplementary Figure 1 from Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T Cells
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Shannon J. Turley, Ananda W. Goldrath, Jessica A. Hamerman, Roderick Bronson, Angelique Bellemare-Pelletier, Ai-ris Yonekura, Mark P. Rubinstein, Kutlu G. Elpek, and Mathieu Epardaud
- Abstract
Supplementary Figure 1 from Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T Cells
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- 2023
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9. Data from Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T Cells
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Shannon J. Turley, Ananda W. Goldrath, Jessica A. Hamerman, Roderick Bronson, Angelique Bellemare-Pelletier, Ai-ris Yonekura, Mark P. Rubinstein, Kutlu G. Elpek, and Mathieu Epardaud
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Tumors often escape immune-mediated destruction by suppressing lymphocyte infiltration or effector function. New approaches are needed that overcome this suppression and thereby augment the tumoricidal capacity of tumor-reactive lymphocytes. The cytokine interleukin-15 (IL-15) promotes proliferation and effector capacity of CD8+ T cells, natural killer (NK) cells, and NKT cells; however, it has a short half-life and high doses are needed to achieve functional responses in vivo. The biological activity of IL-15 can be dramatically increased by complexing this cytokine to its soluble receptor, IL-15Rα. Here, we report that in vivo delivery of IL-15/IL-15Rα complexes triggers rapid and significant regression of established solid tumors in two murine models. Despite a marked expansion of IL-2/IL-15Rβ+ cells in lymphoid organs and peripheral blood following treatment with IL-15/IL-15Rα complexes, the destruction of solid tumors was orchestrated by tumor-resident rather than newly infiltrating CD8+ T cells. Our data provide novel insights into the use of IL-15/IL-15Rα complexes to relieve tumor-resident T cells from functional suppression by the tumor microenvironment and have significant implications for cancer immunotherapy and treatment of chronic infections. [Cancer Res 2008;68(8):2972–83] more...
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- 2023
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10. Supplementary Figure 2 from Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T Cells
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Shannon J. Turley, Ananda W. Goldrath, Jessica A. Hamerman, Roderick Bronson, Angelique Bellemare-Pelletier, Ai-ris Yonekura, Mark P. Rubinstein, Kutlu G. Elpek, and Mathieu Epardaud
- Abstract
Supplementary Figure 2 from Interleukin-15/Interleukin-15Rα Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8+ T Cells
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- 2023
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11. Rhinovirus infection of the airway epithelium enhances mast cell immune responses via epithelial-derived interferons
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Ryan C. Murphy, Ying Lai, Matthew C. Altman, Kaitlyn A. Barrow, Kimberly A. Dill-McFarland, Matthew Liu, Jessica A. Hamerman, Adam Lacy-Hulbert, Adrian M. Piliponsky, Steven F. Ziegler, William A. Altemeier, Jason S. Debley, Sina A. Gharib, and Teal S. Hallstrand more...
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Immunology ,Immunology and Allergy - Published
- 2023
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12. Identification of mast cell progenitor cells in the airways of individuals with allergic asthma
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Ryan C. Murphy, Yu‐Hua Chow, Ying Lai, Taha Al‐Shaikhly, Daniel H. Petroni, Michele Black, Jessica A. Hamerman, Adam Lacy‐Hulbert, Adrian M. Piliponsky, and Teal S. Hallstrand
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Immunology ,Immunology and Allergy - Published
- 2022
13. Effects of Asthma and Human Rhinovirus A16 on the Expression of SARS-CoV-2 Entry Factors in Human Airway Epithelium
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Steven F. Ziegler, Sina A. Gharib, Ryan C. Murphy, Jason S. Debley, Kaitlyn A Barrow, William A. Altemeier, Jessica A. Hamerman, Ying Lai, Adam Lacy-Hulbert, Adrian M. Piliponsky, and Teal S. Hallstrand more...
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Pulmonary and Respiratory Medicine ,2019-20 coronavirus outbreak ,Rhinovirus ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Respiratory System ,Clinical Biochemistry ,medicine.disease_cause ,Epithelium ,Correspondence ,medicine ,Humans ,Molecular Biology ,Cells, Cultured ,Asthma ,Picornaviridae Infections ,SARS-CoV-2 ,business.industry ,Serine Endopeptidases ,COVID-19 ,Cell Biology ,Human airway ,Virus Internalization ,medicine.disease ,Virology ,medicine.anatomical_structure ,Angiotensin-Converting Enzyme 2 ,business - Published
- 2020
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14. Intravenous Nanoparticle Vaccination Generates Stem-Like TCF1+ Neoantigen-Specific CD8+ T Cells
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Hidehiro Yamane, Geoffrey M. Lynn, Charles-Antoine Dutertre, John P. Finnigan, Nina Bhardwaj, Matthew P. Mulé, John S. Tsang, Glennys V. Reynoso, Vincent L. Coble, Jessica A. Hamerman, Xiao Meng Zhang, Kennedy Tobin, Andrew S. Ishizuka, Faezzah Baharom, Ramiro A. Ramirez-Valdez, Florent Ginhoux, Robert A. Seder, Heather D. Hickman, Ahad Khalilnezhad, and Andrew J. Martins more...
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0301 basic medicine ,medicine.medical_treatment ,Immunology ,Antigen presentation ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,Article ,GZMB ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Antigens, Neoplasm ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Hepatocyte Nuclear Factor 1-alpha ,Antigen Presentation ,Effector ,Chemistry ,Vaccination ,Dendritic Cells ,Immunity, Innate ,Mice, Inbred C57BL ,030104 developmental biology ,Immunization ,Cancer research ,Nanoparticles ,Female ,Adjuvant ,CD8 ,030215 immunology ,XCL1 - Abstract
Personalized cancer vaccines are a promising approach for inducing T cell immunity to tumor neoantigens. Using a self-assembling nanoparticle vaccine that links neoantigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we show how the route and dose alter the magnitude and quality of neoantigen-specific CD8+ T cells. Intravenous vaccination (SNP-IV) induced a higher proportion of TCF1+PD-1+CD8+ T cells as compared to subcutaneous immunization (SNP-SC). Single-cell RNA sequencing showed that SNP-IV induced stem-like genes (Tcf7, Slamf6, Xcl1) whereas SNP-SC enriched for effector genes (Gzmb, Klrg1, Cx3cr1). Stem-like cells generated by SNP-IV proliferated and differentiated into effector cells upon checkpoint blockade, leading to superior antitumor response as compared to SNP-SC in a therapeutic model. The duration of antigen presentation by dendritic cells controlled the magnitude and quality of CD8+ T cells. These data demonstrate how to optimize antitumor immunity by modulating vaccine parameters for specific generation of effector or stem-like CD8+ T cells. Seder and colleagues use a self-assembling nanoparticle vaccine and adjuvant to expand stem-like CD8+ T cells and trigger potent antitumor responses. more...
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- 2020
15. Cutting Edge: BCAP Promotes Lupus-like Disease and TLR-Mediated Type I IFN Induction in Plasmacytoid Dendritic Cells
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Minjian Ni, Talyn Chu, Jessica A. Hamerman, Shreeram Akilesh, and Chunmo Chen
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Systemic lupus erythematosus ,Lupus erythematosus ,Chemistry ,Immunology ,Signal transducing adaptor protein ,TLR9 ,hemic and immune systems ,macromolecular substances ,TLR7 ,medicine.disease ,ISG15 ,medicine.anatomical_structure ,immune system diseases ,medicine ,Cancer research ,Immunology and Allergy ,PI3K/AKT/mTOR pathway ,B cell - Abstract
Systemic lupus erythematosus severity correlates with elevated serum levels of type I IFNs, cytokines produced in large quantities by plasmacytoid dendritic cells (pDC) in response to engagement of TLR7 and TLR9 with endocytosed nucleic acids. B cell adaptor for PI3K (BCAP) promoted many aspects of TLR7-driven lupus-like disease, including Isg15 and Ifit1 expression in blood and an immature pDC phenotype associated with higher IFN production. BCAP−/− mice produced significantly less serum IFN-α than wild-type mice after injection of TLR9 agonist, and BCAP promoted TLR7 and TLR9-induced IFN-α production specifically in pDC. TLR-induced IFN-α production in pDC requires DOCK2-mediated activation of Rac1 leading to activation of IKKα, a mechanism we show was dependent on BCAP. BCAP−/− pDC had decreased actin polymerization and Rac1 activation and reduced IKKα phosphorylation upon TLR9 stimulation. We show a novel role for BCAP in promoting TLR-induced IFN-α production in pDC and in systemic lupus erythematosus pathogenesis. more...
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- 2019
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16. The COVID-19 immune landscape is dynamically and reversibly correlated with disease severity
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Cate Speake, Daniel J. Campbell, Hamid Bolouri, Anne M. Hocking, Jane H. Buckner, David A. G. Skibinski, Uma Malhotra, S. Alice Long, and Jessica A. Hamerman
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Adult ,Male ,0301 basic medicine ,Coronavirus disease 2019 (COVID-19) ,Disease ,Adaptive Immunity ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Disease severity ,Humans ,Medicine ,Mass cytometry ,Whole blood ,Aged ,Aged, 80 and over ,SARS-CoV-2 ,business.industry ,Critically ill ,COVID-19 ,General Medicine ,Middle Aged ,biochemical phenomena, metabolism, and nutrition ,Flow Cytometry ,Immunity, Innate ,Blockade ,COVID-19 Drug Treatment ,030104 developmental biology ,Disease Presentation ,030220 oncology & carcinogenesis ,Cohort ,Immunology ,Female ,Clinical Medicine ,business - Abstract
BACKGROUND: Despite a rapidly growing body of literature on coronavirus disease 2019 (COVID-19), our understanding of the immune correlates of disease severity, course, and outcome remains poor. METHODS: Using mass cytometry, we assessed the immune landscape in longitudinal whole-blood specimens from 59 patients presenting with acute COVID-19 and classified based on maximal disease severity. Hospitalized patients negative for SARS-CoV-2 were used as controls. RESULTS: We found that the immune landscape in COVID-19 formed 3 dominant clusters, which correlated with disease severity. Longitudinal analysis identified a pattern of productive innate and adaptive immune responses in individuals who had a moderate disease course, whereas those with severe disease had features suggestive of a protracted and dysregulated immune response. Further, we identified coordinate immune alterations accompanying clinical improvement and decline that were also seen in patients who received IL-6 pathway blockade. CONCLUSION: The hospitalized COVID-19 negative cohort allowed us to identify immune alterations that were shared between severe COVID-19 and other critically ill patients. Collectively, our findings indicate that selection of immune interventions should be based in part on disease presentation and early disease trajectory due to the profound differences in the immune response in those with mild to moderate disease and those with the most severe disease. FUNDING: Benaroya Family Foundation, the Leonard and Norma Klorfine Foundation, Glenn and Mary Lynn Mounger, and the National Institutes of Health. more...
