The nature of the attenuation of Salmonella typhimurium strains expressing human papillomavirus type 16 virus-like particles determines the systemic and mucosal antibody responses in nasally immunized mice.
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We have recently shown by using a recombinant Salmonella typhimurium PhoPc strain in mice the feasibility of using a Salmonella-based vaccine to prevent infection by the genital human papillomavirus type 16 (HPV16). Here, we compare the HPV16-specific antibody responses elicited by nasal immunization with recombinant S. typhimurium strains harboring attenuations that, in contrast to PhoPc, are suitable for human use. For this purpose, chi4989 (Deltacya Deltacrp) and chi4990 [Deltacya Delta(crp-cdt)] were constructed in the ATCC 14028 genetic background, and comparison was made with the isogenic PhoPc and PhoP- strains. Although the levels of expression of HPV16 virus-like particle (VLP) were similar in all strains, only PhoPc HPV16 induced sustained specific antibody responses after nasal immunization, while all strains induced high antibody responses with a single nasal immunization when an unrelated viral hepatitis B core antigen was expressed. The level of the specific antibody responses induced did not correlate with the number of recombinant bacteria surviving in various organs 2 weeks after immunization. Our data suggest that the immunogenicity of attenuated Salmonella vaccine strains does not correlate with either the number of persisting bacteria after immunization or the levels of in vitro expression of the antigen carried. Rather, the PhoPc phenotype appears to provide the unique ability in Salmonella to induce immune responses against HPV16 VLPs. (+info)
Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2.
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Invasive infection with Gram-positive and Gram-negative bacteria often results in septic shock and death. The basis for the earliest steps in innate immune response to Gram-positive bacterial infection is poorly understood. The LPS component of the Gram-negative bacterial cell wall appears to activate cells via CD14 and Toll-like receptor (TLR) 2 and TLR4. We hypothesized that Gram-positive bacteria might also be recognized by TLRs. Heterologous expression of human TLR2, but not TLR4, in fibroblasts conferred responsiveness to Staphylococcus aureus and Streptococcus pneumoniae as evidenced by inducible translocation of NF-kappaB. CD14 coexpression synergistically enhanced TLR2-mediated activation. To determine which components of Gram-positive cell walls activate Toll proteins, we tested a soluble preparation of peptidoglycan prepared from S. aureus. Soluble peptidoglycan substituted for whole organisms. These data suggest that the similarity of clinical response to invasive infection by Gram-positive and Gram-negative bacteria is due to bacterial recognition via similar TLRs. (+info)
Myelin oligodendrocyte glycoprotein induces experimental autoimmune encephalomyelitis in the "resistant" Brown Norway rat: disease susceptibility is determined by MHC and MHC-linked effects on the B cell response.
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Experimental autoimmune encephalomyelitis (EAE) induced by active immunization with the myelin oligodendrocyte glycoprotein (MOG) is an Ab-mediated, T cell-dependent autoimmune disease that replicates the inflammatory demyelinating pathology of multiple sclerosis. We report that disease susceptibility and severity are determined by MHC and MHC-linked effects on the MOG-specific B cell response that mediate severe clinical EAE in the EAE-resistant Brown Norway (BN) rat. Immunization with the extracellular domain of MOG in CFA induced fulminant clinical disease associated with widespread demyelination and with an inflammatory infiltrate containing large numbers of polymorphonuclear cells and eosinophils within 10 days of immunization. To analyze the effects of the MHC (RT1 system) we compared BN (RT1 n) rats with Lewis (LEW) (RT1 l) and two reciprocal MHC congenic strains, LEW.1N (RT1n) and BN.1L (RT1 l). This comparison revealed that disease severity and clinical course were strongly influenced by the MHC haplotype that modulated the pathogenic MOG-specific autoantibody response. The intra-MHC recombinant congenic strain LEW.1R38 demonstrated that gene loci located both within the centromeric segment of the MHC containing classical class I and class II genes and within the telomeric RT1.M region containing the MOG gene are involved in determining Ab production and disease susceptibility. This study indicates that the current T cell-centered interpretation of MHC-mediated effects on disease susceptibility must be reassessed in multiple sclerosis and other autoimmune diseases in which autoantibody is involved in disease pathogenesis. (+info)
A novel function of Valpha14+CD4+NKT cells: stimulation of IL-12 production by antigen-presenting cells in the innate immune system.
