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Results for “Self Tolerance”

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PubMed2002

Low-level self-tolerance to arsenite in human HepG2 cells is associated with a depressed induction of micronuclei.

Arsenic (As) is one of the most important global environmental toxicants. There is evidence that humans may develop tolerance to As's toxicity. For instance, it is known that uptake of small amounts of As leads to an acquisition of elevated resistance to the element's acute toxicity. Moreover, it was suggested that As-exposed native Andean females of Atacameño ethnicity may have acquired resistance to skin cancer. It is not known how such adaptation could be mechanistically conferred. In this context, the biological selection and cloning of human cells tolerant to As provides a valuable approach to investigate this question. By the means of a 12 weeks culture with increasing doses of As, three different As-resistant clones of the human hepatoma cell line HepG2 were selected. These three clones were similarly and roughly two-fold resistant to the acute toxicity of arsenite (50% reduction of neutral red (NR) uptake at 65 microM versus 115 microM; HepG2 control versus clones HepG2 K1, HepG2 K11 and HepG2 K14, respectively). Moreover, in the cytokinesis-block micronucleus test, these clones showed a significantly reduced induction of micronuclei (MNi) indicating elevated resistance to As genotoxicity as well (e.g. mean MNi rates at a concentration of 25 microM arsenite: 28.5 (control) versus 21.6 (HepG2 K1), 18 (HepG2 K11), and 16 (HepG2 K14), respectively, each P<0.05). The tolerance was neither associated with mRNA induction of putatively As-extruding membrane transporters multidrug resistance-associated protein 1 (MRP1), 2, or 3 nor to mRNA induction of the ubiquitously expressed mammalian ABC half-transporter UMAT (ABCB6). Changes in the metabolic methylation of As could not be detected. There were no differences in the cellular levels of GSH when comparing the clones and the parental line. Taken together the data showed that low-level tolerance to As-mediated cytotoxicity in human HepG2 cells was associated with enhanced resistance to As-induced DNA damage as well.

ATP-Binding Cassette Transporters↗
PubMed2005

Mucosal immunity and self-tolerance in the ocular surface system.

This paper articulates a new working hypothesis that explains many of the pathophysiological conditions described under the common rubric "dry eye" as altered states of mucosal immune regulation. A central principle of mucosal immune physiology is that the parenchymal tissues at the effector sites, i.e., the sites at which secretory antibodies are produced, maintain local signaling milieus that support differentiation of IgA+ plasmablasts and survival of IgA+ plasmacytes. These local signaling milieus also support robust regulatory networks that maintain tolerance to commensual microbes, benign antigens, and parenchymal autoantigens. The regulatory networks are mediated by cycles of interactions between successive generations of dendritic cells, which normally mature with tolerogenic functions, and regulatory T cells, which normally reinforce the system's ability to generate new tolerogenic dendritic cells. The systemic endocrine environment controls expression of the local signaling milieu in the mammary gland and in the prostate and male urethral glands. Emerging evidence indicates that the local signaling milieu in the lacrimal gland also is determined, in part, by the systemic endocrine environment. This working hypothesis suggests explanations for the excess incidence of Sjogren syndrome among women and for the mechanisms of several different immunophysiological states in addition to Sjogren syndrome that, like Sjogren syndrome, are associated with the classical symptoms and signs of dry eye. It also comprises a promising rationale for specific new approaches to therapy.

Journal Article↗
PubMed2005

Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.

Naturally arising CD25(+)CD4(+) regulatory T cells actively maintain immunological self-tolerance. Deficiency in or dysfunction of these cells can be a cause of autoimmune disease. A reduction in their number or function can also elicit tumor immunity, whereas their antigen-specific population expansion can establish transplantation tolerance. They are therefore a good target for designing ways to induce or abrogate immunological tolerance to self and non-self antigens.

Animals↗
PubMed1991

Altered antigen receptor signaling in anergic T cells from self-tolerant T-cell receptor beta-chain transgenic mice.