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- 2021
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17. IgA and FcαR are critical components of plasmacytoid DC response to autoantibody-containing immune complexes in SLE
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Hayley R Waterman, Matthew Duffort, Sylvia Posso, Jane H Buckner, and Jessica A Hamerman
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Immunology ,Immunology and Allergy - Abstract
Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease characterized by the presence of circulating autoreactive anti-nuclear antibodies (ANAs). ANAs form immune complexes (ICs) upon binding to nuclear antigens and these ANA-ICs promote a feedforward loop by enhancing immune responses in cells that recognize ANA-ICs via Fc receptors (FcRs). Plasmacytoid dendritic cells (pDCs) are FcR expressing cells that promote SLE pathology. ANA-ICs deliver nucleic acids to endosomal TLR7 and TLR9. These TLRs induce type I IFN secretion and immune activation upon nucleic acid recognition. Type I IFNs, including IFNα, and interferon stimulated genes are correlated with SLE disease activity. IgG isotype facilitated ANA-IC internalization via FcgRIIA has been the most studied antibody-mediated route for IFNα production in pDCs. The importance of IgA isotype ANAs remains under investigated despite these autoantibodies being present in half of SLE patients. We show here the novel result that human pDCs express the IgA-specific FcαR (CD89) by flow cytometry, that pDCs from SLE patients express increased FcαR compared to pDCs from healthy controls, and that increased pDC FcαR expression in SLE correlates with hallmark IFNα gene set. Additionally, we found that IgA autoantibodies were a critical component of pDC ANA-IC activation when these ANA-IC were generated with serum from IgA autoantibody positive SLE donors complexed with smRNP nuclear antigen. Therefore, our study shows that IgA-containing immune complexes and FαRI are important contributors to pDC type I IFN production in SLE. Supported by LRA Lupus Mechanisms and Targets Award (JAH), R21AI154841 (JAH), and ITHS TL1 training grant (HRW). more...
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- 2022
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18. Functional SARS-CoV-2-Specific Immune Memory Persists after Mild COVID-19
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Kurt B Pruner, Yu Chen, Neil P. King, Michael Gale, Lauren Carter, Kennidy K Takehara, Lauren B. Rodda, Jason Netland, Hayley R Waterman, Malika Hale, Julie Eggenberger, Daniel J. Campbell, Brooke Fiala, Mitchell L Fahning, Laila Shehata, Christopher D. Thouvenel, David J. Rawlings, Caleb Stokes, Samuel Wrenn, Jennifer A Rathe, Peter A. Morawski, Emily A. Hemann, Jessica A. Hamerman, and Marion Pepper more...
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Male ,Monoclonal Antibody ,viruses ,T-Lymphocytes ,Immunological memory ,Severity of Illness Index ,Immunoglobulin G ,0302 clinical medicine ,Adaptive Immune Response ,Immunology and Allergy ,Receptor ,Memory B cell ,0303 health sciences ,B-Lymphocytes ,biology ,Middle Aged ,Acquired immune system ,medicine.anatomical_structure ,Spike Glycoprotein, Coronavirus ,Female ,Antibody ,Human ,Adult ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunology ,Memory T cell ,General Biochemistry, Genetics and Molecular Biology ,Virus ,Article ,Herd immunity ,03 medical and health sciences ,Antigen ,Immunity ,medicine ,Humans ,030304 developmental biology ,business.industry ,SARS-CoV-2 ,COVID-19 ,Antibodies, Neutralizing ,SARS-CoV2 ,biology.protein ,business ,Vaccine ,Immunologic Memory ,030217 neurology & neurosurgery - Abstract
The SARS-CoV-2 virus is causing a global pandemic and cases continue to rise. Most infected individuals experience mildly symptomatic coronavirus disease 2019 (COVID-19), but it is unknown whether this can induce persistent immune memory that could contribute to immunity. We performed a longitudinal assessment of individuals recovered from mild COVID-19 to determine if they develop and sustain multifaceted SARS-CoV-2-specific immunological memory. Recovered individuals developed SARS-CoV-2-specific IgG antibodies, neutralizing plasma, memory B and memory T cells that persisted for at least three months. Our data further reveal that SARS-CoV-2-specific IgG memory B cells increased over time. Additionally, SARS-CoV-2-specific memory lymphocytes exhibited characteristics associated with potent antiviral function: memory T cells secreted cytokines and expanded upon antigen re-encounter, while memory B cells expressed receptors capable of neutralizing virus when expressed as monoclonal antibodies. Therefore, mild COVID-19 elicits memory lymphocytes that persist and display functional hallmarks of antiviral immunity., Highlights • Longitudinal analysis of multifaceted immune memory following mild COVID-19 • Antibodies capable of neutralizing virus persist for at least 3 months in most subjects • Virus-specific memory B and T cells display hallmarks of anti-viral immunity • MBCs increase in number and express antibodies capable of neutralizing SARS-CoV-2, Longitudinal analysis of immune memory following mild COVID-19 elicits memory lymphocytes that persist and display functional hallmarks of antiviral immunity. more...
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- 2020
19. B Cell αv Integrins Regulate TLR-Driven Autoimmunity
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Quan Z. Li, Lauren Kadavy, Sara Sagadiev, Emily Gilbertson, Mei Yan, Mridu Acharya, Adam Lacy-Hulbert, Jessica A. Hamerman, Fiona Raso, and Lynda M. Stuart
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Genetically modified mouse ,Immunology ,Autoimmunity ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Lymphocyte Activation ,Immune Regulation ,Immunomodulation ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans ,Lupus Erythematosus, Systemic ,B cell ,Cells, Cultured ,Autoantibodies ,B-Lymphocytes ,Membrane Glycoproteins ,Autoantibody ,RNA ,Integrin alphaV ,Cell biology ,Disease Models, Animal ,medicine.anatomical_structure ,chemistry ,Toll-Like Receptor 7 ,Immunoglobulin G ,Regulatory Pathway ,DNA ,030215 immunology - Abstract
Systemic lupus erythematosus (SLE) is defined by loss of B cell tolerance, resulting in production of autoantibodies against nucleic acids and other cellular Ags. Aberrant activation of TLRs by self-derived RNA and DNA is strongly associated with SLE in patients and in mouse models, but the mechanism by which TLR signaling to self-ligands is regulated remains poorly understood. In this study, we show that αv integrin plays a critical role in regulating B cell TLR signaling to self-antigens in mice. We show that deletion of αv from B cells accelerates autoantibody production and autoimmune kidney disease in the Tlr7.1 transgenic mouse model of SLE. Increased autoimmunity was associated with specific expansion of transitional B cells, extrafollicular IgG2c-producing plasma cells, and activation of CD4 and CD8 T cells. Our data show that αv-mediated regulation of TLR signaling in B cells is critical for preventing autoimmunity and indicate that loss of αv promotes escape from tolerance. Thus, we identify a new regulatory pathway in autoimmunity and elucidate upstream signals that adjust B cell activation to prevent development of autoimmunity in a mouse model. more...
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- 2020
20. Functional SARS-CoV-2-specific immune memory persists after mild COVID-19
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Michael Gale, Emily A. Hemann, Jason Netland, Brooke Fiala, Neil P. King, Jessica A. Hamerman, Laila Shehata, Lauren Carter, Kennidy K Takehara, Yu Chen, Peter A. Morawski, Marion Pepper, Julie Eggenberger, Daniel J. Campbell, Chris Thouvenel, Lauren B. Rodda, Kurt B Pruner, Samuel Wrenn, Jennifer A Rathe, Mitchell L Fahning, David J. Rawlings, Caleb Stokes, and Hayley R Waterman more...
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Coronavirus disease 2019 (COVID-19) ,biology ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunological memory ,Article ,Virus ,Herd immunity ,Antigen ,Immunology ,biology.protein ,Medicine ,Antibody ,business ,Receptor - Abstract
SummaryThe recently emerged SARS-CoV-2 virus is currently causing a global pandemic and cases continue to rise. The majority of infected individuals experience mildly symptomatic coronavirus disease 2019 (COVID-19), but it is unknown whether this can induce persistent immune memory that might contribute to herd immunity. Thus, we performed a longitudinal assessment of individuals recovered from mildly symptomatic COVID-19 to determine if they develop and sustain immunological memory against the virus. We found that recovered individuals developed SARS-CoV-2-specific IgG antibody and neutralizing plasma, as well as virus-specific memory B and T cells that not only persisted, but in some cases increased numerically over three months following symptom onset. Furthermore, the SARS-CoV-2-specific memory lymphocytes exhibited characteristics associated with potent antiviral immunity: memory T cells secreted IFN-γ and expanded upon antigen re-encounter, while memory B cells expressed receptors capable of neutralizing virus when expressed as antibodies. These findings demonstrate that mild COVID-19 elicits memory lymphocytes that persist and display functional hallmarks associated with antiviral protective immunity. more...
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- 2020
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21. A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood Glucose in a Mouse Model of Metabolic Syndrome
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Vishal Kothari, Stephan D. Bouman, Jeffrey M. Duggan, Masami Shimizu-Albergine, Grith Skytte Olsen, Alan Chait, Jenny E. Kanter, Karin E. Bornfeldt, Farah Kramer, Bo Falck Hansen, Shelley Barnhart, and Jessica A. Hamerman more...
