Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ligand for CD40 (CD40L) is expressed on the surface of activated CD4+ T cells and its role in T-B cell collaborations and thymus-dependent humoral immunity is well established. Recently, by generating CD40L-knockout mice, we have confirmed its previously described role in humoral immunity and defined another important function of this molecule in the in vivo clonal expansion of antigen-specific CD4+ T cells. Here, we investigated the potential in vivo role of CD40L in antiviral immunity by examining the immune response mounted by CD40L-deficient mice following infection with lymphocytic choriomeningitis virus (LCMV), Pichinde virus, or vesicular stomatitis virus. Humoral immune responses of CD40L-deficient mice to these viruses were severely compromised, although moderate titres of antiviral IgM and some IgG2a were produced by virus-infected CD40L-deficient mice by a CD4+ T cell-independent mechanism. By contrast, CD40L-deficient mice made strong primary CTL responses to all three viruses. Interestingly however, although memory CTL activity was detectable in CD40L-deficient mice two months after infection with LCMV, the memory CTL response was much less efficient than in wild-type mice. Together, the results show that CD40-CD40L interactions are required for strong antiviral humoral immune responses, and reveal a novel role for CD40L in the establishment and/or maintenance of CD8+ CTL memory.
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PMID:CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response. 864 23

CD40-CD40 ligand (CD40L) interaction is required for the generation of antibody responses to T-dependent antigens as well as for the development of germinal centers and memory B cells. The role of the CD40-CD40L interaction in the induction of antigen-specific. Th cells and in mediating Th cell effector functions other than cognate help for B cells is less well understood. Using CD40- and CD40L-deficient mice together with lymphocytic choriomeningitis virus and vesicular stomatitis virus as viral model antigens, this study corroborates earlier findings that no lg isotype switching of virus-specific antibodies was measurable upon infection of CD40- or CD40L-deficient mice. In contrast, in vivo induction of virus-specific CD4+ T cells measured by proliferation and cytokine secretion of primed virus-specific Th cells in vitro was not crucially dependent on the CD40-CD40L interaction. In addition, virus-specific Th cells primed in a CD40-deficient environment, adoptively transferred into CD40-competent recipients, were able to mediate lg isotype switch. Th-mediated effector functions distinct from and in addition to T-B collaboration were analyzed in CD40- and CD40L-deficient and normal mice: (a) local inflammatory reactions upon LCMV infection mediated by LCMV-specific Th cells were not dependent on a functional CD40-CD40L interaction, (b) cytokine-mediated protection by CD4+ T cells primed by vesicular stomatitis virus against a challenge infection with recombinant vaccinia virus expressing the glycoprotein of vesicular stomatitis virus was found to be equivalent in CD40L-deficient and normal mice. Thus, CD40-CD40L interaction plays a crucial role in T-B interactions for Th-dependent activation of B cells but not, or to a much lesser extent, in T cell activation, antigen-specific Th cell responses in vitro, and for interleukin-mediated Th cell effector functions in vivo.
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PMID:CD40-CD40 ligand interactions are critical in T-B cooperation but not for other anti-viral CD4+ T cell functions. 864 30