T-cell tolerance to the minor lymphocyte-stimulating antigen Mls-1a in a T-cell receptor (TcR) V beta 8.1 transgenic line of mice is maintained by both clonal deletion and clonal anergy. Approximately 20-50% of peripheral CD4+ (but not CD8+) T cells isolated from these mice are anergic and fail to proliferate following TcR ligation. We have examined key events in T-cell signaling in peripheral T cells isolated from these mice. In this report, we show that the anergic CD4+ T cells did not mobilize calcium or express receptors for interleukin 2 (IL-2) following TcR ligation. However, the cells retained viability and functional potential because stimulation with phorbol 12-myristate 13-acetate and ionomycin bypassed the block in receptor-mediated signaling and induced IL-2 receptor expression and proliferation of the anergic cells.

Animals↗
PubMed1977

Passive transfer of autoimmune disease with isologous IgG1 and IgG2 antibodies to the tubular basement membrane in strain XIII guinea pigs: loss of self-tolerance induced by autoantibodies.

Initiation of an autoimmune tubulointerstitial disease was achieved in strain XIII guinea pigs by passive transfer of functionally pure IgG1 or IgG2 fractions of isologous anti-tubular basement membrane (TBM) serum. IgG2 appeared to be somewhat more effective than IgG1. The immunopathologic features in the IgG1 and IgG2 recipients were similar at the time of sacrifice, 14 days after transfer. The recipients that developed disease had higher than expected anti-TBM titers at 14 days. Furthermore, anti-TBM antibodies were of both IgG isotypes. In contrast, simultaneously administered IgG1 or IgG2 anti-BGG antibodies declined in titer in the recipients and were never found in the isotype fraction that had not been transferred. These findings indicate that the recipients of anti-TBM antibodies of either IgG1 or IgG2 isotype were stimulated to produce anti-TBM autoantibodies, which participated in the pathogenesis of the renal disease. The model demonstrates that autoantibodies may provide a mechanism (autoimmune amplification) for the intensification and perpetuation of antibody-mediated autoimmune diseases.

Animals↗
PubMed1985

Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease.

Organ-specific autoimmune diseases such as oophoritis, gastritis, thyroiditis, and orchitis were induced in female or male nude (nu/nu) mice by the transfer of nu/+spleen cells from which particular Lyt T cell subset(s) had been removed: nu/+spleen cells treated with anti-Lyt-1 plus complement (C) caused disease in recipient nude mice; anti-Lyt-2 plus C-treated spleen cells, in contrast, did not. The cells responsible for disease induction are believed to be Thy-1+, Lyt-1-, 2,3- (Thy-1, Lyt-1, 2,3), since spleen cells treated with mixed antisera, including anti-Lyt-1 and anti-Lyt-2, plus C, could induce the disease with almost the same incidence as anti-Lyt-1 plus C-treated cells (oophoritis 50%, gastritis 25%, thyroiditis 10-20%, and orchitis 40%). Cells treated with mixed antisera of anti-Thy-1, anti-Lyt-1, and anti-Lyt-2, plus C, could not induce autoimmune disease. Each induced autoimmune disease could be adoptively transferred to other nude mice via spleen cells, with resulting histological lesion of corresponding organs and development of specific circulating autoantibodies. Since anti-Thy-1 plus C treatment of donor spleen cells abrogated the capacity to transfer the disease, we conclude that T cells are required as effector cells, and that these may develop from Lyt-1-, 2,3- cells. Lyt-1+, 2,3- cells were demonstrated to have suppressive activity upon the development of the diseases; induction of autoimmunity was completely inhibited by the cotransfer of Lyt-1+, 2,3- cells with Lyt-1-, 2,3- cells. When anti-Lyt-2 plus C-treated cells (i.e., Lyt-1+, 2,3- and Lyt-1-, 2,3- cells) were mixed with anti-Lyt-1 and anti-Lyt-2 plus C-treated cells (i.e., Lyt-1-, 2,3- cells) in various ratios, then transferred to nude mice, the development of each autoimmune disease was clearly inhibited, even by small doses of Lyt-1+, 2,3- cells. The autoimmune disease we were able to induce was quite similar to human organ-specific autoimmune disease in terms of the spectrum of organs involved, histopathological features, and the development of autoantibodies to corresponding organ components (oocytes, parietal cells, thyroid colloid, including thyroglobulin, and sperm).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Interferon gamma plays a critical role in induced cell death of effector T cell: a possible third mechanism of self-tolerance.