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Blood Glucose ,Male ,0301 basic medicine ,medicine.medical_specialty ,Complications ,MAP Kinase Signaling System ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Monocytes ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,Animals ,Medicine ,Leukocytosis ,Protein kinase B ,Metabolic Syndrome ,Mice, Knockout ,biology ,business.industry ,Insulin ,Atherosclerosis ,medicine.disease ,Plaque, Atherosclerotic ,Receptor, Insulin ,Disease Models, Animal ,Insulin receptor ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Receptors, LDL ,biology.protein ,Metabolic syndrome ,medicine.symptom ,Stem cell ,Peptides ,business ,Proto-Oncogene Proteins c-akt ,Diabetic Angiopathies ,Signal Transduction - Abstract
Cardiovascular disease caused by atherosclerosis is the leading cause of mortality associated with type 2 diabetes and metabolic syndrome. Insulin therapy is often needed to improve glycemic control, but it does not clearly prevent atherosclerosis. Upon binding to the insulin receptor (IR), insulin activates distinct arms of downstream signaling. The IR-Akt arm is associated with blood glucose lowering and beneficial effects, whereas the IR-Erk arm might exert less desirable effects. We investigated whether selective activation of the IR-Akt arm, leaving the IR-Erk arm largely inactive, would result in protection from atherosclerosis in a mouse model of metabolic syndrome. The insulin mimetic peptide S597 lowered blood glucose and activated Akt in insulin target tissues, mimicking insulin’s effects, but only weakly activated Erk and even prevented insulin-induced Erk activation. Strikingly, S597 retarded atherosclerotic lesion progression through a process associated with protection from leukocytosis, thereby reducing lesional accumulation of inflammatory Ly6Chi monocytes. S597-mediated protection from leukocytosis was accompanied by reduced numbers of the earliest bone marrow hematopoietic stem cells and reduced IR-Erk activity in hematopoietic stem cells. This study provides a conceptually novel treatment strategy for advanced atherosclerosis associated with metabolic syndrome and type 2 diabetes. more...
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- 2018
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22. BCAP inhibits proliferation and differentiation of myeloid progenitors in the steady state and during demand situations
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Jessica A. Hamerman, Jeffrey M. Duggan, Tobias M. Hohl, Matthew B. Buechler, and Rebecca M. Olson
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0301 basic medicine ,Myeloid ,Neutrophils ,Cellular differentiation ,Immunology ,Biology ,Biochemistry ,Monocytes ,Mice ,Phagocytes, Granulocytes, and Myelopoiesis ,03 medical and health sciences ,medicine ,Animals ,Homeostasis ,Cell Lineage ,Progenitor cell ,Myeloid Progenitor Cells ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Myelopoiesis ,Monocyte ,Cell Differentiation ,Cell Biology ,Hematology ,Molecular biology ,Bone marrow purging ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,IRF8 - Abstract
B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) is a signaling adaptor expressed in mature hematopoietic cells, including monocytes and neutrophils. Here we investigated the role of BCAP in the homeostasis and development of these myeloid lineages. BCAP−/− mice had more bone marrow (BM) monocytes than wild-type (WT) mice, and in mixed WT:BCAP−/− BM chimeras, monocytes and neutrophils skewed toward BCAP−/− origin, showing a competitive advantage for BCAP−/− myeloid cells. BCAP was expressed in BM hematopoietic progenitors, including lineage−Sca-1+c-kit+ (LSK), common myeloid progenitor, and granulocyte/macrophage progenitor (GMP) cells. At the steady state, BCAP−/− GMP cells expressed more IRF8 and less C/EBPα than did WT GMP cells, which correlated with an increase in monocyte progenitors and a decrease in granulocyte progenitors among GMP cells. Strikingly, BCAP−/− progenitors proliferated and produced more myeloid cells of both neutrophil and monocyte/macrophage lineages than did WT progenitors in myeloid colony-forming unit assays, supporting a cell-intrinsic role of BCAP in inhibiting myeloid proliferation and differentiation. Consistent with these findings, during cyclophosphamide-induced myeloablation or specific monocyte depletion, BCAP−/− mice replenished circulating monocytes and neutrophils earlier than WT mice. During myeloid replenishment after cyclophosphamide-induced myeloablation, BCAP−/− mice had increased LSK proliferation and increased numbers of LSK and GMP cells compared with WT mice. Furthermore, BCAP−/− mice accumulated more monocytes and neutrophils in the spleen than did WT mice during Listeria monocytogenes infection. Together, these data identify BCAP as a novel inhibitor of myelopoiesis in the steady state and of emergency myelopoiesis during demand conditions. more...
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- 2017
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23. The signaling adaptor BCAP inhibits NLRP3 and NLRC4 inflammasome activation in macrophages through interactions with Flightless-1
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Minjian Ni, Samuel J. Carpentier, Brad T. Cookson, Richard G. James, Jessica A. Hamerman, and Jeffrey M. Duggan
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Inflammasomes ,Priming (immunology) ,Plasma protein binding ,Biochemistry ,Article ,03 medical and health sciences ,0302 clinical medicine ,NLRC4 ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,0303 health sciences ,Chemistry ,Macrophages ,HEK 293 cells ,Calcium-Binding Proteins ,Caspase 1 ,Microfilament Proteins ,Signal transducing adaptor protein ,Inflammasome ,Cell Biology ,Cell biology ,Mice, Inbred C57BL ,HEK293 Cells ,Yersinia pseudotuberculosis ,030220 oncology & carcinogenesis ,Mutation ,Trans-Activators ,Apoptosis Regulatory Proteins ,medicine.drug ,Protein Binding - Abstract
B cell adaptor for PI3-kinase (BCAP) is a signaling adaptor that activates the phosphoinositide 3-kinase (PI3K) pathway downstream of B cell receptor signaling in B cells and Toll-like receptor (TLR) signaling in macrophages. BCAP binds to the regulatory p85 subunit of class I PI3K, and is a large, multidomain protein. We used proteomic analysis to identify other BCAP-interacting proteins in macrophages and found that BCAP specifically associated with the caspase-1 pseudosubstrate inhibitor Flightless-1 and its binding partner leucine-rich repeat flightless-interacting protein 2 (LRRFIP2). Because these proteins inhibit the NLRP3 inflammasome, we investigated the role of BCAP in inflammasome function. Independent of its effects on TLR priming, BCAP inhibited NLRP3- and NLRC4-induced caspase-1 activation, cell death, and IL-1β release from macrophages. Accordingly, caspase-1–dependent clearance of a Yersinia pseudotuberculosis mutant was enhanced in BCAP-deficient mice. Mechanistically, BCAP delayed the recruitment and activation of pro-caspase-1 within the NLRP3-ASC pre-inflammasome through its association with Flightless-1. Thus, BCAP is a multifunctional signaling adaptor that inhibits key pathogen-sensing pathways in macrophages. more...
- Published
- 2019
24. Rhinovirus Infected Airway Epithelial Cells from Children with Asthma Enhance the Type-2 Immune Environment in Mast Cells
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Steven F. Ziegler, Jessica A. Hamerman, Adam Lacy-Hulbert, Teal S. Hallstrand, Matthew C. Altman, Adrian M. Piliponsky, K.A. Barrow, Ying Lai, William A. Altemeier, S.R. Reeves, and Jason S. Debley
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Immune system ,business.industry ,Immunology ,medicine ,Rhinovirus ,medicine.disease_cause ,business ,Airway ,medicine.disease ,Asthma - Published
- 2019
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25. Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes
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Elizabeth Whalen, Holly M. Akilesh, Bharati Matta, Jessica A. Hamerman, Xizhang Sun, Michael Mason, Jeffrey M. Duggan, Matthew B. Buechler, Betsy J. Barnes, Marion Pepper, William O. Hahn, Adam Lacy-Hulbert, Keith B. Elkon, Griffin Gessay, and Scott R. Presnell more...
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Anemia ,Cellular differentiation ,Population ,Inflammation ,Article ,Monocytes ,Mice ,hemic and lymphatic diseases ,medicine ,Animals ,education ,Cells, Cultured ,Mice, Knockout ,education.field_of_study ,Mice, Inbred BALB C ,Phagocytes ,Multidisciplinary ,Membrane Glycoproteins ,business.industry ,Monocyte ,Macrophage Activation Syndrome ,virus diseases ,Cell Differentiation ,Plasmodium yoelii ,medicine.disease ,Thrombocytopenia ,DNA-Binding Proteins ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Toll-Like Receptor 7 ,Macrophage activation syndrome ,Toll-Like Receptor 9 ,Immunology ,Interferon Regulatory Factors ,Myeloid Differentiation Factor 88 ,medicine.symptom ,business ,Transcriptome ,IRF5 ,Spleen ,Interferon regulatory factors ,Signal Transduction - Abstract
Unmasking an agent of inflammatory anemia Infectious and autoimmune diseases are associated with anemia and thrombocytopenia. A severe form of inflammatory cytopenia called macrophage activation syndrome (MAS) may occur during rheumatological disorders and viral infections. Akilesh et al. show that monocyte recognition of self- or pathogen-derived nucleic acids via Toll-like receptors 7 and 9 (TLR7 and TLR9) drives MAS-like disease in mice. TLR7 or TLR9 signaling in monocytes causes these cells to differentiate into inflammatory hematophagocytes (iHPCs), which are similar to but distinct from red pulp macrophages. Preventing iHPC differentiation by depleting monocytes relieves MAS-like symptoms. When mice were subjected to a model of malarial anemia, MyD88- and endosomal TLR-dependent iHPC differentiation also occurred. Thus, iHPCs may play a role in both MAS-driven and malarial anemia, as well as thrombocytopenia. Science , this issue p. eaao5213 more...
