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  1. Article ; Online: ICOS signaling promotes a secondary humoral response after re-challenge with Plasmodium chabaudi chabaudi AS.

    Latham, Leah E / Wikenheiser, Daniel J / Stumhofer, Jason S

    PLoS pathogens

    2020  Volume 16, Issue 4, Page(s) e1008527

    Abstract: The co-stimulatory molecule ICOS is associated with the induction and regulation of T helper cell responses, including the differentiation of follicular helper T (Tfh) cells and the formation and maintenance of memory T cells. However, the role of ICOS ... ...

    Abstract The co-stimulatory molecule ICOS is associated with the induction and regulation of T helper cell responses, including the differentiation of follicular helper T (Tfh) cells and the formation and maintenance of memory T cells. However, the role of ICOS signaling in secondary immune responses is largely unexplored. Here we show that memory T cell formation and maintenance are influenced by persistent infection with P. chabaudi chabaudi AS infection, as memory T cell numbers decline in wild-type and Icos-/- mice after drug-clearance. Following drug-clearance Icos-/- mice display a relapsing parasitemia that occurs more frequently and with higher peaks compared to wild-type mice after re-challenge. The secondary immune response in Icos-/- mice is characterized by significant impairment in the expansion of effector cells with a Tfh-like phenotype, which is associated with a diminished and delayed parasite-specific Ab response and the absence of germinal centers. Similarly, the administration of an anti-ICOSL antagonizing antibody to wild-type mice before and after reinfection with P. c. chabaudi AS leads to an early defect in Tfh cell expansion and parasite-specific antibody production, confirming a need for ICOS-ICOSL interactions to promote memory B cell responses. Furthermore, adoptive transfer of central memory T (TCM) cells from wild-type and Icos-/- mice into tcrb-/- mice to directly evaluate the ability of TCM cells to give rise to Tfh cells revealed that TCM cells from wild-type mice acquire a mixed Th1- and Tfh-like phenotype after P. c. chabaudi AS infection. While TCM cells from Icos-/- mice expand and display markers of activation to a similar degree as their WT counterparts, they displayed a reduced capacity to upregulate markers indicative of a Tfh cell phenotype, resulting in a diminished humoral response. Together these findings verify that ICOS signaling in memory T cells plays an integral role in promoting T cell effector responses during secondary infection with P. c. chabaudi AS.
    MeSH term(s) Adoptive Transfer ; Animals ; B-Lymphocytes/immunology ; Cell Differentiation/immunology ; Germinal Center/immunology ; Immunity, Humoral/immunology ; Immunologic Memory ; Inducible T-Cell Co-Stimulator Protein/immunology ; Inducible T-Cell Co-Stimulator Protein/metabolism ; Lymphocyte Activation/immunology ; Malaria/immunology ; Malaria/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Plasmodium chabaudi/metabolism ; Plasmodium chabaudi/pathogenicity ; Signal Transduction ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/metabolism
    Chemical Substances ICOS protein, human ; Icos protein, mouse ; Inducible T-Cell Co-Stimulator Protein
    Language English
    Publishing date 2020-04-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1008527
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: IgM

    Brown, Susie L / Bauer, Jonathan J / Lee, Juhyung / Ntirandekura, Enatha / Stumhofer, Jason S

    Journal of leukocyte biology

    2022  Volume 112, Issue 5, Page(s) 1115–1135

    Abstract: Memory B cells (MBCs) are essential for maintaining long-term humoral immunity to infectious organisms, including Plasmodium. MBCs are a heterogeneous population whose function can be dictated by isotype or expression of particular surface proteins. Here, ...

    Abstract Memory B cells (MBCs) are essential for maintaining long-term humoral immunity to infectious organisms, including Plasmodium. MBCs are a heterogeneous population whose function can be dictated by isotype or expression of particular surface proteins. Here, aided by antigen-specific B-cell tetramers, MBC populations were evaluated to discern their phenotype and function in response to infection with a nonlethal strain of P. yoelii. Infection of mice with P. yoelii 17X resulted in 2 predominant MBC populations: somatically hypermutated isotype-switched (IgM
    MeSH term(s) Animals ; Mice ; B7-1 Antigen ; Cytidine Deaminase ; Germinal Center ; Immunoglobulin G ; Immunoglobulin M ; Immunologic Memory ; Memory B Cells/immunology ; Plasmodium yoelii ; Malaria/immunology
    Chemical Substances B7-1 Antigen ; Cytidine Deaminase (EC 3.5.4.5) ; Immunoglobulin G ; Immunoglobulin M
    Language English
    Publishing date 2022-06-03
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1002/JLB.4A0921-523R
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: ICOS Co-Stimulation: Friend or Foe?

