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  • The American Association of Immunologists  (10)
  • 1
    Online Resource
    Online Resource
    A Sphingosine-1-Phosphate Receptor 1-Directed Agonist Reduces Central Nervous System Inflammation in a Plasmacytoid Dendritic Cell-Dependent Manner
    The American Association of Immunologists ; 2012
    In:  The Journal of Immunology Vol. 189, No. 7 ( 2012-10-01), p. 3700-3706
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 189, No. 7 ( 2012-10-01), p. 3700-3706
    Abstract: Gradients of the sphingolipid sphingosine-1-phosphate (S1P) are responsible for the egress of lymphocytes from lymph nodes by activating the S1P1 receptor expressed on the surface of lymphocytes. Small molecule drugs that downregulate S1P receptors induce the sequestration of lymphocytes within lymph nodes, thus preventing lymphocytes from accessing sites of inflammation. In particular, FTY720, a pan-S1P receptor agonist, has been efficacious in the treatment of multiple sclerosis as well as its animal model, experimental autoimmune encephalomyelitis (EAE), by virtue of its ability to restrain lymphocytes within the lymph nodes, thus precluding their migration into the CNS. However, multiple leukocyte subsets express S1P receptors of varying types, and although it is beneficial to prevent transmigration of proinflammatory lymphocytes into the CNS, allowing access of regulatory leukocyte subsets to the CNS is desirable. In this study, we show that an S1P1-specific agonist (AUY954) is clinically efficacious in ameliorating pre-established EAE in SJL/J mice. Efficacy of AUY954 correlated with a reduction of lymphocytes in the CNS, but access of plasmacytoid dendritic cells (pDCs) to the CNS was unimpaired, and the presence of pDCs was found to be an important cofactor in mediating the clinical efficacy of AUY954. These results indicate that pDCs are important in quieting autoimmune responses during EAE, and that trafficking inhibitors that are permissive for pDC accumulation in the CNS may be of therapeutic value for the treatment of multiple sclerosis.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1102261
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2012
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Human Anti-IgG1 Hinge Autoantibodies Reconstitute the Effector Functions of Proteolytically Inactivated IgGs
    The American Association of Immunologists ; 2008
    In:  The Journal of Immunology Vol. 181, No. 5 ( 2008-09-01), p. 3183-3192
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 181, No. 5 ( 2008-09-01), p. 3183-3192
    Abstract: A number of proteases of potential importance to human physiology possess the ability to selectively degrade and inactivate Igs. Proteolytic cleavage within and near the hinge domain of human IgG1 yielded products including Fab and F(ab′)2 possessing full Ag binding capability but absent several functions needed for immune destruction of cellular pathogens. In parallel experiments, we showed that the same proteolytically generated Fabs and F(ab′)2s become self-Ags that were widely recognized by autoantibodies in the human population. Binding analyses using various Fab and F(ab′)2, as well as single-chain peptide analogues, indicated that the autoantibodies targeted the newly exposed sequences where proteases cleave the hinge. The point of cleavage may be less of a determinant for autoantibody binding than the exposure of an otherwise cryptic stretch of hinge sequence. It was noted that the autoantibodies possessed an unusually high proportion of the IgG3 isotype in contrast to Abs induced against foreign immunogens in the same human subjects. In light of the recognized potency of IgG3 effector mechanisms, we adopted a functional approach to determine whether human anti-hinge (HAH) autoantibodies could reconstitute the (missing) Fc region effector functions to Fab and F(ab′)2. Indeed, in in vitro cellular assays, purified HAH autoantibodies restored effector functions to F(ab′)2 in both Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity assays. The results indicate that HAH autoantibodies selectively bind to proteolytically cleaved IgGs and can thereby provide a surrogate Fc domain to reconstitute cell lytic functions.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.181.5.3183
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2008
    detail.hit.zdb_id: 1475085-5
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  • 3
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    Online Resource
    Mass-cytometry reveals global immune remodeling with multi-lineage hypersensitivity to Type I Interferon in Down syndrome
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 202, No. 1_Supplement ( 2019-05-01), p. 52.1-52.1
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 52.1-52.1