- Published
- 2019
26. Blood-eating cells: a defense or a threat?
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Holly Marie Akilesh, Hayley R Waterman, and Jessica A. Hamerman
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- 2019
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27. Cutting Edge: Direct Sensing of TLR7 Ligands and Type I IFN by the Common Myeloid Progenitor Promotes mTOR/PI3K-Dependent Emergency Myelopoiesis
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Matthew B. Buechler, Holly M. Akilesh, and Jessica A. Hamerman
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0301 basic medicine ,Myeloid ,Cellular differentiation ,Immunology ,Biology ,Ligands ,Article ,Mice ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,medicine ,Animals ,Immunology and Allergy ,Progenitor cell ,Myeloid Progenitor Cells ,PI3K/AKT/mTOR pathway ,Mice, Knockout ,Myelopoiesis ,Membrane Glycoproteins ,Macrophages ,TOR Serine-Threonine Kinases ,Monocyte ,Cell Differentiation ,Cell biology ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Toll-Like Receptor 7 ,Interferon Type I ,Interferon type I ,medicine.drug - Abstract
During infection, recognition of pathogens and inflammatory cytokines skews hematopoiesis toward myeloid development, although the precise mechanisms responsible for this are unclear. In this study, we show that accelerated myeloid differentiation, known as emergency myelopoiesis, involves recognition of pathogen-associated molecular patterns by the common myeloid progenitor (CMP) and is dependent on type I IFN for monocyte/macrophage differentiation. Direct sensing of TLR agonists by CMP induced rapid proliferation and induction of myeloid-differentiation genes. Lack of type I IFN signaling in CMP abrogated macrophage differentiation in response to TLR stimuli, whereas exogenous type I IFN amplified this process. Mechanistically, TLR7 induced PI3K/mammalian target of rapamycin signaling in CMP, which was enhanced by type I IFN, and this pathway was essential for emergency myelopoiesis. This work identifies a novel mechanism by which TLR and type I IFN synergize to promote monocyte/macrophage development from hematopoietic progenitors, a process critical in triggering rapid immune responses during infection. more...
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- 2016
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28. Flightless-1 promotes lung CD103+ cDC phagocytosis and migration
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Allison R O’Rourke and Jessica A Hamerman
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Immunology ,Immunology and Allergy - Abstract
Dendritic cells are specialized antigen-presenting cells integral for bridging the innate and adaptive immune responses. Critical to dendritic cell function is the need for a dynamic actin cytoskeleton. Flightless-1 is an actin capping protein linked to processes vital for dendritic cell immune functions including cell extension formation, phagocytosis, cell migration, and cell adhesion. Consistent with an important role in actin dynamics, whole body Flightless-1 knockouts are embryonic lethal. To enable further study of Flightless-1 in the immune response, we made mice with dendritic cell Flightless-1 deficiency using the CD11c-CRE driver. Homeostatic cDC1 and cDC2 populations in the spleen and lymph nodes were unchanged in DC-Flightless-1 knockouts relative to control animals. However, DC-Flightless-1 ablation led to a developmental disadvantage when in competition with WT DCs in mixed bone marrow chimeras. Upon LPS challenge in the airways, the Flightless-deficient cDC1 population showed reduced phagocytosis and migration to the lung draining lymph nodes. The DC migratory defect in the absence of Flightless-1 was supported by decreased CCR7 expression in both cDC1 and cDC2 populations. We hypothesize that the observed defects in phagocytosis and migration in Flightless-1-deficient dendritic cells are due to an altered actin cytoskeleton, which may also affect other actin-based immune structures. Current experiments are testing this hypothesis, and investigating the ability of Flightless-deficient DC to prime T cell responses. more...
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- 2020
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29. cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses
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D. Noah Sather, Noah S. Butler, Stefan H. I. Kappe, W. Conrad Liles, Holly Marie Akilesh, Michael Gale, Scott E. Lindner, Marion Pepper, Jessica A. Hamerman, and William O. Hahn
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0301 basic medicine ,CD4-Positive T-Lymphocytes ,Male ,Parasite Load ,03 medical and health sciences ,Antimalarials ,Mice ,0302 clinical medicine ,Immune system ,Animals ,Humans ,Memory B cell ,Mice, Knockout ,B-Lymphocytes ,Innate immune system ,biology ,Pattern recognition receptor ,Germinal center ,General Medicine ,Plasmodium yoelii ,biology.organism_classification ,Acquired immune system ,Germinal Center ,Nucleotidyltransferases ,Immunity, Humoral ,Malaria ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Immunology ,Humoral immunity ,030215 immunology ,Research Article - Abstract
Sensing of pathogens by host pattern recognition receptors is essential for activating the immune response during infection. We used a nonlethal murine model of malaria (Plasmodium yoelii 17XNL) to assess the contribution of the pattern recognition receptor cyclic GMP-AMP synthase (cGAS) to the development of humoral immunity. Despite previous reports suggesting a critical, intrinsic role for cGAS in early B cell responses, cGAS-deficient (cGAS-/-) mice had no defect in the early expansion or differentiation of Plasmodium-specific B cells. As the infection proceeded, however, cGAS-/- mice exhibited higher parasite burdens and aberrant germinal center and memory B cell formation when compared with littermate controls. Antimalarial drugs were used to further demonstrate that the disrupted humoral response was not B cell intrinsic but instead was a secondary effect of a loss of parasite control. These findings therefore demonstrate that cGAS-mediated innate-sensing contributes to parasite control but is not intrinsically required for the development of humoral immunity. Our findings highlight the need to consider the indirect effects of pathogen burden in investigations examining how the innate immune system affects the adaptive immune response. more...
- Published
- 2018
30. Negative regulation of TLR signaling in myeloid cells-implications for autoimmune diseases
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Jessica A. Hamerman, Yantao He, Jane H. Buckner, Jessica Pottle, Zhong Yin Zhang, and Minjian Ni
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0301 basic medicine ,Immunology ,Inflammation ,Biology ,medicine.disease_cause ,Article ,Autoimmune Diseases ,Autoimmunity ,Proinflammatory cytokine ,Immunomodulation ,03 medical and health sciences ,Interferon ,medicine ,Animals ,Humans ,Immunology and Allergy ,Myeloid Cells ,Tumor Necrosis Factor alpha-Induced Protein 3 ,PI3K/AKT/mTOR pathway ,Autoimmune disease ,Macrophages ,Toll-Like Receptors ,Intracellular Signaling Peptides and Proteins ,Pattern recognition receptor ,Nuclear Proteins ,Protein Tyrosine Phosphatase, Non-Receptor Type 22 ,Dendritic Cells ,medicine.disease ,DNA-Binding Proteins ,030104 developmental biology ,medicine.symptom ,Signal transduction ,Carrier Proteins ,Signal Transduction ,medicine.drug - Abstract
Toll-like receptors (TLR) are transmembrane pattern recognition receptors that recognize microbial ligands and signal for production of inflammatory cytokines and type I interferon in macrophages and dendritic cells (DC). Whereas TLR-induced inflammatory mediators are required for pathogen clearance, many are toxic to the host and can cause pathological inflammation when over-produced. This is demonstrated by the role of TLR-induced cytokines in autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Because of the potent effects of TLR-induced cytokines, we have diverse mechanisms to dampen TLR signaling. Here, we highlight three pathways that participate in inhibition of TLR responses in macrophages and DC, and their implications in autoimmunity; A20, encoded by the TNFAIP3 gene, Lyp encoded by the PTPN22 gene, and the BCAP/PI3K pathway. We present new findings that Lyp promotes TLR responses in primary human monocytes and that the autoimmunity risk Lyp620W variant is more effective at promoting TLR-induced interleukin-6 than the non-risk Lyp620R protein. This suggests that Lyp serves to downregulate a TLR inhibitory pathway in monocytes, and we propose that Lyp inhibits the TREM2/DAP12 inhibitory pathway. Overall, these pathways demonstrate distinct mechanisms of negative regulation of TLR responses, and all impact autoimmune disease pathogenesis and treatment. more...
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- 2015
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31. Hematopoietic and nonhematopoietic cells promote Type I interferon- and TLR7-dependent monocytosis during low-dose LCMV infection
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Jessica A. Hamerman, Shivani Srivastava, Daniel J. Campbell, Matthew B. Buechler, and Griffin Gessay
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CCR2 ,Immunology ,virus diseases ,hemic and immune systems ,TLR7 ,Biology ,Lymphocytic choriomeningitis ,medicine.disease ,Haematopoiesis ,medicine.anatomical_structure ,Monocytosis ,Interferon ,medicine ,Immunology and Allergy ,Bone marrow ,Interferon type I ,medicine.drug - Abstract
Release of inflammatory monocytes from the bone marrow (BM) into the blood is an important physiological response to infection, but the mechanisms regulating this phenomenon during viral infection are not completely defined. Here, we show that low-dose infection with lymphocytic choriomeningitis virus (LCMV) caused rapid, transient inflammatory monocytosis that required type I interferon (IFN) and Toll-like receptor (TLR) 7 signaling. Type I IFN and TLR7 signals were critical for induction of IFN-stimulated gene expression and CCR2 ligand upregulation in the BM microenvironment in response to LCMV infection. Experiments utilizing BM chimeric mice demonstrated that type I IFN and TLR7 signaling on either hematopoietic or nonhematopoietic cells was sufficient to initiate monocytosis in response to LCMV infection. BM plasmacytoid dendritic cells (pDCs) generated type I IFN directly ex vivo, suggesting that pDCs are a hematopoietic contributor of type I IFN in the BM early during LCMV infection. Overall, we describe novel roles for type I IFN and TLR7 signaling in nonhematopoietic cells and BM pDCs in directing IFN-stimulated gene and CCR2 ligand expression in the BM to initiate an increase in blood inflammatory monocytes during viral infection. more...
- Published
- 2015
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32. The Tec Kinase–Regulated Phosphoproteome Reveals a Mechanism for the Regulation of Inhibitory Signals in Murine Macrophages
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Albanus O. Moguche, Deqiang Niu, Tahmina A. Jahan, Richard G. James, Socheath Khim, Hannah M. Kerns, Beth Browning, Katherine A. Bosch, Swati Singh, Jessica A. Hamerman, M. Nacht, David J. Rawlings, Giacomo Tampella, Alejandro Wolf-Yadlin, Alessandro Plebani, Erica Evans, and Meghan E. Garrett more...
