Subject(s)
Cardiovascular Diseases/immunology , Dendritic Cells/immunology , Lupus Erythematosus, Systemic/immunology , Animals , Cardiovascular Diseases/genetics , Cardiovascular Diseases/pathology , Dendritic Cells/pathology , Humans , Immune Tolerance , Immunity , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/pathology , MiceABSTRACT
SUMMARY: Oral tolerance (OT) is being studied with great interest because of its therapeutic potential in allergy and autoimmunity. In the present study, two mouse strains with extreme phenotypes of OT susceptibility (TS) or resistance (TR) to ovalbumin (OVA) were used to demonstrate whether the tr and ts genes, cumulated during 18 generations of bi-directional genetic selection, influence expression of immunobiological traits in naive or antigen-gavaged TR/TS mice. The difference in anti-OVA titres was 2048-fold between OVA-gavaged TS and TR mice. Tolerance susceptibility to OVA gavage in individuals from a (TS x TR)F(2) population was 24% high-susceptibility, 62% low-susceptibility and 14% non-tolerant. Different antigens, unrelated to OVA, were tested by gavage and TS mice were generally susceptible while TR mice were resistant. The stability of TS and TR phenotypes was not affected by the use of strict protocols of intraperitoneal immunization or feeding over 30 consecutive days. The levels of interleukin-2 (IL-2), IL-4, interferon-gamma and IL-10 cytokines evaluated in concanavalin A-stimulated spleen cells from naive mice and in OVA-stimulated spleen cells from OVA-gavaged mice were higher in TS mice. Interleukin-10 was up-regulated in OVA-gavaged TS mice and down-regulated in TR mice. In naive mice, the percentage of CD4(+) CD25(+) and CD4(+) Foxp3(+) spleen cells and IL-10 expression by CD4(+) cells was significantly higher in TS mice. These results indicate that regulation of IL-10 expression could be an important factor contributing to the mechanisms controlling OT susceptibility, and that the OT responses of TR and TS individuals strongly correlate with their innate potential to secrete this cytokine.
Subject(s)
Cytokines/metabolism , Food Hypersensitivity/immunology , Immune Tolerance/immunology , Immunity, Humoral/immunology , Adjuvants, Immunologic/administration & dosage , Animals , Antibodies/pharmacology , Antibody Formation/immunology , Antigens/administration & dosage , Antigens/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Count , Cell Proliferation/drug effects , Concanavalin A/pharmacology , Crosses, Genetic , Cytokines/immunology , Female , Food Hypersensitivity/genetics , Forkhead Transcription Factors/metabolism , Genes, Dominant/immunology , Immune Tolerance/genetics , Immunoglobulin G/blood , Immunoglobulin G/immunology , Interferon-gamma/metabolism , Interleukin-10/metabolism , Interleukin-2/metabolism , Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-4/metabolism , Lipopolysaccharides/pharmacology , Lymphocyte Activation/immunology , Male , Mice , Mice, Inbred Strains , Ovalbumin/administration & dosage , Ovalbumin/immunology , Phenotype , Spleen/cytology , Spleen/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , VaccinationABSTRACT
Nup98 and Nup96 are components of the nuclear transport machinery and are induced by interferons (IFN). Nup98 is a constituent of an mRNA export pathway that is targeted by viruses and regulated by IFN. However, the role of Nup96 in IFN-related mechanisms has not been established. To investigate the function of Nup96 in vivo, we generated Nup96(+/-) mice that express low levels of Nup96, as Nup96(-/-) mice are lethal. The Nup96(+/-) mice presented selective alterations of the immune system, which resulted in downregulation and impaired IFN alpha- and gamma-mediated induction of MHC I and IFNgamma induction of MHC II, ICAM-1, and other proteins. Frequency of TCRalphabeta+ and CD4+ T cells, which depends on MHC function, is reduced in NUP96(+/-) mice. Upon immunization, Nup96(+/-) mice showed impaired antigen presentation and T cell proliferation. Nup96(+/-) cells and mice were highly susceptible to viral infection, demonstrating a role for Nup96 in innate and adaptive immunity.