The dual specific kinase SAPK/ERK1 kinase (SEK1; mitogen-activated protein kinase kinase 4/Jun NH2 terminal kinase [ JNK] kinase) is a direct activator of stress-activated protein kinases ([SAPKs]/JNKs) in response to CD28 costimulation, CD40 signaling, or activation of the germinal center kinase. Here we show that SEK1(-/-) recombination-activating gene (RAG)2(-/-) chimeric mice have a partial block in B cell maturation. However, peripheral B cells displayed normal responses to IL-4, IgM, and CD40 cross-linking. SEK1(-/-) peripheral T cells showed decreased proliferation and IL-2 production after CD28 costimulation and PMA/Ca2+ ionophore activation. Although CD28 expression was absolutely crucial to generate vesicular stomatitis virus (VSV)-specific germinal centers, SEK1(-/-)RAG2(-/-) chimeras mounted a protective antiviral B cell response, exhibited normal IgG class switching, and made germinal centers in response to VSV. Interestingly, PMA/Ca2+ ionophore stimulation, which mimics TCR-CD3 and CD28-mediated signal transduction, induced SAPK/JNK activation in peripheral T cells, but not in thymocytes, from SEK1(-/-) mice. These results show that signaling pathways for SAPK activation are developmentally regulated in T cells. Although SEK1(-/-) thymocytes failed to induce SAPK/JNK in response to PMA/Ca2+ ionophore, SEK1(-/-)RAG2(-/-) thymocytes proliferated and made IL-2 after PMA/Ca2+ ionophore and CD3/CD28 stimulation, albeit at significantly lower levels compared to SEK1(+/+)RAG2(-/-) thymocytes, implying that CD28 costimulation and PMA/Ca2+ ionophore-triggered signaling pathways exist that can mediate proliferation and IL-2 production independently of SAPK activation. Our data provide the first genetic evidence that SEK1 is an important effector molecule that relays CD28 signaling to IL-2 production and T cell proliferation.
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PMID:Impaired CD28-mediated interleukin 2 production and proliferation in stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes. 929 48

The proto-oncogene product Vav is required for receptor clustering, proliferation, and differentiation of T cells, and Vav was identified as a substrate in the TCR and B cell receptor signaling pathway. The role of Vav in B cell responses to Ag challenge in vivo is not known. In this study, we show that Vav regulates B cell proliferation following in vitro activation of Ag receptors, but Vav has no apparent role in CD40-, IL-4-, or LPS-induced B cell activation. Increased degrees of Ag receptor cross-linking can partially reverse the proliferative defect in the anti-IgM response of vav-/- B cells. In vivo, vav-/- mice mounted protective antiviral IgM and IgG responses to infections with vesicular stomatitis virus and recombinant vaccinia virus expressing the vesicular stomatitis virus glycoprotein, which harbor repetitive surface epitopes that directly cross-link the Ag receptor and activate B cells in the absence of T cell help. vav-/- B cells also responded normally to the polyvalent, repetitive hapten Ag trinitrophenyl (TNP)-Ficoll that effectively cross-links B cell receptors. However, vav-/- mice failed to mount immune responses to the nonrepetitive, T cell-dependent hapten Ag (4-hydroxy-5-iodo-3-nitrophenyl)acetyl (NIP)-OVA. These results provide the first genetic evidence on the role of the guanine exchange factor Vav in immune responses to viral infections and antigenic challenge in vivo, and suggest that Vav adjusts the threshold for Ag receptor-mediated B cell activation depending on the nature of the Ag.
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PMID:The guanine-nucleotide exchange factor Vav is a crucial regulator of B cell receptor activation and B cell responses to nonrepetitive antigens. 1038 9

The primary aim of this report was to evaluate the immune responses of CD40 ligand-deficient (CD40L-/-) mice infected with two viruses known to differ markedly in their capacity to replicate in the host. Lymphocytic choriomeningitis virus (LCMV) is a natural mouse pathogen that replicates widely and extensively, whereas vesicular stomatitis virus (VSV) spreads poorly. We found that the primary response of CD40L-/- mice toward VSV is significantly impaired; proliferation of both CD4+ and CD8+ cells is reduced 2- to 3-fold, few CD8+ cells acquire an activated phenotype, and little functional activity is induced. Very similar results were obtained in VSV-infected, CD28-deficient mice. In contrast, neither CD40L nor CD28 was required for induction of a primary CD8+ response toward LCMV. Surprisingly, lack of CD4+ T cells had no impact on the primary immune response toward any of the viruses, even though the CD40 ligand dependence demonstrated for VSV would be expected to be associated with CD4 dependence. Upon coinfection of VSV-infected mice with LCMV, the requirement for CD40 ligand (but not CD28) could be partially bypassed, as evidenced by a 3-fold increase in the frequency of VSV-specific CD8+ T cells on day 6 postinfection. Finally, despite the fact that the primary LCMV-specific CD8+ response is virtually unimpaired in CD40L-/- mice, their capacity to maintain CD8+ effector activity and to permanently control the infection is significantly reduced. Thus, our results demonstrate that the importance of CD40/CD40L interaction for activation of CD8+ T cells varies between viruses and over time.
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PMID:Role of CD40 ligand and CD28 in induction and maintenance of antiviral CD8+ effector T cell responses. 1072 27