We have used anti-T cell monoclonal antibodies (mAbs) as mimic ligands to study the effects of T cell receptor (TCR) ligation of cloned T helper type 1 cells in the presence or absence of accessory cells. Our results demonstrate that ligation of the TCR in the absence of accessory cells rapidly induces cell death. Cell death can be prevented by addition of spleen adherent cells, leading to strong clonal expansion. Induced cell death is inhibited by cyclosporin A and by anti-interferon gamma (IFN-gamma), and is restored by adding exogenous recombinant IFN-gamma to cyclosporin A-treated cells. These results demonstrate that IFN-gamma plays a critical role in cell death induced by anti-TCR mAbs in the absence of costimulatory cells. We propose that induced cell death of active effector T cells provides a third mechanism of tolerance in addition to intrathymic deletion of developing autoreactive T cells and peripheral inactivation of mature, naive T cells.

Animals↗
PubMed1992

A fail-safe mechanism for maintaining self-tolerance.

Using cytotoxic T lymphocyte (CTL) responses to the class I histocompatibility antigen Qa1 and to the minor histocompatibility antigen H-Y, we show that the immune system maintains a peripheral screening process that is able to tolerize a wide variety of potentially autoimmune CTL. The critical factor is the presence or absence of specific T helper cells. If T help is available, CTL precursors that recognize antigen are activated. In the absence of help, they are tolerized. Thus, T helper cells are guardians of peripheral tolerance in CTL.

Animals↗
PubMed1995

In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. IV. Affinity-dependent, antigen-driven B cell apoptosis in germinal centers as a mechanism for maintaining self-tolerance.

Germinal centers (GCs) are the sites of antigen-driven V(D)J gene hypermutation and selection necessary for the generation of high affinity memory B lymphocytes. Despite the antigen dependence of this reaction, injection of soluble antigen during an established primary immune response induces massive apoptotic death in GC B cells, but not in clonally related populations of nonfollicular B lymphoblasts and plasmacytes. Cell death in GCs occurs predominantly among light zone centrocytes, is antigen specific, and peaks within 4-8 h after injection. Antigen-induced programmed death does not involve cellular interactions mediated by CD40 ligand (CD40L) or Fas; disruption of GCs by antibody specific for CD40L was not driven by apoptosis and C57BL/6.lpr mice, though unable to express the Fas death trigger, remained fully susceptible to soluble antigen. Single injections of antigen did not significantly decrease GC numbers or average size, but repeated injections during an 18-h period resulted in fewer and substantially smaller GCs. As cell loss appeared most extensive in the light zone, decreased GC cellularity after prolonged exposure to soluble antigen implies that the Ig- centroblasts of the dark zone may require replenishment from light zone cells that have survived antigenic selection. GC cell death is avidity-dependent; oligovalent antigen induced relatively little apoptosis and GC B cells that survived long exposures to multivalent antigen expressed atypical VDJ rearrangements unlikely to encode high affinity antibody. Antigen-induced apoptotic death in GCs may represent a mechanism for the peripheral deletion of autoreactive B cell mutants much as the combinatorial repertoire of immature B lymphocytes is censored in the bone marrow.

Amino Acid Sequence↗
PubMed1997

Discordant expression of major histocompatibility complex class II antigens and invariant chain in interstitial dendritic cells. Implications for self-tolerance and immunity.

BACKGROUND: The invariant chain plays a crucial role in antigen presentation by influencing the expression and peptide loading of major histocompatibility complex (MHC) class II molecules. Therefore, coordinate expression of these molecules is important for antigen presentation. METHODS: Immunohistological studies were performed on frozen sections of many rat tissues in order to examine expression of invariant chain and MHC class II antigens. RESULTS: Although coordinately regulated in most tissues, the interstitial dendritic cell (and the renal tubular epithelial cell) was always negative for invariant chain, while strongly positive for MHC class II antigens. However, renal tubular epithelial cells strongly expressed invariant chain during kidney graft rejection. CONCLUSIONS: The absence of invariant chain in interstitial dendritic cells is unexpected, in view of their presumed function as sentinel antigen-presenting cells in the connective tissues. This might have important implications for antigen presentation for tolerance and immunity.

Animals↗