- Subjects
Lipopolysaccharides ,Cell type ,Knockout ,TEC ,Primary Cell Culture ,education ,Immunology ,Bone Marrow Cells ,Inbred C57BL ,Article ,Proinflammatory cytokine ,Mice ,Phosphatidylinositol 3-Kinases ,hemic and lymphatic diseases ,Agammaglobulinaemia Tyrosine Kinase ,Animals ,Immunology and Allergy ,Bruton's tyrosine kinase ,Phosphorylation ,Peritoneal Cavity ,PI3K/AKT/mTOR pathway ,Mice, Knockout ,biology ,Kinase ,Chemistry ,Gene Expression Profiling ,Macrophages ,Toll-Like Receptors ,hemic and immune systems ,Protein-Tyrosine Kinases ,Phosphoproteins ,Cell biology ,Mice, Inbred C57BL ,Gene Expression Regulation ,Organ Specificity ,Signal Transduction ,biology.protein ,Signal transduction ,tissues - Abstract
Previous work has shown conflicting roles for Tec family kinases in regulation of TLR-dependent signaling in myeloid cells. In the present study, we performed a detailed investigation of the role of the Tec kinases Btk and Tec kinases in regulating TLR signaling in several types of primary murine macrophages. We demonstrate that primary resident peritoneal macrophages deficient for Btk and Tec secrete less proinflammatory cytokines in response to TLR stimulation than do wild-type cells. In contrast, we found that bone marrow–derived and thioglycollate-elicited peritoneal macrophages deficient for Btk and Tec secrete more proinflammatory cytokines than do wild-type cells. We then compared the phosphoproteome regulated by Tec kinases and LPS in primary peritoneal and bone marrow–derived macrophages. From this analysis we determined that Tec kinases regulate different signaling programs in these cell types. In additional studies using bone marrow–derived macrophages, we found that Tec and Btk promote phosphorylation events necessary for immunoreceptor-mediated inhibition of TLR signaling. Taken together, our results are consistent with a model where Tec kinases (Btk, Tec, Bmx) are required for TLR-dependent signaling in many types of myeloid cells. However, our data also support a cell type–specific TLR inhibitory role for Btk and Tec that is mediated by immunoreceptor activation and signaling via PI3K. more...
- Published
- 2015
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33. Overexpression of TLR7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells
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Xizhang Sun, Jinoh Kim, Nikita S. Kolhatkar, Edward A. Clark, Matthew B. Buechler, Craig P. Chappell, Keith B. Elkon, Lena Tanaka, Thereza Imanishi-Kari, Natalia V. Giltiay, Jessica A. Hamerman, Thomas H. Teal, and Alice E. Wiedeman more...
- Subjects
Cellular differentiation ,Immunology ,Cell ,B-Lymphocyte Subsets ,Receptors, Antigen, B-Cell ,Apoptosis ,Mice, Transgenic ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Cytidine Deaminase ,medicine ,Animals ,Humans ,Immunology and Allergy ,Receptor ,Autoantibodies ,Cell Proliferation ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Membrane Glycoproteins ,Systemic lupus erythematosus ,biology ,Precursor Cells, B-Lymphoid ,Autoantibody ,virus diseases ,Cell Differentiation ,TLR7 ,medicine.disease ,Immunoglobulin Class Switching ,Molecular biology ,Up-Regulation ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Toll-Like Receptor 7 ,Interferon Type I ,biology.protein ,RNA ,Antibody ,T-Box Domain Proteins ,Spleen ,030215 immunology - Abstract
Transgenic expression of TLR7 results in the expansion and hyperactivation of T1 B cells in response to endogenous RNA complexes, leading to increased autoantibody production., Toll-like receptor (TLR), a ligand for single-stranded RNA, has been implicated in the development of pathogenic anti-RNA autoantibodies both in systemic lupus erythematous (SLE) patients and in murine models of lupus. It is still unclear, however, where and how TLR7-mediated interactions affect the development of autoreactive B cells. We found that overexpression of TLR7 in transgenic mice (TLR7.1Tg) leads to marked alterations of transitional (T1) B cells, associated with their expansion and proliferation within the splenic red pulp (RP). This phenotype was intrinsic to the T1 subset of B cells and occurred independently of type 1 IFN signals. Overexpression of RNase in TLR7.1Tg mice significantly limited the expansion and proliferation of T1 cells, indicating that endogenous RNA complexes are driving their activation. TLR7.1Tg T1 cells were hyper-responsive to anti-IgM and TLR7 ligand stimulation in vitro and produced high concentrations of class-switched IgG2b and IgG2c, including anti-RNA antibodies. Our results demonstrate that initial TLR7 stimulation of B cells occurs at the T1 stage of differentiation in the splenic RP and suggest that dysregulation of TLR7 expression in T1 cells can result in production of autoantibodies. more...
- Published
- 2013
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34. Increased Ribonuclease Expression Reduces Inflammation and Prolongs Survival in TLR7 Transgenic Mice
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Jessica A. Hamerman, Jeffrey A. Ledbetter, Nalini Agrawal, Thomas H. Teal, Denny Liggitt, Charles E. Alpers, Matthew B. Buechler, Lena Tanaka, Kelly L. Hudkins, Xizhang Sun, Keith B. Elkon, Alice E. Wiedeman, and Silvia Bolland more...
- Subjects
Male ,Genetically modified mouse ,medicine.medical_specialty ,RNase P ,Transgene ,Immunology ,Down-Regulation ,Mice, Transgenic ,Inflammation ,Biology ,Article ,Hepatitis ,Pathogenesis ,Mice ,Internal medicine ,medicine ,Animals ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Cells, Cultured ,Embryonic Stem Cells ,Mice, Inbred C3H ,Membrane Glycoproteins ,Autoantibody ,virus diseases ,Glomerulonephritis ,Ribonuclease, Pancreatic ,TLR7 ,medicine.disease ,Survival Analysis ,Molecular biology ,Up-Regulation ,Mice, Inbred C57BL ,Endocrinology ,Toll-Like Receptor 7 ,Cattle ,medicine.symptom ,Spleen - Abstract
TLR7 activation is implicated in the pathogenesis of systemic lupus erythematosus. Mice that overexpress TLR7 develop a lupus-like disease with autoantibodies and glomerulonephritis and early death. To determine whether degradation of the TLR7 ligand RNA would alter the course of disease, we created RNase A transgenic (Tg) mice. We then crossed the RNase Tg to TLR7 Tg mice to create TLR7 × RNase double Tg (DTg) mice. DTg mice had a significantly increased survival associated with reduced activation of T and B lymphocytes and reduced kidney deposition of IgG and C3. We observed massive hepatic inflammation and cell death in TLR7 Tg mice. In contrast, hepatic inflammation and necrosis were strikingly reduced in DTg mice. These findings indicate that high concentrations of serum RNase protect against immune activation and inflammation associated with TLR7 stimulation and that RNase may be a useful therapeutic strategy in the prevention or treatment of inflammation in systemic lupus erythematosus and, possibly, liver diseases. more...
- Published
- 2013
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35. β2integrins inhibit TLR responses by regulating NF-κB pathway and p38 MAPK activation
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Jessica A. Hamerman and Nathan Yee
- Subjects
Chemokine ,medicine.medical_treatment ,Immunology ,Integrin ,NF-κB ,Biology ,NFKB1 ,Molecular biology ,Proinflammatory cytokine ,Cell biology ,chemistry.chemical_compound ,IκBα ,Cytokine ,chemistry ,medicine ,biology.protein ,Immunology and Allergy ,Signal transduction - Abstract
Outside-in signals from β(2) integrins require immunoreceptor tyrosine-based activation motif adapters in myeloid cells that are known to dampen TLR responses. However, the relationship between β(2) integrins and TLR regulation is unclear. Here we show that deficiency in β(2) integrins (Itgb2(-/-) ) causes hyperresponsiveness to TLR stimulation, demonstrating that β(2) integrins inhibit signals downstream of TLR ligation. Itgb2(-/-) macrophages and dendritic cells produced more IL-12 and IL-6 than WT cells when stimulated with TLR agonists and Itgb2(-/-) mice produced more inflammatory cytokines than WT mice when injected with LPS. TLR hypersensitivity was not the result of insufficient ABIN-3, A20, Hes-1, or IRAK-M expression, nor to changes in IL-10 production or sensitivity, though Itgb2(-/-) macrophages had reduced p38 MAPK phosphorylation after LPS treatment. Furthermore, a Cbl-b-MyD88 regulatory axis is not required for TLR inhibition in macrophages. Instead, Itgb2(-/-) macrophages presented with enhanced IκBα degradation, leading to changes in NF-κB recruitment to target promoters and elevated cytokine, chemokine, and anti-apoptotic gene transcription. Thus, β(2) integrins limit TLR signaling by inhibiting NF-κB pathway activation and promoting p38 MAPK activation, thereby fine-tuning TLR-induced inflammatory responses. more...
- Published
- 2013
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36. Cutting Edge: Type I IFN Drives Emergency Myelopoiesis and Peripheral Myeloid Expansion during Chronic TLR7 Signaling
- Author
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Keith B. Elkon, Matthew B. Buechler, Jessica A. Hamerman, and Thomas H. Teal
- Subjects
Myeloid ,Immunology ,Population ,Mice, Transgenic ,Receptor, Interferon alpha-beta ,Biology ,Granulocyte ,Article ,Mice ,Bone Marrow ,medicine ,Animals ,Antigens, Ly ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Cell Lineage ,Myeloid Cells ,RNA, Messenger ,Progenitor cell ,education ,Myelopoiesis ,education.field_of_study ,Membrane Glycoproteins ,Macrophages ,Models, Immunological ,Membrane Proteins ,virus diseases ,Dendritic Cells ,TLR7 ,Disease Models, Animal ,medicine.anatomical_structure ,Gene Expression Regulation ,Toll-Like Receptor 7 ,Radiation Chimera ,Interferon Type I ,Bone marrow ,Cell Division ,Spleen ,Interferon type I ,Granulocytes ,Signal Transduction ,medicine.drug - Abstract
Mice overexpressing TLR7 (TLR7.1 mice) are a model of systemic lupus erythematosus pathogenesis and exhibit peripheral myeloid expansion. We show that TLR7.1 mice have a dramatic expansion of splenic cells that derive from granulocyte/macrophage progenitors (GMP) compared with wild-type mice. In the bone marrow, TLR7.1 mice exhibited hallmarks of emergency myelopoiesis and contained a discrete population of Sca-1+ GMP, termed emergency GMP, which are more proliferative and superior myeloid precursors than classical Sca-1− GMP. The emergency myelopoiesis and peripheral myeloid expansion in TLR7.1 mice was dependent on type I IFN signaling. TLR7 agonist administration to nontransgenic mice also drove type I IFN–dependent emergency myelopoiesis. TLR7.1 plasmacytoid dendritic cells were cell-intrinsically activated by TLR7 overexpression and constitutively produced type I IFN mRNA. This study shows that type I IFN can act upon myeloid progenitors to promote the development of emergency GMP, which leads to an expansion of their progeny in the periphery. more...