    Wikenheiser, Daniel J / Stumhofer, Jason S

    Frontiers in immunology

    2016  Volume 7, Page(s) 304

    Abstract: Over the last 15 years, the inducible T cell co-stimulator (ICOS) has been implicated in various immune outcomes, including the induction and regulation of Th1, Th2, and Th17 immunity. In addition to its role in directing effector T cell differentiation, ...

    Abstract Over the last 15 years, the inducible T cell co-stimulator (ICOS) has been implicated in various immune outcomes, including the induction and regulation of Th1, Th2, and Th17 immunity. In addition to its role in directing effector T cell differentiation, ICOS has also been consistently linked with the induction of thymus-dependent (TD) antibody (Ab) responses and the germinal center (GC) reaction. ICOS co-stimulation, therefore, appears to play a complex role in dictating the course of adaptive immunity. In this article, we summarize the initial characterization of ICOS and its relationship with the related co-stimulatory molecule CD28. We then address the contribution of ICOS in directing an effector T cell response, and ultimately disease outcome, against various bacterial, viral, and parasitic infections. Next, we assess ICOS in the context of TD Ab responses, connecting ICOS signaling to follicular helper T cell differentiation and its role in the GC reaction. Finally, we address the link between ICOS and human autoimmune disorders and evaluate potential therapies aiming to mitigate disease progression by modulating ICOS signaling.
    Language English
    Publishing date 2016
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2016.00304
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Intrinsic p53 Activation Restricts Gammaherpesvirus-Driven Germinal Center B Cell Expansion during Latency Establishment.

    Owens, Shana M / Sifford, Jeffrey M / Li, Gang / Murdock, Steven J / Salinas, Eduardo / Manzano, Mark / Ghosh, Debopam / Stumhofer, Jason S / Forrest, J Craig

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Gammaherpesviruses (GHV) are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68), this is accomplished through a viral gene-expression program ... ...

    Abstract Gammaherpesviruses (GHV) are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68), this is accomplished through a viral gene-expression program that promotes cellular proliferation and differentiation, especially of germinal center (GC) B cells. Intrinsic host mechanisms that control virus-driven cellular expansion are incompletely defined. Using a small-animal model of GHV pathogenesis, we demonstrate
    Importance: Gammaherpesviruses cause lifelong infections of their hosts, commonly referred to as latency, that can lead to cancer. Latency establishment benefits from the functions of viral proteins that augment and amplify B cell activation, proliferation, and differentiation signals. In uninfected cells, off-schedule cellular differentiation would typically trigger anti-proliferative responses by effector proteins known as tumor suppressors. However, tumor suppressor responses to gammaherpesvirus manipulation of cellular processes remain understudied, especially those that occur during latency establishment in a living organism. Here we identify p53, a tumor suppressor commonly mutated in cancer, as a host factor that limits virus-driven B cell proliferation and differentiation, and thus, viral colonization of a host. We demonstrate that p53 activation occurs in response to viral latency proteins that induce B cell activation. This work informs a gap in our understanding of intrinsic cellular defense mechanisms that restrict lifelong GHV infection.
    Language English
    Publishing date 2023-11-01
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.31.563188
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: NK1.1 Expression Defines a Population of CD4

    Wikenheiser, Daniel J / Brown, Susie L / Lee, Juhyung / Stumhofer, Jason S

    Frontiers in immunology

    2018  Volume 9, Page(s) 2277

    Abstract: Early plasmablast induction is a hallmark ... ...