    Abstract: People with Down syndrome (DS), the genetic condition caused by trisomy of chromosome 21 (chr21), have an altered disease spectrum. For example, adults with DS are largely protected from solid tumors while predisposed to various autoimmune disorders, early-onset Alzheimer’s disease, and severe respiratory infection. While the immune system is known to play a key role in these comorbidities among the disomic population, there is a dearth of immune studies in adults with DS. Here, we applied the single-cell, systems-level approach of mass-cytometry, or Cytometry by Time-Of-Flight (CyTOF), to broadly define phenotypic and functional alterations in immune homeostasis in adults with DS that are relevant to the potentiation of comorbidities associated with T21. We developed an innovative strategy to analyze CyTOF data, by incorporating techniques commonly used in genomics and even topography to eliminate batch bias and efficiently resolve ~100 immune cell types. This approach revealed that adults with DS have global immune dysregulation reminiscent of various inflammatory and autoimmune states enriched among older individuals of the disomic population. Upon stimulation directly ex vivo with Type I Interferon (IFN) and simultaneous detection of diverse phosphorylation events across the lymphoid and myeloid lineages, all immune subsets from individuals with T21 were hyper-responsive, but the degree of response and signaling pathways used varied among specific cell types. Notably, 4 of the 6 IFN receptor subunits for Types I, II, and III IFNs are encoded on chr21. Altogether, these results establish a critical foundation to pursue immune dysregulation and IFN hyperactivity as a driver of the altered disease spectrum in adults with DS.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.202.Supp.52.1
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
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  • 4
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    Online Resource
    Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo
    The American Association of Immunologists ; 2005
    In:  The Journal of Immunology Vol. 174, No. 3 ( 2005-02-01), p. 1393-1404
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 174, No. 3 ( 2005-02-01), p. 1393-1404
    Abstract: Phosphatidylserine (PS) on apoptotic cells promotes their uptake and induces anti-inflammatory responses in phagocytes, including TGF-β release. Little is known regarding the effects of PS on adaptive immune responses. We therefore investigated the effects of PS-containing liposomes on immune responses in mice in vivo. PS liposomes specifically inhibited responses to Ags as determined by decreased draining lymph node tissue mass, with reduced numbers of total leukocytes and Ag-specific CD4+ T cells. There was also a decrease in formation and size of germinal centers in spleen and lymph nodes, accompanied by decreased levels of Ag-specific IgG in blood. Many of these effects were mimicked by an agonistic Ab-specific for the PS receptor. TGF-β appears to play a critical role in this inhibition, as the inhibitory effects of PS were reversed by in vivo administration of anti-TGF-β Ab. PS-containing liposomes did not appear to directly inhibit dendritic cell maturation in vitro in response to a variety of stimuli, nor did it prevent their migration to regional lymph nodes in vivo, suggesting that the inhibitory effects may have resulted from complicated interactions between tissue cells and dendritic cells, subsequently inhibiting their ability to productively activate T lymphocytes.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.174.3.1393
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2005
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    Requirements for Eomesodermin and Promyelocytic Leukemia Zinc Finger in the Development of Innate-Like CD8+ T Cells
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 186, No. 8 ( 2011-04-15), p. 4573-4578
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 186, No. 8 ( 2011-04-15), p. 4573-4578
    Abstract: Conventional and nonconventional T cell development occur in the thymus. Nonconventional thymocytes that bear characteristics typically associated with innate immune cells are termed innate-like lymphocytes (ILLs). Mice harboring a tyrosine to phenylalanine mutation in the adaptor protein Src homology 2 domain-containing leukocyte protein of 76 kDa at residue 145 (Y145F mice) develop an expanded population of CD8+CD122+CD44+ ILLs, typified by expression of the T-box transcription factor eomesodermin. Y145F mice also have an expanded population of γδ T cells that produce copious amounts of IL-4 via a mechanism that is dependent on the BTB-ZF transcription factor promyelocytic leukemia zinc finger. Using mice with T cell-specific deletion of Eomes, we demonstrate that this transcription factor is required for CD8+ ILL development in Y145F as well as wild-type mice. Moreover, we show that promyelocytic leukemia zinc finger and IL-4 are also required for the generation of this ILL population. Taken together, these data shed light on the cell-intrinsic and cell-extrinsic factors that drive CD8+ ILL differentiation.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1100037
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
    detail.hit.zdb_id: 1475085-5
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  • 6
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    Memory T Cells and Their Costimulators in Human Allograft Injury
    The American Association of Immunologists ; 2005
    In:  The Journal of Immunology Vol. 175, No. 8 ( 2005-10-15), p. 4886-4896