- Published
- 2013
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37. Tracing Conidial Fate and Measuring Host Cell Antifungal Activity Using a Reporter of Microbial Viability in the Lung
- Author
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Brahm H. Segal, Katrina B. Mar, Clifford A. Lowell, Anupam Jhingran, Xin Lin, Yoichiro Iwakura, Jessica A. Hamerman, Tobias M. Hohl, Debra K. Kumasaka, Sue E. Knoblaugh, and Lisa Y. Ngo
- Subjects
Spores ,Medical Physiology ,Cell ,Syk ,Aspergillus fumigatus ,Mice ,Innate ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,Aetiology ,lcsh:QH301-705.5 ,Lung ,Pathogen ,Mice, Knockout ,0303 health sciences ,Microbial Viability ,biology ,Intracellular Signaling Peptides and Proteins ,Adaptor Proteins ,Spores, Fungal ,Protein-Tyrosine Kinases ,Cell biology ,Fungal ,Infectious Diseases ,medicine.anatomical_structure ,Host-Pathogen Interactions ,Infection ,Knockout ,Integrin ,Article ,General Biochemistry, Genetics and Molecular Biology ,Microbiology ,Vaccine Related ,03 medical and health sciences ,Biodefense ,medicine ,Animals ,Aspergillosis ,Syk Kinase ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,Aspergillus ,Innate immune system ,030306 microbiology ,Prevention ,Signal Transducing ,Immunity ,Pneumonia ,biology.organism_classification ,Immunity, Innate ,CARD Signaling Adaptor Proteins ,Emerging Infectious Diseases ,lcsh:Biology (General) ,biology.protein ,Biochemistry and Cell Biology - Abstract
SummaryFluorescence can be harnessed to monitor microbial fate and to investigate functional outcomes of individual microbial cell-host cell encounters at portals of entry in native tissue environments. We illustrate this concept by introducing fluorescent Aspergillus reporter (FLARE) conidia that simultaneously report phagocytic uptake and fungal viability during cellular interactions with the murine respiratory innate immune system. Our studies using FLARE conidia reveal stepwise and cell-type-specific requirements for CARD9 and Syk, transducers of C-type lectin receptor and integrin signals, in neutrophil recruitment, conidial uptake, and conidial killing in the lung. By achieving single-event resolution in defined leukocyte populations, the FLARE method enables host cell profiling on the basis of pathogen uptake and killing and may be extended to other pathogens in diverse model host organisms to query molecular, cellular, and pharmacologic mechanisms that shape host-microbe interactions. more...
- Published
- 2012
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38. B-cell adaptor for PI3K (BCAP) negatively regulates Toll-like receptor signaling through activation of PI3K
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Jessica A. Hamerman, Kerry S. Campbell, Michelle Toft, Minjian Ni, Alexander W. MacFarlane, and Clifford A. Lowell
- Subjects
Lipopolysaccharides ,Protein subunit ,Receptor, Macrophage Colony-Stimulating Factor ,Biology ,Mice ,Phosphatidylinositol 3-Kinases ,NF-KappaB Inhibitor alpha ,medicine ,Animals ,Syk Kinase ,Phosphorylation ,Phosphotyrosine ,Receptor ,PI3K/AKT/mTOR pathway ,B cell ,Adaptor Proteins, Signal Transducing ,Inflammation ,B-Lymphocytes ,Toll-like receptor ,Multidisciplinary ,Activator (genetics) ,Macrophages ,Toll-Like Receptors ,Intracellular Signaling Peptides and Proteins ,Protein-Tyrosine Kinases ,Biological Sciences ,Cell biology ,Enzyme Activation ,Mice, Inbred C57BL ,Protein Subunits ,medicine.anatomical_structure ,Cytoplasm ,Proteolysis ,Cytokines ,I-kappa B Proteins ,Mitogen-Activated Protein Kinases ,Proto-Oncogene Proteins c-akt ,Protein Binding ,Subcellular Fractions - Abstract
Toll-like receptors (TLRs) recognize pathogens and their components, thereby initiating immune responses to infectious organisms. TLR ligation leads to the activation of NF-κB and MAPKs through well-defined pathways, but it has remained unclear how TLR signaling activates PI3K, which provides an inhibitory pathway limiting TLR responses. Here, we show that the signaling adapter B-cell adaptor for PI3K (BCAP) links TLR signaling to PI3K activation. BCAP-deficient macrophages and mice are hyperresponsive to TLR agonists and have reduced PI3K activation. The ability of BCAP to inhibit TLR responses requires its capacity to bind PI3K. BCAP is constitutively phosphorylated and associated with the p85 subunit of PI3K in macrophages. This tyrosine-phosphorylated BCAP is transiently enriched in the membrane fraction in response to LPS treatment, suggesting a model whereby TLR signaling causes the phosphorylation of the small amount of BCAP that is associated with membranes in the resting state or the translocation of phosphorylated BCAP from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated BCAP at the membrane with its associated PI3K would then allow for the catalysis of Ptd Ins P2 to Ptd Ins P3 and downstream PI3K-dependent signals. Therefore, BCAP is an essential activator of the PI3K pathway downstream of TLR signaling, providing a brake to limit potentially pathogenic excessive TLR responses. more...
- Published
- 2011
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39. TREM-2, triggering receptor expressed on myeloid cell-2, negatively regulates TLR responses in dendritic cells
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Hiroaki Ito and Jessica A. Hamerman
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biology ,medicine.diagnostic_test ,medicine.medical_treatment ,Immunology ,Cell ,Signal transducing adaptor protein ,Proinflammatory cytokine ,Flow cytometry ,Membrane glycoproteins ,Cytokine ,medicine.anatomical_structure ,biology.protein ,medicine ,Immunology and Allergy ,Signal transduction ,Receptor - Abstract
DCs play a key role in defense against infections and also in preventing inflammatory and autoimmune diseases. The response of DCs to pathogens is tightly regulated by many mechanisms to allow for appropriate, but not pathogenic, responses. We previously showed that DCs with deficiencies for two ITAM-bearing signaling adapters, DAP12 and FcRγ, produce more inflammatory cytokines upon treatment with Toll-like receptor (TLR) agonists than WT DCs. Here, we investigated whether the TREM-2 receptor pairs with DAP12 to inhibit TLR responses in DCs. TREM-2-deficient BMDCs showed increased inflammatory cytokine and type I IFN production in response to TLR ligation. Additionally, TREM-2-deficient BMDCs had increased TLR-induced maturation and were more efficient at inducing antigen-specific T-cell proliferation upon CpG DNA stimulation compared with WT BMDCs. Finally, we showed that a TREM-2 ligand is expressed on the surface of BMDCs, suggesting that the TREM-2 receptor transduces inhibitory signals due to recognition of an endogenous ligand. more...
- Published
- 2011
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40. S100A9 Differentially Modifies Phenotypic States of Neutrophils, Macrophages, and Dendritic Cells
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Clemens Sorg, Claus Kerkhoff, Shelley Barnhart, Michelle M. Averill, Karin E. Bornfeldt, Renee C. LeBoeuf, Jay W. Heinecke, Lev Becker, Jessica A. Hamerman, and Xin Li
- Subjects
Lipopolysaccharides ,Male ,Neutrophils ,Adipose tissue ,Inflammation ,Biology ,Article ,S100A9 ,Mice ,Peritoneal cavity ,Insulin resistance ,Physiology (medical) ,medicine ,Animals ,Calgranulin B ,Macrophage ,Calgranulin A ,Macrophages ,Dendritic Cells ,Dendritic cell ,Atherosclerosis ,medicine.disease ,Toll-Like Receptor 2 ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,Phenotype ,medicine.anatomical_structure ,Adipose Tissue ,Receptors, LDL ,Immunology ,Bone marrow ,Insulin Resistance ,medicine.symptom ,Cardiology and Cardiovascular Medicine - Abstract
Background— S100A9 is constitutively expressed in neutrophils, dendritic cells, and monocytes; is associated with acute and chronic inflammatory conditions; and is implicated in obesity and cardiovascular disease in humans. Most of the constitutively secreted S100A9 is derived from myeloid cells. A recent report demonstrated that mice deficient in S100A9 exhibit reduced atherosclerosis compared with controls and suggested that this effect was due in large part to loss of S100A9 in bone marrow–derived cells. Methods and Results— To directly investigate the role of bone marrow–derived S100A9 in atherosclerosis and insulin resistance in mice, low-density lipoprotein receptor–deficient, S100A9-deficient bone marrow chimeras were generated. Neither atherosclerosis nor insulin resistance was reduced in S100A9-deficient chimeras fed a diet rich in fat and carbohydrates. To investigate the reason for this lack of effect, myeloid cells were isolated from the peritoneal cavity or bone marrow. S100A9-deficient neutrophils exhibited a reduced secretion of cytokines in response to toll-like receptor-4 stimulation. In striking contrast, S100A9-deficient dendritic cells showed an exacerbated release of cytokines after toll-like receptor stimulation. Macrophages rapidly lost S100A9 expression during maturation; hence, S100A9 deficiency did not affect the inflammatory status of macrophages. Conclusions— S100A9 differentially modifies phenotypic states of neutrophils, macrophages, and dendritic cells. The effect of S100A9 deficiency on atherosclerosis and other inflammatory diseases is therefore predicted to depend on the relative contribution of these cell types at different stages of disease progression. Furthermore, S100A9 expression in nonmyeloid cells is likely to contribute to atherosclerosis. more...
