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PubMed1995

T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen.

Two unusual characteristics of the memory response to the immunodominant Epstein-Barr virus (EBV) epitope FLRGRAYGL, which associates with HLA B8, have provided an unique opportunity to investigate self tolerance and T cell receptor (TCR) plasticity in humans. First, the response is exceptionally restricted, dominated by cytotoxic T lymphocytes (CTL) with identical TCR protein sequences (Argaet, V. P., C. W. Schmidt, S. R. Burrows, S. L. Silins, M. G. Kurilla, D. L. Doolan, A. Suhrbier, D. J. Moss, E. Kieff, T. B. Sculley, and I. S. Misko. 1994. J. Exp. Med. 180:2335-2340). Second, CTL expressing this receptor are cross-reactive with the alloantigen HLA B* 4402 on uninfected cells (Burrows, S. R., R. Khanna, J. M. Burrows, and D. J. Moss. 1994. J. Exp. Med. 179:1155-1161). No CTL using this conserved public TCR could be reactivated from the peripheral blood of EBV exposed individuals expressing both HLA B8 and B*4402, demonstrating the clonal inactivation of potentially self-reactive T cells in humans. A significant FLRGRAYGL-specific response was still apparent, however, and TCR sequence analysis of multiple CTL clones revealed an oligoclonal TCR repertoire for this determinant within these individuals, using diverse V and J gene segments and CDR3 regions. In addition, a significant public TCR component was identified in which several distinct alpha/beta rearrangements are shared by CTL clones from a number of unrelated HLA B8+, B*4402+ donors. The striking dominance of public TCR in the response to this EBV epitope suggests a strong genetic bias in TCR gene recombination. Fine specificity analysis using peptide analogues showed that, of six different antigen receptors for FLRGRAYGL/HLA B8, none associate closely with the peptide's full array of potential TCR contact residues. Whereas the HLA B*4402-cross-reactive receptor binds amino acids toward the COOH terminus of the peptide, others preferentially favor an NH2-terminal determinant, presumably evading an area that mimics a structure presented on HLA B*4402. Thus, tolerance to a background major histocompatibility antigen can effectively diversify the TCR repertoire for a foreign epitope by deflecting the response away from an immunodominant combination of TCR-binding residues.

Amino Acid Sequence↗
PubMed2003

Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling.

CpG sequences in self-DNA are an important potential trigger for autoantibody secretion in systemic lupus and other systemic autoimmune disorders. It is not known how this ubiquitous threat may be controlled by active mechanisms for maintaining self tolerance. Here we show that two distinct mechanisms oppose autoantibody secretion induced by CpG DNA in anergic B cells that are constantly binding self-antigen. Uncoupling of the antigen receptor (BCR) from a calcineurin-dependent pathway prevents signals that synergize with CpG DNA for proliferation. The BCR does not become desensitized by activating the extracellular response kinase (ERK) MAP kinase pathway, however, and continuous self-antigen signaling to ERK inhibits CpG DNA-induced plasma cell differentiation. These two mechanisms seem to act as a general control against autoantibody production elicited by Toll-like receptors, and their regulation of T cell-independent responses to Toll-like receptor 9 (TLR9) is probably crucial for resistance to systemic autoimmunity.

Animals↗
PubMed2004

Novosphingobium aromaticivorans: a potential initiator of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is characterized by a T-cell-mediated destruction of bile duct epithelial cells that line the small intrahepatic bile ducts. The targets of activated T-lymphocytes are the dihydrolipoamide acetyltransferase components of the 2 oxo acid dehydrogenases, enzyme complexes that are important in oxidative energy metabolism. Pyruvate dehydrogenase is the best known of these. Its dihydrolipoamide acetyltransferase component is referred to as PDC-E2. A major question in understanding the pathogenesis of PBC is why PBC patients lose their tolerance to antigens that are found in virtually every cell in the body. A possible cause is molecular mimicry between microbial agents and self-antigens. Infection with or exposure to a microorganism whose PDC-E2 bears close homology with human PDC-E2 could act as an immunological trigger that initiates the development of PBC. Emerging data suggest that there is a microorganism that may initiate the onset of PBC. Novosphingobium aromaticivorans is a gram negative strictly aerobic bacteria that is found worldwide in soil, water, and coastal plain sediments. Its PDC-E2-like proteins have a higher degree of homology with the immunodominant region of human PDC-E2 than any microorganism thus far studied (100-1,000 times greater than that of Escherichia coli). In addition, N. aromaticivorans can metabolize xenobiotics that are similar to the chemical compounds that react with sera from PBC patients. Some of these xenobiotics are immunologically related to lipoic acid, the cofactor that is at the active center of PDC-E2. Thus, N. aromaticivorans can theoretically break down self-tolerance in two ways: by molecular mimicry due to subclinical infection and by the metabolism of xenobiotics that are present in the environment. In an initial study, investigators found that antibodies against N. aromaticivorans were found in 77 of 77 PBC patients from Milan, Italy, who had antibodies to PDC-E2 and that the titers to N. aromaticivorans proteins were similar to those to human PDC-E2. The report in this issue of The American Journal of Gastroenterology confirms these earlier findings and demonstrates that exposure to N. aromaticivorans occurs in genetically different PBC patients from other regions. Thirteen of 14 Icelandic PBC patients who were AMA positive reacted against at least one of the 2 oxo acid dehydrogenase-E2 complexes. These observations provide additional evidence that exposure to N. aromaticivorans may trigger the development of PBC.