Dependence of the primary antiviral immune response on costimulatory interactions between CD28/CD80-86 and between CD40/CD154 (CD40 ligand) has been correlated with the extent of viral replication in two models of systemic infection, lymphocytic choriomeningitis virus and vesicular stomatitis virus. To determine the role of these costimulatory interactions in the context of an acute cytolytic, but locally replicating viral infection, herpes simplex virus (HSV) infection was assessed in mice that had the CD28/CD80-86 or CD40/CD154 interactions disrupted either genetically or with blocking reagents (CTLA4Ig and MR1, respectively). CTLA4Ig treatment greatly reduced paralysis-free survival during primary acute HSV infection. This reflected an almost total ablation of the anti-HSV CD4(+) and CD8(+) T-cell responses due to anergy and reduced cell numbers, respectively. Disruption of CD40/CD154 interactions impaired survival, but the effect was less severe than that observed in CTLA4Ig-treated mice, with reductions observed in the CD4(+) T-cell but not CD8(+) T-cell responses. These two costimulatory pathways functioned in part independently, since disruption of both further impaired survival. The dependence on these costimulatory interactions for the control of primary HSV infection may represent a more widespread paradigm for nonsystemic viruses, which have restricted sites of replication and which employ immunoevasive measures.
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PMID:Role of CD28/CD80-86 and CD40/CD154 costimulatory interactions in host defense to primary herpes simplex virus infection. 1113 74

The CD8 T cell response to vesicular stomatitis virus infection was characterized in the spleen and intestinal mucosa using MHC tetramers. Surprisingly, the primary response persisted in the lamina propria long after the splenic response had declined. Furthermore, the response was characterized by a protracted effector phase in which cytolytic activity in the lamina propria, but not in the spleen, was maintained. The appearance of Ag-specific cells in the intestinal mucosa was largely, though not exclusively, a result of beta(7) integrin-mediated migration. Infection with Listeria monocytogenes or with vaccinia virus also led to sustained mucosal responses. After reinfection of vesicular stomatitis virus-primed mice with a serotypically distinct virus, a sustained recall response was detected in all tissues. In CD40(-/-) mice, the mucosal, but not the splenic, response was compromised, resulting in diminished mucosal memory. The recall response was CD40 independent and correlated with memory levels, indicating that the mucosal and systemic responses operated independently. These findings illustrated the integrated yet distinct nature of systemic vs mucosal immune responses.
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PMID:Direct analysis of the dynamics of the intestinal mucosa CD8 T cell response to systemic virus infection. 1116 Feb 92

Links have been observed between infections and the development of autoimmunity. Proposed explanations include activation of self-Ag-bearing APC. Using a model system in which transgenic OVA is expressed in enterocytes, we showed that CD8 T cell recognition of cross-presented Ag in gut-associated lymph nodes was tolerogenic. However, concomitant infection with vesicular stomatitis virus encoding OVA abrogated tolerance and induced disease. We now show that following transfer of naive OT-I T cells, the addition of wild-type vesicular stomatitis virus, oral cholera toxin, or CD40 triggering can induce intestinal disease in transgenic mice. Tissue damage accompanied dramatic increases in cytokine release by activated OT-I cells in the intestine. The data indicated that products of antigenically unrelated infections can combine with cross-presented self-Ags on APC to prime autoaggressiveness, independent of additional Ag release. These results help explain how diverse pathogens, lacking any homology to self-proteins, could be causative agents in induction of organ-specific autoimmunity.
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PMID:Cutting edge: inflammatory signals drive organ-specific autoimmunity to normally cross-tolerizing endogenous antigen. 1247 Oct 97