- Published
- 2011
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41. Short-term IL-1β blockade reduces monocyte CD11b integrin expression in an IL-8 dependent fashion in patients with type 1 diabetes
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Nathan Standifer, Carla J. Greenbaum, Gerald T. Nepom, Jenna Bollyky, Srinath Sanda, and Jessica A. Hamerman
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Adult ,Adolescent ,medicine.medical_treatment ,Interleukin-1beta ,Immunology ,Inflammation ,Monocytes ,Young Adult ,Humans ,Hypoglycemic Agents ,Immunology and Allergy ,Medicine ,Interleukin 8 ,Anakinra ,CD11b Antigen ,biology ,business.industry ,Monocyte ,Interleukin-8 ,Interleukin ,Middle Aged ,Blockade ,Interleukin 1 Receptor Antagonist Protein ,Diabetes Mellitus, Type 1 ,Cytokine ,medicine.anatomical_structure ,Integrin alpha M ,biology.protein ,medicine.symptom ,business ,medicine.drug - Abstract
Objective Interleukin 1-beta (IL-1β) is a major inflammatory cytokine. Blockade of the IL-1β pathway is therapeutically efficacious in type 2 diabetes, but the mechanistic effects on the immune system are incompletely understood. Research design We administered an IL-1 receptor antagonist, anakinra, to 7 type 1 diabetes patients in order to investigate the immunologic and metabolic effects of this drug. Mechanistic assays were performed before and after drug administration. Results A novel signature was observed, with reduced serum interleukin 8 (IL-8) levels and reduced CD11b integrin expression on monocytes associated with increased CXCR1 expression. Conclusions This set of linked phenotypes suggests that blockade of the IL-1β pathway results in the reduced ability of mononuclear cells to traffic to sites of inflammation. Mechanistic studies from large scale trials using IL-1 blockade in type 1 diabetes should focus on changes in monocyte trafficking and the IL-8 pathway. more...
- Published
- 2010
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42. DAP12 Is Required for Macrophage Recruitment to the Lung in Response to Cigarette Smoke and Chemotaxis toward CCL2
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Clare L. Abram, Prescott G. Woodruff, Lewis L. Lanier, Jessica A. Hamerman, C.J. Cambier, Margaret Solon, Lydia Hou, Laura L. Koth, and Almut Ellwanger
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Myeloid ,Blotting, Western ,Immunology ,Fluorescent Antibody Technique ,Inflammation ,Cell Separation ,CCL2 ,Biology ,Article ,Mice ,Pulmonary Disease, Chronic Obstructive ,Smoke ,Macrophages, Alveolar ,medicine ,Animals ,Humans ,Immunoprecipitation ,Immunology and Allergy ,Receptors, Immunologic ,Receptor ,Lung ,Chemokine CCL2 ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,Membrane Glycoproteins ,Reverse Transcriptase Polymerase Chain Reaction ,TREM2 ,Membrane Proteins ,Chemotaxis ,respiratory system ,Flow Cytometry ,Mice, Inbred C57BL ,Chemotaxis, Leukocyte ,medicine.anatomical_structure ,Alveolar macrophage ,medicine.symptom - Abstract
DAP12 is an adapter protein that associates with several receptors in macrophages. Little is known about the biological role of DAP12 in alveolar macrophages. In genome-wide profiling, we previously found that two DAP12-associated receptors, myeloid DAP12-associated lectin-1 and triggering receptor expressed on myeloid cells 2 (TREM2), were highly induced in alveolar macrophages from habitual smokers. Here, we found that transcript levels for these receptors in alveolar macrophages increased with packs per day of cigarettes smoked and expression of TREM2 protein was increased in lung macrophages of former smokers with emphysema compared with that in controls. In vitro, cigarette smoke directly induced expression of myeloid DAP12-associated lectin-1 and TREM2 and activation of DAP12 signaling in mouse macrophages. To determine whether DAP12 plays a role in cigarette smoke-induced pulmonary inflammation, we exposed wild-type and DAP12-deficient mice to chronic cigarette smoke and found significant reduction in recruitment of alveolar macrophages in DAP12-deficient mice. Because cigarette smoking induces the macrophage chemoattractant CCL2, we tested the chemotactic ability of DAP12-deficient macrophages and found abrogation of chemotaxis toward CCL2 in vitro. Airway administration of CCL2 also resulted in a significant reduction of macrophage recruitment to the lungs of DAP12-deficient mice compared with that in controls. DAP12 was also required for normal macrophage migration in a “scratch” assay. Reconstitution studies revealed that phosphorylation of the DAP12 ITAM was required for normal migration in vitro and association with TREM2 was sufficient for normal migration. These findings indicate that DAP12, possibly through association with TREM2, contributes to alveolar macrophage chemotaxis and recruitment to the lung and may mediate macrophage accumulation in lung diseases such as emphysema. more...
- Published
- 2010
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43. BCAP promotes Lupus-like disease and regulates IFNα production in pDC
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Talyn Chu, Hayley Waterman, Griffin Gessay, and Jessica A. Hamerman
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Immunology ,Immunology and Allergy - Abstract
Systemic lupus erythematosus (SLE) severity is correlated with elevated serum type I interferons (IFN), mainly IFNα, which is produced in large amounts by pDC in response to nucleic acid sensing by TLR7 and TLR9. TLR7 and TLR9-induced IRF7 translocation to the nucleus and subsequent IFNα production by pDC is dependent on phosphatidylinositol-3 kinase (PI3K), but how PI3K regulates this process remains undefined. We showed that B cell adaptor for PI3K (BCAP) links TLRs to PI3K activation in macrophages, thus we asked if BCAP plays a role in pDC IFNα production and SLE pathogenesis. We show BCAP promoted many aspects of TLR7-driven lupus-like disease including interferon-stimulated gene expression in blood. BCAP promoted TLR7 and TLR9-induced IFNα production in pDC, and BCAP−/− mice produced significantly less serum IFNα after injection of TLR9 agonist than WT mice, consistent with a pDC IFNα defect. TLR-induced IFNα production in pDC involves dual signaling pathways that run in parallel and converge upon the phosphorylation and activation of IKKα. There is a TLR-independent pathway initiated by nucleic acid recognition at the plasma membrane that involves Dock2-mediated activation of Rac1, required for phosphorylation of IKKα. The TLR-dependent pathway occurs upon nucleic acid recognition by endosomal TLR7 or 9 and leads to MyD88 activation. BCAP regulated IFNα production independently of the TLR-MyD88 pathway and both BCAP and PI3K were required for CpG DNA-induced early actin remodeling, a readout of Rac1 activation, and IKKα phosphorylation in pDC. Our data suggest BCAP and PI3K specifically regulate the TLR-parallel pathway in pDC. Overall, we show a novel role for BCAP in regulating IFNα production in pDC and SLE pathogenesis. more...
- Published
- 2018
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44. The expanding roles of ITAM adapters FcRγ and DAP12 in myeloid cells
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Ching-Liang Chu, Clifford A. Lowell, Jessica A. Hamerman, Minjian Ni, and Justin R Killebrew
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Toll-like receptor ,Innate immune system ,biology ,Receptors, IgG ,Immunology ,Integrin ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Immune receptor ,Immunity, Innate ,Article ,Cell biology ,Immunoreceptor tyrosine-based activation motif ,biology.protein ,Animals ,Humans ,Tyrosine ,Immunology and Allergy ,Immunoglobulin superfamily ,Myeloid Cells ,Protein Interaction Domains and Motifs ,Signal transduction ,Receptor ,Adaptor Proteins, Signal Transducing ,Signal Transduction - Abstract
The adapter proteins DAP12 and FcRgamma associate with a wide spectrum of receptors in a variety of innate immune cells to mediate intracellular signaling pathways when their cognate receptor is engaged. These adapter proteins are coupled to their receptors through charged residues within the transmembrane regions of the adapter and receptor. DAP12 and FcRgamma contain specific protein domains (referred to as immunoreceptor tyrosine-based activation motifs) that serve as the substrates and docking sites for kinases, allowing amplification of intracellular signaling reactions. Recent research has broadened the repertoire of receptors that utilize these adapters for signaling to include not only novel immunoglobulin superfamily members but also cytokine receptors, integrins, and other adhesion molecules. There is abundant evidence that these multifunctional signaling adapters also mediate inhibitory activity, downmodulating signaling from Toll-like receptors and other heterologous receptors. In this review, we discuss the newly described receptors that utilize DAP12 and/or FcRgamma adapters to modulate innate immune responses. more...
- Published
- 2009
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45. TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria
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Jessica A. Hamerman, Lisette Nevarez, Steven S. Branda, Clifford A. Lowell, Marco Colonna, William E. Seaman, Elsa-Noah N'Diaye, and Catherine S. Branda
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Staphylococcus aureus ,Cells ,Knockout ,Phagocytosis ,Immunology ,CHO Cells ,Biology ,Bacterial Physiological Phenomena ,Medical and Health Sciences ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Immune system ,Cricetulus ,Immunologic ,Cell surface receptor ,Report ,Cricetinae ,Receptors ,Escherichia coli ,Immunology and Allergy ,Animals ,Myeloid Cells ,Receptors, Immunologic ,Receptor ,Research Articles ,Cells, Cultured ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,0303 health sciences ,Cultured ,Membrane Glycoproteins ,Bacteria ,Chinese hamster ovary cell ,Signal Transducing ,Adaptor Proteins ,Tyrosine phosphorylation ,Cell Biology ,Biological Sciences ,Actin cytoskeleton ,Cell biology ,chemistry ,030217 neurology & neurosurgery ,Developmental Biology ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Phagocytosis, which is essential for the immune response to pathogens, is initiated by specific interactions between pathogens and cell surface receptors expressed by phagocytes. This study identifies triggering receptor expressed on myeloid cells 2 (TREM-2) and its signaling counterpart DAP12 as a molecular complex that promotes phagocytosis of bacteria. Expression of TREM-2–DAP12 enables nonphagocytic Chinese hamster ovary cells to internalize bacteria. This function depends on actin cytoskeleton dynamics and the activity of the small guanosine triphosphatases Rac and Cdc42. Internalization also requires src kinase activity and tyrosine phosphorylation. In bone marrow–derived macrophages, phagocytosis is decreased in the absence of DAP12 and can be restored by expression of TREM-2–DAP12. Depletion of TREM-2 inhibits both binding and uptake of bacteria. Finally, TREM-2–dependent phagocytosis is impaired in Syk-deficient macrophages. This study highlights a novel role for TREM-2–DAP12 in the immune response to bacterial pathogens. more...