Autoantibodies↗
PubMed2004

Alteration of an autoantigen by chlorination, a process occurring during inflammation, can overcome adaptive immune tolerance.

Autoimmune diseases are characterized by chronic inflammation in target organs and immunoreactivity towards one or multiple autoantigens. Several potential mechanisms of tolerance breaking have been postulated, one being inflammation-associated events. We have investigated whether chlorination of an autoantigen can lead to disruption of self-tolerance. Chlorination of antigens might occur during inflammation via the granulocyte-specific, myeloperoxidase-catalysed conversion of hydrogen peroxide to hypochlorous acid (HOCl). HOCl, being a strong oxidant, reacts with proteins both within cellular phagosomes and in the immediate extracellular environment. By immunizing Lew.1AV1 rats with chlorinated or unmodified rat serum albumin (RSA), we could detect tolerance-breaking effects of chlorination. RSA is a systemic autoantigen in rat not inducing antibody production upon immunization in its unmodified form. Rats immunized with chlorinated RSA (RSA-Cl) developed high titres of immunoglobulin G (IgG) specific for RSA-Cl which cross-reacted with native RSA. T cells reactive with both RSA-Cl and RSA were detected by [(3)H]-thymidine incorporation. We hence speculated that immunological tolerance established for unmodified proteins, during certain circumstances such as inflammation, might be broken by induced protein chlorination. T cells specific for the chlorinated protein can confer help to B cells recognizing both the chlorinated and the native form of the protein, leading to the formation of high-affinity autoreactive antibodies and possibly autoimmune disease.

Adjuvants, Immunologic↗
PubMed2003

Signaling mutations and autoimmunity.

Mutations in a number of signaling components in mice can lead to strong autoimmune phenotypes. In some cases, these mutations likely compromise important feedback inhibitory pathways that downregulate antigen receptor signaling. For example, a deficiency of Lyn leads to a severe lupus-like autoimmunity. This autoimmunity may result from loss of a feedback inhibitory pathway in which Lyn phosphorylates CD22, triggering recruitment of the tyrosine phosphatase SHP-1 to the plasma membrane, which then dampens BCR signaling. Loss of Lyn also compromises an inhibitory pathway involving Fc gamma RIIb and SHIP, an inositol phosphatase. Mutation of Fyn exacerbates the autoimmunity caused by loss of Lyn. This may be due in part to a nonimmunological compromise in the integrity of the podocytes in the kidney, which may make the kidneys more susceptible to immune complex-induced damage. Fyn-deficient mice exhibit a number of immunological abnormalities and also exhibit some autoimmunity, although this is less severe than what is seen in Lyn-deficient mice. Recently a gain of function mutation in CD45 that may enhance activity of Src family tyrosine kinases has also been found to cause autoimmune disease, suggesting that the level of Src family tyrosine kinase activity is an important determinant of immune tolerance. Finally, several studies suggest that there is a significant interaction between Src family tyrosine kinases and the Fas pathway that is important for self-tolerance. Although these studies are still at an early stage, it seems clear that alterations in regulators of antigen receptor signaling can contribute to autoimmunity.

Animals↗
PubMed2004

Targeting the interleukin-15/interleukin-15 receptor system in inflammatory autoimmune diseases.

Interleukin (IL)-15 is a dangerous inflammatory cytokine that induces tumor-necrosis factor-alpha, IL-1beta and inflammatory chemokines. It inhibits self-tolerance mediated by IL-2 mediated activation-induced cell death and facilitates maintenance of CD8+ memory T-cell survival including that of self-directed memory cells. Disordered IL-15 expression has been reported in patients with an array of inflammatory autoimmune diseases. A series of therapeutic agents that inhibit IL-15 action have been introduced, including the soluble IL-15 receptor (IL-15R) alpha chain, mutant IL-15, and antibodies directed against the IL-15 cytokine and against the IL-2R/IL-15R beta subunit used by IL-2 and IL-15.

Animals↗
PubMed2002

Peripheral antigen-expressing cells and autoimmunity.

There is growing evidence that self-molecules with tissue-restricted expression are also expressed at low levels in the thymus, where such expression may affect the development of self-tolerance. Genetic factors may modulate such expression and, in turn, influence susceptibility to autoimmune responses against specific molecules. Contrasting reports exist regarding the phenotype of the cells that express self-molecules in the thymus. Indeed, both bone marrow derived antigen-presenting cells and thymic epithelial cells were reported to express self-molecules with tissue-restricted expression. Further studies of these cells and the mechanisms by which they exert their putative tolerogenic effects clearly are necessary.