    Abstract Early plasmablast induction is a hallmark of
    MeSH term(s) Animals ; Antibodies, Protozoan/immunology ; Antigens, Ly/genetics ; Antigens, Ly/immunology ; Antigens, Ly/metabolism ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/parasitology ; Gene Expression/immunology ; Malaria/immunology ; Malaria/parasitology ; Malaria/prevention & control ; Malaria Vaccines/administration & dosage ; Malaria Vaccines/immunology ; Male ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; NK Cell Lectin-Like Receptor Subfamily B/genetics ; NK Cell Lectin-Like Receptor Subfamily B/immunology ; NK Cell Lectin-Like Receptor Subfamily B/metabolism ; Plasmodium yoelii/immunology ; Plasmodium yoelii/physiology ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/metabolism ; T-Lymphocytes, Helper-Inducer/parasitology ; Th1 Cells/immunology ; Th1 Cells/metabolism ; Th1 Cells/parasitology
    Chemical Substances Antibodies, Protozoan ; Antigens, Ly ; Klrb1c protein, mouse ; Malaria Vaccines ; NK Cell Lectin-Like Receptor Subfamily B
    Language English
    Publishing date 2018-10-15
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2018.02277
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: ICOS signaling promotes a secondary humoral response after re-challenge with Plasmodium chabaudi chabaudi AS.

    Leah E Latham / Daniel J Wikenheiser / Jason S Stumhofer

    PLoS Pathogens, Vol 16, Iss 4, p e

    2020  Volume 1008527

    Abstract: The co-stimulatory molecule ICOS is associated with the induction and regulation of T helper cell responses, including the differentiation of follicular helper T (Tfh) cells and the formation and maintenance of memory T cells. However, the role of ICOS ... ...

    Abstract The co-stimulatory molecule ICOS is associated with the induction and regulation of T helper cell responses, including the differentiation of follicular helper T (Tfh) cells and the formation and maintenance of memory T cells. However, the role of ICOS signaling in secondary immune responses is largely unexplored. Here we show that memory T cell formation and maintenance are influenced by persistent infection with P. chabaudi chabaudi AS infection, as memory T cell numbers decline in wild-type and Icos-/- mice after drug-clearance. Following drug-clearance Icos-/- mice display a relapsing parasitemia that occurs more frequently and with higher peaks compared to wild-type mice after re-challenge. The secondary immune response in Icos-/- mice is characterized by significant impairment in the expansion of effector cells with a Tfh-like phenotype, which is associated with a diminished and delayed parasite-specific Ab response and the absence of germinal centers. Similarly, the administration of an anti-ICOSL antagonizing antibody to wild-type mice before and after reinfection with P. c. chabaudi AS leads to an early defect in Tfh cell expansion and parasite-specific antibody production, confirming a need for ICOS-ICOSL interactions to promote memory B cell responses. Furthermore, adoptive transfer of central memory T (TCM) cells from wild-type and Icos-/- mice into tcrb-/- mice to directly evaluate the ability of TCM cells to give rise to Tfh cells revealed that TCM cells from wild-type mice acquire a mixed Th1- and Tfh-like phenotype after P. c. chabaudi AS infection. While TCM cells from Icos-/- mice expand and display markers of activation to a similar degree as their WT counterparts, they displayed a reduced capacity to upregulate markers indicative of a Tfh cell phenotype, resulting in a diminished humoral response. Together these findings verify that ICOS signaling in memory T cells plays an integral role in promoting T cell effector responses during secondary infection with P. c. chabaudi AS.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Towards rainbow portable Cytophone with laser diodes for global disease diagnostics.

    Jawad, Hind J / Yadem, Aayire C / Menyaev, Yulian A / Sarimollaoglu, Mustafa / Armstrong, Jillian N / Watanabe, Fumiya / Biris, Alexandru S / Stumhofer, Jason S / Nedosekin, Dmitry / Suen, James Y / Parikh, Sunil / Zharov, Vladimir P

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 8671

    Abstract: In vivo, Cytophone has demonstrated the capability for the early diagnosis of cancer, infection, and cardiovascular disorders through photoacoustic detection of circulating disease markers directly in the bloodstream with an unprecedented 1,000-fold ... ...