- Published
- 2009
46. Increased TLR responses in dendritic cells lacking the ITAM-containing adapters DAP12 and FcRγ
- Author
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Ching-Liang Chu, Jessica A. Hamerman, Kuan-Yin Shen, Yen-Ling Yu, Lewis L. Lanier, and Clifford A. Lowell
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medicine.medical_treatment ,T cell ,Immunology ,Antigen presentation ,Enzyme-Linked Immunosorbent Assay ,Lymphocyte Activation ,Article ,Mice ,medicine ,Animals ,Immunology and Allergy ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,CD86 ,Antigen Presentation ,MHC class II ,biology ,Receptors, IgG ,Toll-Like Receptors ,Dendritic Cells ,Dendritic cell ,Flow Cytometry ,Molecular biology ,Cell biology ,Mice, Inbred C57BL ,Cytokine ,medicine.anatomical_structure ,biology.protein ,Cytokines ,Tumor necrosis factor alpha ,CD80 - Abstract
The inhibitory effect of DAP12 on macrophages has been revealed by examining myeloid cells from DAP12-deficient mice. In this report, we demonstrate that both DAP12 and the FcepsilonRIgamma-chain (FcRgamma) are required for negative regulation of TLR responses in bone marrow-derived dendritic cells (DC). Loss of both DAP12 and FcRgamma enhanced the pro-inflammatory cytokine production and maturation of DC after TLR stimulation, resulting in a greater percentage of DC that produced IL-12 p40, TNF, and IL-6, and expressed high levels of MHC class II, CD80, and CD86. Whereas DC lacking only DAP12 showed some increased TLR responses, those lacking only FcRgamma had a greater enhancement of maturation and cytokine production, though to a lesser extent than DC lacking both DAP12 and FcRgamma. Additionally, antigen-specific T cell proliferation was enhanced by DAP12(-/-)FcRgamma(-/-) DC relative to wild-type DC after maturation. Similar to DAP12(-/-)FcRgamma(-/-) DC, Syk-deficient DC also had increased inflammatory cytokine production, maturation, and antigen presentation. These results confirm the inhibitory effect of immunoreceptor tyrosine-based activation motif (ITAM) signaling in myeloid cells and show that DC and macrophages differ in their dependence on the ITAM-containing adapters DAP12 and FcRgamma for negative regulation of TLR signaling. more...
- Published
- 2008
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47. The Activating Immunoreceptor NKG2D and Its Ligands Are Involved in Allograft Transplant Rejection
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Jessica A. Hamerman, Jim Kim, Jonathan Benjamin, Catherine K. Chang, Tracy Hayden, Sang-Mo Kang, Fengchun Liu, and Lewis L. Lanier
- Subjects
Graft Rejection ,medicine.medical_treatment ,Immunology ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Biology ,Ligands ,Antibodies ,Natural killer cell ,Mice ,CD28 Antigens ,Antigen ,Immunity ,medicine ,Animals ,Antigens, Ly ,Transplantation, Homologous ,Immunology and Allergy ,Lectins, C-Type ,Receptors, Immunologic ,Heart transplantation ,Mice, Inbred BALB C ,hemic and immune systems ,Acquired immune system ,NKG2D ,medicine.disease ,Immunity, Innate ,biological factors ,Up-Regulation ,Transplant rejection ,Transplantation ,surgical procedures, operative ,medicine.anatomical_structure ,NK Cell Lectin-Like Receptor Subfamily K ,Antigens, Surface ,Heart Transplantation ,Receptors, Natural Killer Cell ,NK Cell Lectin-Like Receptor Subfamily B - Abstract
Although the linkage between innate and adaptive immunity in transplantation has been recognized, the mechanisms underlying this cooperation remain to be fully elucidated. In this study, we show that early “danger” signals associated with transplantation lead to rapid up-regulation of NKG2D ligands. A second wave of NKG2D ligand up-regulation is mediated by the adaptive immune response to allografts. Treatment with an Ab to NKG2D was highly effective in preventing CD28-independent rejection of cardiac allografts. Notably, NKG2D blockade did not deplete CD8+ T cells or NK1.1+ cells nor affect their migration to the allografts. These results establish a functional role of NKG2D and its ligands in the rejection of solid organ transplants. more...
- Published
- 2007
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48. Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12
- Author
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Clifford A. Lowell, Nadia K. Tchao, Jessica A. Hamerman, and Lewis L. Lanier
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Anti-Inflammatory Agents ,Syk ,Inbred C57BL ,P.H.S ,Mice ,Protein-Tyrosine Kinase ,Receptors ,Immunology and Allergy ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Non-U.S. Gov't ,Receptor ,Mice, Knockout ,Enzyme Precursors ,Toll-like receptor ,Membrane Glycoproteins ,CLEC7A ,Toll-Like Receptors ,Intracellular Signaling Peptides and Proteins ,Adaptor Proteins ,Signal transducing adaptor protein ,Shock ,Protein-Tyrosine Kinases ,Shock, Septic ,Cell biology ,Cell Surface ,Natural ,Cytokines ,Tumor necrosis factor alpha ,Signal transduction ,Signal Transduction ,Knockout ,Immunology ,Receptors, Cell Surface ,Biology ,Research Support ,Article ,N.I.H ,Proinflammatory cytokine ,Syk Kinase ,Animals ,Adaptor Proteins, Signal Transducing ,Septic ,Tumor Necrosis Factor-alpha ,Macrophages ,Signal Transducing ,Immunity ,Extramural ,Listeria monocytogenes ,Immunity, Innate ,Mice, Inbred C57BL ,U.S. Gov't - Abstract
DAP12 is a signaling adaptor containing an immunoreceptor tyrosine-based activation motif (ITAM) that pairs with receptors on myeloid cells and natural killer cells. We examine here the responses of mice lacking DAP12 to stimulation through Toll-like receptors (TLRs). Unexpectedly, DAP12-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli. Additionally, macrophages deficient in spleen tyrosine kinase (Syk), which signals downstream of DAP12, showed a phenotype identical to that of DAP12-deficient macrophages. DAP12-deficient mice were more susceptible to endotoxic shock and had enhanced resistance to infection by the intracellular bacterium Listeria monocytogenes. These data suggest that one or more DAP12-pairing receptors negatively regulate signaling through TLRs. more...
- Published
- 2005
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49. NK cells in innate immunity
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Jessica A. Hamerman, Lewis L. Lanier, and Kouetsu Ogasawara
- Subjects
Cell signaling ,Innate immune system ,Cell growth ,Immunology ,Innate lymphoid cell ,chemical and pharmacologic phenomena ,Cell Communication ,Dendritic Cells ,Biology ,Acquired immune system ,NKG2D ,Immunity, Innate ,Cell biology ,Killer Cells, Natural ,Virus Diseases ,Immunity ,Viruses ,Animals ,Humans ,Immunology and Allergy ,Signal transduction ,Signal Transduction - Abstract
NK cells have an important role in innate immune responses, particularly in anti-viral immunity. Recent studies have revealed a molecular basis for NK cell recognition of virus-infected cells, implicating the activating KIR and Ly49 receptors and NKG2D in this process. Additionally, mutual cooperation between NK cells and dendritic cells suggests that these innate cells can shape the nature of an adaptive immune response. These findings, as well as advances in understanding NK cell development and homeostasis, indicate that NK cell biology is more sophisticated than previously appreciated. more...
- Published
- 2005
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50. Cutting Edge: Toll-Like Receptor Signaling in Macrophages Induces Ligands for the NKG2D Receptor
- Author
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Kouetsu Ogasawara, Jessica A. Hamerman, and Lewis L. Lanier
- Subjects
Lipopolysaccharides ,Immunology ,Retinoic acid ,Receptors, Cell Surface ,Tretinoin ,chemical and pharmacologic phenomena ,Biology ,Ligands ,Mice ,chemistry.chemical_compound ,Escherichia coli ,Animals ,Immunology and Allergy ,RNA, Messenger ,Receptors, Immunologic ,Receptor ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,Mice, Inbred BALB C ,Toll-like receptor ,Membrane Glycoproteins ,Innate immune system ,Toll-Like Receptors ,Zymosan ,Membrane Proteins ,Macrophage Activation ,NKG2D ,Antigens, Differentiation ,Listeria monocytogenes ,Cell biology ,Mice, Inbred C57BL ,Interleukin 10 ,Poly I-C ,chemistry ,NK Cell Lectin-Like Receptor Subfamily K ,Myeloid Differentiation Factor 88 ,Macrophages, Peritoneal ,Myeloid-derived Suppressor Cell ,Receptors, Natural Killer Cell ,CD8 ,Signal Transduction - Abstract
Macrophages recognize the presence of infection by using the Toll-like receptor (TLR) family of proteins that detect ligands on bacterial, viral, and fungal pathogens. We show that murine macrophages stimulated with pathogen products known to signal through TLRs express ligands for the NKG2D receptor, found on NK cells, activated CD8+ T cells and activated macrophages. TLR signaling, through the MyD88 adaptor, up-regulates transcription of the retinoic acid early inducible-1 (RAE-1) family of NKG2D ligands, but not H-60 or murine UL16-binding protein-like transcript-1. RAE-1 proteins are found on the surface of activated, but not resting, macrophages and can be detected by NKG2D on NK cells resulting in down-regulation of this receptor both in vitro and in vivo. RAE-1-NKG2D interactions provide a mechanism by which NK cells and infected macrophages communicate directly during an innate immune response to infection. more...
- Published
- 2004
- Full Text
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