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The balance between Th1 and Th2 development is determined by IL-4 and IL-12. While the role for CD4+ NK1.1+ T (NKT) cells in influencing this balance has been recognized based on their capacity to produce IL-4, it is unknown how IL-12 is produced in the innate immune system in which they participate. This study demonstrates that Ag-activated CD4+ NKT cells express CD40 ligand (CD40L) (CD154), which engages CD40 on APC and stimulates them to produce IL-12. Culture of B cell-depleted spleen cells from C57BL/6 mice with alpha-galactosylceramide (alpha-GalCer) capable of selectively stimulating Valpha14/Jalpha281+ NKT cells resulted in the production of IL-12 together with IFN-gamma and IL-4. alpha-GalCer-induced IL-12 production occurred in I-Abbeta-deficient mice, but not in beta2-microglobulin-deficient and Valpha14/Jalpha281 TCR-deficient mice, and was inhibited by anti-CD40L mAb. Of CD4+ and CD4- NKT cells, the capacity to express CD40L/CD154 and trigger IL-12 production following alpha-GalCer stimulation was exhibited preferentially by the CD4+ NKT subset. IL-12 production was also observed in alpha-GalCer-treated mice. Production of IL-12 preceded IFN-gamma production, and IL-12 was required for IFN-gamma, but not IL-4, production. A stimulatory/inhibitory relationship existed between IL-12 and IL-4 production. These results illustrate a novel function of CD4+ NKT cells that could be involved in the regulation of Th1 vs Th2 development. (+info)
A model for CD8+ CTL tumor immunosurveillance and regulation of tumor escape by CD4 T cells through an effect on quality of CTL.
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Understanding immune mechanisms influencing cancer regression, recurrence, and metastasis may be critical to developing effective immunotherapy. Using a tumor expressing HIV gp160 as a model viral tumor Ag, we found a growth-regression-recurrence pattern, and used this to investigate mechanisms of immunosurveillance. Regression was dependent on CD8 T cells, and recurrent tumors were resistant to CTL, had substantially reduced expression of epitope mRNA, but retained the gp160 gene, MHC, and processing apparatus. Increasing CTL numbers by advance priming with vaccinia virus expressing gp160 prevented only the initial tumor growth but not the later appearance of escape variants. Unexpectedly, CD4 cell depletion protected mice from tumor recurrence, whereas IL-4 knockout mice, deficient in Th2 cells, did not show this protection, and IFN-gamma knockout mice were more susceptible. Purified CD8 T cells from CD4-depleted mice following tumor regression had more IFN-gamma mRNA and lysed tumor cells without stimulation ex vivo, in contrast to CD4-intact mice. Thus, the quality as well as quantity of CD8+ CTL determines the completeness of immunosurveillance and is controlled by CD4 T cells but not solely Th2 cytokines. This model of immunosurveillance may indicate ways to enhance the efficacy of surveillance and improve immunotherapy. (+info)
Positive selection of natural autoreactive B cells.
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Lymphocyte development is critically influenced by self-antigens. T cells are subject to both positive and negative selection, depending on their degree of self-reactivity. Although B cells are subject to negative selection, it has been difficult to test whether self-antigen plays any positive role in B cell development. A murine model system of naturally generated autoreactive B cells with a germ line gene-encoded specificity for the Thy-1 (CD90) glycoprotein was developed, in which the presence of self-antigen promotes B cell accumulation and serum autoantibody secretion. Thus, B cells can be subject to positive selection, generated, and maintained on the basis of their autoreactivity. (+info)
Heterophile antibodies segregate in families and are associated with protection from type 1 diabetes.
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Markedly elevated levels of serum IL-4 were reported previously in 50% of a small group of type 1 diabetes nonprogessors. To determine the patterns of expression for this phenotype, a larger cohort of 58 families containing type 1 diabetic patients was examined. Analysis of the two-site ELISA assay used to measure serum IL-4 revealed evidence for heterophile antibodies, i.e., nonanalyte substances in serum capable of binding antibodies mutivalently and providing erroneous analyte (e.g., IL-4) quantification. Interestingly, relatives without type 1 diabetes were significantly more likely to have this phenotype than were patients with the disease (P = 0.003). In addition, the trait appears to have clustered within certain families and was associated with the protective MHC allele DQB1*0602 (P = 0.008). These results suggest that heterophile antibodies represent an in vivo trait associated with self-tolerance and nonprogression to diabetes. (+info)
How specific should immunological memory be?
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Protection against infection hinges on a close interplay between the innate immune system and the adaptive immune system. Depending on the type and context of a pathogen, the innate system instructs the adaptive immune system to induce an appropriate immune response. Here, we hypothesize that the adaptive immune system stores these instructions by changing from a naive to an appropriate memory phenotype. In a secondary immune reaction, memory lymphocytes adhere to their instructed phenotype. Because cross-reactions with unrelated Ags can be detrimental, such a qualitative form of memory requires a sufficient degree of specificity of the adaptive immune system. For example, lymphocytes instructed to clear a particular pathogen may cause autoimmunity when cross-reacting with ignored self molecules. Alternatively, memory cells may induce an immune response of the wrong mode when cross-reacting with subsequent pathogens. To maximize the likelihood of responding to a wide variety of pathogens, it is also required that the immune system be sufficiently cross-reactive. By means of a probabilistic model, we show that these conflicting requirements are met optimally by a highly specific memory lymphocyte repertoire. This explains why the lymphocyte system that was built on a preserved functional innate immune system has such a high degree of specificity. Our analysis suggests that 1) memory lymphocytes should be more specific than naive lymphocytes and 2) species with small lymphocyte repertoires should be more vulnerable to both infection and autoimmune diseases. (+info)