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 175, No. 8 ( 2005-10-15), p. 4886-4896
    Abstract: Both CD4+ and CD8+ human memory but not naive T cells respond to allogeneic human dermal microvascular endothelial cells (HDMEC) in vitro by secreting cytokines and by proliferating. Several recently identified costimulators, namely, 4-1BB ligand, ICOS ligand, and OX40 ligand, are up-regulated on cultured HDMEC in response to TNF or coculture with allogeneic T cells. Blockade of these costimulators each partially reduces IFN-γ and IL-2 secretion and proliferation of previously resting memory T cells. The effects of these costimulators are overlapping but not identical. Memory but not naive T cells are the principal effectors of microvascular injury in human skin allografts following adoptive transfer into immunodeficient mice. Furthermore, blocking 4-1BB ligand, ICOS ligand, or OX40 ligand in this model reduces human skin allograft injury and T cell effector molecule expression. These data demonstrate that human memory T cells respond to microvascular endothelial cells and can injure allografts in vivo without priming. Furthermore, several recently described costimulators contribute to these processes.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.175.8.4886
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2005
    detail.hit.zdb_id: 1475085-5
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  • 7
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    Germline hypomorphic, dominant interfering CARD11 mutations drive severe atopic disease
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1_Supplement ( 2017-05-01), p. 59.6-59.6
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 59.6-59.6
    Abstract: Monogenic causes for serious manifestations of common allergic disease inform our mechanistic understanding of the pathogenesis of atopy. However, infections and other syndromic phenotypes often accompany such disorders. We performed next-generation sequencing on a cohort of patients with severe atopic dermatitis with evidence of familial inheritance, regardless of comorbidities. We discovered 9 individuals from 5 families harboring distinct, novel heterozygous mutations in CARD11, a lymphocyte scaffolding protein that facilitates NF-κB and mTOR signaling following antigen receptor (AgR) engagement. Significant infections beyond the skin, and non-immunologic comorbidities, were documented in some but not all patients. Improvement of skin and infectious history were noted in the majority of the patients. Each CARD11 mutant exhibited attenuated AgR-driven signaling to NF-κB and mTORC1, and dominantly interfered with the ability of WT CARD11 to activate these pathways in transfected T cell lines. Primary patient T cells also showed defects in AgR-induced activation of NF-κB and mTORC1, which is critical for promoting Th1 and preventing Th2 responses. Impaired proliferation, mTORC1 signaling and IFN-γ production were partially rescued by supplementing with excess glutamine, which requires CARD11 for import into T cells. In contrast to B cell lymphoproliferative disease associated with gain-of-function CARD11 mutations, and severe combined immunodeficiency associated with null CARD11 mutations, our new findings indicate single hypomorphic mutations in CARD11 can cause potentially correctable cellular defects that lead to severe atopy.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.198.Supp.59.6
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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  • 8
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    Online Resource
    Mice with a Selective Impairment of IFN-γ Signaling in Macrophage Lineage Cells Demonstrate the Critical Role of IFN-γ–Activated Macrophages for the Control of Protozoan Parasitic Infections In Vivo
    The American Association of Immunologists ; 2010
    In:  The Journal of Immunology Vol. 184, No. 2 ( 2010-01-15), p. 877-885
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 184, No. 2 ( 2010-01-15), p. 877-885
    Abstract: IFN-γ has long been recognized as a cytokine with potent and varied effects in the immune response. Although its effects on specific cell types have been well studied in vitro, its in vivo effects are less clearly understood because of its diverse actions on many different cell types. Although control of multiple protozoan parasites is thought to depend critically on the direct action of IFN-γ on macrophages, this premise has never been directly proven in vivo. To more directly examine the effects of IFN-γ on cells of the macrophage lineage in vivo, we generated mice called the “macrophages insensitive to IFN-γ” (MIIG) mice, which express a dominant negative mutant IFN-γ receptor in CD68+ cells: monocytes, macrophages, dendritic cells, and mast cells. Macrophage lineage cells and mast cells from these mice are unable to respond to IFN-γ, whereas other cells are able to produce and respond to this cytokine normally. When challenged in vitro, macrophages from MIIG mice were unable produce NO or kill Trypanosoma cruzi or Leishmania major after priming with IFN-γ. Furthermore, MIIG mice demonstrated impaired parasite control and heightened mortality after T. cruzi, L. major, and Toxoplasma gondii infection, despite an appropriate IFN-γ response. In contrast, MIIG mice displayed normal control of lymphocytic choriomeningitis virus, despite persistent insensitivity of macrophages to IFN-γ. Thus, the MIIG mouse formally demonstrates for the first time in vivo, the specific importance of direct, IFN-γ mediated activation of macrophages for controlling infection with multiple protozoan parasites.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.0902346