B lymphocytes are attractive targets for gene therapy of genetic diseases associated with B-cell dysfunction and for immunotherapy. Transduction of B lymphocytes was evaluated using green fluorescent protein (GFP)-encoding onco-retroviral and HIV-derived lentiviral vectors which were pseudotyped with ecotropic, amphotropic or vesicular stomatitis virus (VSV-G) envelopes. Transduction of mouse B lymphocytes activated with lipopolysaccharides (LPS) or by cross-linking CD40 in conjunction with interleukin-4 (IL-4) was significantly more efficient (p < 0.003) with ecotropic (11%) than with VSV-G pseudotyped onco-retroviral vectors (1%). Using high-titer cell-free ecotropic viral supernatant or by coculture with ecotropic onco-retroviral vector-producing cells, transduction efficiency increased significantly (p < 0.001) to approximately 50%, whereas transduction efficiency by coculture with VSV-G pseudotyped vector-producing cells remained low (< 2%). Similarly, transduction of mouse B lymphocytes was significantly more efficient (twofold, p < 0.01) with the ecotropic (7%) than with the VSV-G pseudotyped lentiviral vectors although gene transfer efficiency remained low because of dose-limiting toxicity of the concentrated vector preparations on the LPS-activated murine B cells. Consistent with murine B-cell transduction, human B cells activated with CD40L and IL-4 were also found to be relatively refractory to VSV-G pseudotyped onco-retroviral vectors (< 1%). However, higher transduction efficiencies could be achieved in activated primary human B lymphocytes using VSV-G pseudotyped lentiviral vectors instead (5%-6%). Contrary to the significant increase in mouse B-cell transduction efficiency with ecotropic vectors, the use of amphotropic onco-retroviral or lentiviral vectors did not increase transduction efficiency in primary human B cells. The present study shows that the transduction efficiency of onco-retroviral and lentiviral vectors in human and mouse B lymphocytes is pseudotype-dependent and challenges the widely held assumption that VSV-G pseudotyping facilitates gene transfer into all cell types.
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PMID:Efficiency of onco-retroviral and lentiviral gene transfer into primary mouse and human B-lymphocytes is pseudotype dependent. 1263 6

The role of CD4 T cells in providing help to CD8 T cells in primary and secondary responses to infection remains controversial. Using recombinant strains of virus and bacteria expressing the same Ag, we determined the requirement for CD4 T cells in endogenous CD8 T cell responses to infection with vesicular stomatitis virus and Listeria monocytogenes (LM). Depletion of CD4 T cells had no effect on the frequency of primary or secondary vesicular stomatitis virus-specific CD8 T cells in either lymphoid or nonlymphoid tissues. In contrast, the primary LM-specific CD8 T cell response was CD4 T cell dependent. Surprisingly, the LM-specific CD8 T cell recall response was also CD4 T cell dependent, which correlated with a requirement for CD40/CD40L interactions. However, concomitant inhibition of CD40L and CD4 T cell removal revealed that these pathways may be operating independently. Importantly, despite the absence of CD4 T cells during the recall response or throughout the entire response, CD8 memory T cells were functional effectors and proliferated equivalently to their "helped" counterparts. These data call into question the contention that CD4 T cells condition memory CD8 T cells during the primary response and indicate that the principal role of CD4 T cells in generating CD8 memory cells after infection is augmentation of proliferation or survival through costimulatory signals.
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PMID:Fully functional memory CD8 T cells in the absence of CD4 T cells. 1524 Jun 84


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