    Abstract In vivo, Cytophone has demonstrated the capability for the early diagnosis of cancer, infection, and cardiovascular disorders through photoacoustic detection of circulating disease markers directly in the bloodstream with an unprecedented 1,000-fold improvement in sensitivity. Nevertheless, a Cytophone with higher specificity and portability is urgently needed. Here, we introduce a novel Cytophone platform that integrates a miniature multispectral laser diode array, time-color coding, and high-speed time-resolved signal processing. Using two-color (808 nm/915 nm) laser diodes, we demonstrated spectral identification of white and red clots, melanoma cells, and hemozoin in malaria-infected erythrocytes against a blood background and artifacts. Data from a Plasmodium yoelii murine model and cultured human P. falciparum were verified in vitro with confocal photothermal and fluorescent microscopy. With these techniques, we detected infected cells within 4 h after invasion, which makes hemozoin promising as a spectrally selective marker at the earliest stages of malaria progression. Along with the findings from our previous application of Cytophone with conventional lasers for the diagnosis of melanoma, bacteremia, sickle anemia, thrombosis, stroke, and abnormal hemoglobin forms, this current finding suggests the potential for the development of a portable rainbow Cytophone with multispectral laser diodes for the identification of these and other diseases.
    MeSH term(s) Animals ; Early Detection of Cancer ; Erythrocytes ; Lasers, Semiconductor ; Malaria/diagnosis ; Melanoma ; Mice ; Plasmodium falciparum ; Plasmodium yoelii
    Language English
    Publishing date 2022-05-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-11452-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: The Costimulatory Molecule ICOS Regulates Host Th1 and Follicular Th Cell Differentiation in Response to Plasmodium chabaudi chabaudi AS Infection.

    Wikenheiser, Daniel J / Ghosh, Debopam / Kennedy, Brian / Stumhofer, Jason S

    Journal of immunology (Baltimore, Md. : 1950)

    2016  Volume 196, Issue 2, Page(s) 778–791

    Abstract: Blood-stage Plasmodium chabaudi chabaudi AS infection requires cell- and Ab-mediated immunity to control acute and persistent infection, respectively. ICOS regulates CD4(+) T cell activation and promotes the induction of follicular Th (TFH) cells, CD4(+) ...

    Abstract Blood-stage Plasmodium chabaudi chabaudi AS infection requires cell- and Ab-mediated immunity to control acute and persistent infection, respectively. ICOS regulates CD4(+) T cell activation and promotes the induction of follicular Th (TFH) cells, CD4(+) T cells that support B cell affinity maturation within germinal centers (GCs), resulting in the production of high-affinity Abs. In this article, we demonstrate that, in response to P. c. chabaudi AS infection, the absence of ICOS resulted in an enhanced Th1 immune response that reduced peak parasitemia. Despite the absence of ICOS, CD4(+) T cells were capable of expressing PD-1, B cell lymphoma 6, and CXCR5 during early infection, indicating TFH development was not impaired. However, by day 21 postinfection, Icos(-/-) mice accumulated fewer splenic TFHs compared with Icos(+/+) mice, leading to substantially fewer GC B cells and a decrease in affinity, but not production, of parasite-specific isotype-switched Abs. Moreover, treatment of mice with anti-ICOS ligand Abs to modulate ICOS-ICOS ligand signaling revealed a requirement for ICOS in TFH differentiation only after day 6 postinfection. Ultimately, the quality and quantity of isotype-switched Abs produced in Icos(-/-) mice declined over time, resulting in impaired control of persistent parasitemia. Collectively, these data suggest ICOS is not required for TFH induction during P. c. chabaudi AS infection or production of isotype-switched Abs, but it is necessary for maintenance of a sustained high-affinity, protective Ab response.
    MeSH term(s) Animals ; Cell Differentiation/immunology ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Fluorescent Antibody Technique ; Germinal Center/cytology ; Germinal Center/immunology ; Inducible T-Cell Co-Stimulator Protein/immunology ; Lymphocyte Activation/immunology ; Malaria/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Plasmodium chabaudi ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes, Helper-Inducer/immunology ; Th1 Cells/immunology
    Chemical Substances Icos protein, mouse ; Inducible T-Cell Co-Stimulator Protein
    Language English
    Publishing date 2016-01-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1403206
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Towards rainbow portable Cytophone with laser diodes for global disease diagnostics

    Hind J. Jawad / Aayire C. Yadem / Yulian A. Menyaev / Mustafa Sarimollaoglu / Jillian N. Armstrong / Fumiya Watanabe / Alexandru S. Biris / Jason S. Stumhofer / Dmitry Nedosekin / James Y. Suen / Sunil Parikh / Vladimir P. Zharov

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 17

    Abstract: Abstract In vivo, Cytophone has demonstrated the capability for the early diagnosis of cancer, infection, and cardiovascular disorders through photoacoustic detection of circulating disease markers directly in the bloodstream with an unprecedented 1,000- ... ...