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2010
    detail.hit.zdb_id: 1475085-5
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  • 9
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    Human Effector Memory CD4+ T Cells Directly Recognize Allogeneic Endothelial Cells In Vitro and In Vivo
    The American Association of Immunologists ; 2007
    In:  The Journal of Immunology Vol. 179, No. 7 ( 2007-10-01), p. 4397-4404
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 179, No. 7 ( 2007-10-01), p. 4397-4404
    Abstract: The frequency of circulating alloreactive human memory T cells correlates with allograft rejection. Memory T cells may be divided into effector memory (TEM) and central memory (TCM) cell subsets, but their specific roles in allograft rejection are unknown. We report that CD4+ TEM (CD45RO+CCR7−CD62L−) can be adoptively transferred readily into C.B-17 SCID/bg mice and mediate the destruction of human endothelial cells (EC) in vascularized human skin grafts allogeneic to the T cell donor. In contrast, CD4+ TCM (CD45RO+CCR7+CD62L+) are inefficiently transferred and do not mediate EC injury. In vitro, CD4+ TEM secrete more IFN-γ within 48 h in response to allogeneic ECs than do TCM. In contrast, TEM and TCM secrete comparable amounts of IFN-γ in response to allogeneic monocytes (Mo). In the same cultures, both TEM and TCM produce IL-2 and proliferate in response to IFN-γ-treated allogeneic human EC or Mo, but TCM respond more vigorously in both assays. Blockade of LFA-3 strongly inhibits both IL-2 and IFN-γ secretion by CD4+ TEM cultured with allogeneic EC but only minimally inhibits responses to allogeneic Mo. Blockade of CD80 and CD86 strongly inhibits IL-2 but not IFN-γ production by in response to allogeneic EC or Mo. Transduction of EC to express B7-2 enhances allogeneic TEM production of IL-2 but not IFN-γ. We conclude that human CD4+ TEM directly recognize and respond to allogeneic EC in vitro by secreting IFN-γ and that this response depends on CD2 but not CD28. Consistent with EC activation of effector functions, human CD4+ TEM can mediate allogeneic EC injury in vivo.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.179.7.4397
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2007
    detail.hit.zdb_id: 1475085-5
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  • 10
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    Online Resource
    High-Dimensional Analysis of Postsplenectomy Peripheral Immune Cell Changes
    The American Association of Immunologists ; 2020
    In:  ImmunoHorizons Vol. 4, No. 2 ( 2020-02-01), p. 82-92
    Details
    In: ImmunoHorizons, The American Association of Immunologists, Vol. 4, No. 2 ( 2020-02-01), p. 82-92
    Abstract: Although the consequences of splenectomy are well understood in mice, much less is known about the immunologic changes that occur following splenectomy in humans. We sought to characterize the circulating immune cell populations of patients before and after elective splenectomy to determine if these changes are related to postsplenectomy survival outcomes. Retrospective clinical information was collected from 95 patients undergoing elective splenectomy compared with 91 patients undergoing pancreaticoduodenectomy (Whipple procedure). We further analyzed peripheral blood from five patients in the splenectomy group, collected before and after surgery, using single-cell cytometry by time-of-flight mass spectrometry. We compared pre- and postsplenectomy data to characterize both the major and minor immune cell populations in significantly greater detail. Compared with patients undergoing a Whipple procedure, splenectomized patients had significant and long-lasting elevated counts of lymphocytes, monocytes, and basophils. Cytometry by time-of-flight mass spectroscopy analysis demonstrated that the elevated lymphocytes primarily consisted of naive CD4+ T cells and a population of activated CD25+CD56+CD4+ T cells, whereas the elevated monocyte counts were mainly mature, activated monocytes. We also observed a significant increase in the expression of the chemokine receptors CCR6 and CCR4 on several cellular populations. Taken together, these data indicate that significant immunological changes take place following splenectomy. Whereas other groups have compared splenectomized patients to healthy controls, this study compared patients undergoing elective splenectomy to those undergoing a similar major abdominal surgery. Overall, we found that splenectomy results in significant long-lasting changes in circulating immune cell populations and function.
    Type of Medium: Online Resource
    ISSN: 2573-7732
    URL: Article
    DOI: 10.4049/immunohorizons.1900089
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 2882729-6
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