    Abstract Abstract In vivo, Cytophone has demonstrated the capability for the early diagnosis of cancer, infection, and cardiovascular disorders through photoacoustic detection of circulating disease markers directly in the bloodstream with an unprecedented 1,000-fold improvement in sensitivity. Nevertheless, a Cytophone with higher specificity and portability is urgently needed. Here, we introduce a novel Cytophone platform that integrates a miniature multispectral laser diode array, time-color coding, and high-speed time-resolved signal processing. Using two-color (808 nm/915 nm) laser diodes, we demonstrated spectral identification of white and red clots, melanoma cells, and hemozoin in malaria-infected erythrocytes against a blood background and artifacts. Data from a Plasmodium yoelii murine model and cultured human P. falciparum were verified in vitro with confocal photothermal and fluorescent microscopy. With these techniques, we detected infected cells within 4 h after invasion, which makes hemozoin promising as a spectrally selective marker at the earliest stages of malaria progression. Along with the findings from our previous application of Cytophone with conventional lasers for the diagnosis of melanoma, bacteremia, sickle anemia, thrombosis, stroke, and abnormal hemoglobin forms, this current finding suggests the potential for the development of a portable rainbow Cytophone with multispectral laser diodes for the identification of these and other diseases.
    Keywords Medicine ; R ; Science ; Q
    Subject code 290 ; 610
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article: Advances in understanding the anti-inflammatory properties of IL-27.

    Stumhofer, J S / Hunter, C A

    Immunology letters

    2008  Volume 117, Issue 2, Page(s) 123–130

    Abstract: Initial studies on the biology of IL-27 provided evidence of a role for this cytokine in the initiation of Th1 responses; however, subsequent work using models of pathogen-induced and autoimmune inflammation have indicated that IL-27 has broad inhibitory ...

    Abstract Initial studies on the biology of IL-27 provided evidence of a role for this cytokine in the initiation of Th1 responses; however, subsequent work using models of pathogen-induced and autoimmune inflammation have indicated that IL-27 has broad inhibitory effects on Th1, Th2 and Th17 subsets of T cells as well as the expansion of inducible regulatory T cells. While, the aim of this review is to highlight the functions of IL-27 in the context of inflammation it will also serve to elaborate on the molecular mechanisms involved in the production of this cytokine. The initial description of IL-27 indicated that classical antigen-presenting cells such as macrophages and dendritic cells produce IL-27, however, the agonists and signaling pathways involved in activating transcription of the two subunits of IL-27, p28 and EBV-induced gene 3 (EBI3) have only recently been described.
    MeSH term(s) Animals ; Autoimmune Diseases/immunology ; Bacterial Infections/immunology ; Bacterial Infections/metabolism ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Feedback, Physiological/immunology ; Humans ; Inflammation/immunology ; Inflammation/microbiology ; Interleukin-10/metabolism ; Interleukin-17/biosynthesis ; Interleukin-17/immunology ; Interleukin-17/metabolism ; Interleukins/biosynthesis ; Interleukins/immunology ; Lymphocyte Activation ; MAP Kinase Signaling System/immunology ; Minor Histocompatibility Antigens ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Toll-Like Receptor 4/immunology ; Toll-Like Receptor 4/metabolism
    Chemical Substances EBI3 protein, human ; Interleukin-17 ; Interleukins ; MYDGF protein, human ; Minor Histocompatibility Antigens ; Toll-Like Receptor 4 ; Interleukin-10 (130068-27-8)
    Language English
    Publishing date 2008-03-03
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 445150-8
    ISSN 1879-0542 ; 0165-2478
    ISSN (online) 1879-0542
    ISSN 0165-2478
    DOI 10.1016/j.imlet.2008.01.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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