Autoantigens↗
PubMed1995

FAS is highly expressed in the germinal center but is not required for regulation of the B-cell response to antigen.

In establishing the memory B-cell population and maintaining self-tolerance during an immune response, apoptosis mediates the removal of early, low-affinity antibody-forming cells, unselected germinal center (GC) cells, and, potentially, self-reactive B cells. To address the role of the apoptosis-signaling cell surface molecule FAS in the B-cell response to antigen, we have examined the T-cell-dependent B-cell response to the carrier-conjugated hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) in lpr mice in which the fas gene is mutated. High levels of FAS were expressed on normal GC B cells but the absence of FAS did not perturb the progressive decline in numbers of either GC B cells or extrafollicular antibody-forming cells. Furthermore, the rate of formation and eventual size of the NP-specific memory B-cell population in lpr mice were normal. The accumulation of cells with affinity-enhancing mutations and the appearance of high-affinity anti-NP IgG1 antibody in the serum were also normal in lpr mice. Thus, although high levels of FAS are expressed on GC B cells, FAS is not required for GC selection or for regulation of the major antigen-specific B-cell compartments. The results suggest that the size and composition of B-cell compartments in the humoral immune response are regulated by mechanisms that do not require FAS.

Amino Acid Sequence↗
PubMed1990

Cyclosporine-induced autoimmunity in rats carrying thymus allografts.

An autoimmune syndrome occurs in cyclosporine-treated, lethally irradiated, and marrow-reconstituted rats after cyclosporine is discontinued. This syndrome, referred to as cyclosporine-induced autoimmunity, requires the presence of a thymus. In this report, we demonstrate that the disease will occur in animals transplanted with thymus tissue from an allogeneic donor, incompatible with the recipient at the major histocompatibility complex. T cells generated from these allogeneic thymic chimeras respond in vitro to thymic donor antigens, suggesting that cyclosporine inhibits self-tolerance induction in the thymus. Because disease is more frequent when the tolerizing antigens expressed in the thymus differ from those expressed in the periphery, the possibility that cyclosporine may mediate its effect via the downregulation of self-antigen presented in the thymus is discussed.

Animals↗
PubMed2000

Induction of xenotransplant tolerance.

Clinical xenotransplantation will depend on the induction of xeno-tolerance. Conversely, xenotransplantation may offer opportunities to induce transplantation tolerance. We have previously shown that, xenotransplant tolerance for vascularized hamster organs could be achieved in athymic rats as far as the T-cell independent xeno-reactivity is concerned. This tolerance was shown to be based on specific T-independent B lymphocyte and NK cell unresponsiveness. In the present study we have shown that this T-independent xeno-tolerance can be achieved also in a semi-discordant situation using rat recipients with high titers of pre-existing anti-hamster IgM xenoantibodies. In addition, we showed that T-independent xeno-tolerance can also be induced together with T-dependent xeno-tolerance using xeno-thymus transplantation. These experiments may be of relevance for clinical xenotransplantation. The major next question to be addressed is to see how self tolerance in xeno-thymus grafted recipients can be improved as until now the latter recipients usually develop a multi-organ autoimmune syndrome, several weeks after transplanting a xeno-thymus.

Animals↗
PubMed2003

Individual differences in self-reported heat tolerance. Is there a link to the cardiocirculatory, thermoregulatory and hormonal response to endurance exercise in heat?

AIM: Tolerance to exercise in heat exhibits great interindividual variability. We questioned whether individual differences in self-reported heat tolerance within a group of endurance trained athletes are linked to the cardiocirculatory, thermoregulatory and hormonal response to endurance exercise in heat. METHODS: Using a rating scale to assess the individual degree of tolerance to exercise in heat we allocated 12 non-heat-acclimated trained runners into two groups of 5 highly heat tolerant (HHT) and 7 less heat tolerant (LHT) athletes. Both groups performed a 60-min treadmill run (velocity 90% of individual anaerobic threshold, room temperature and humidity 28 inverted exclamation mark C and 50%, respectively). RESULTS: Sweating rate did not differ between HHT (mean +/- SEM: 0.44+/-0.02) and LHT (0.40+/-0.02 ml x kg(-1) x min(-1)). Compared to LHT, exercise-induced rises in core temperature (39.3+/-0.2/40.0+/-0.2 inverted exclamation mark C), heart rate, plasma norepinephrine and cortisol were significantly lower in HHT, while epinephrine did not exhibit differences between the groups. In contrast, response of human growth hormone (hGH) was significantly more pronounced in HHT. CONCLUSION: Our initial results, obtained in a small group of endurance-trained runners, show that self-reported tolerance to exercise in heat is associated with an attenuated rise in body core temperature during prolonged exercise under elevated ambient temperatures. This finding in heat tolerant athletes is paralleled by a lower stress response as reflected by lower rises in heart rate and stress hormones such as norepinephrine and cortisol. The functional significance (i.e. with respect to sweating function) of the more pronounced response of hGH in heat tolerant athletes warrants further research.

Body Temperature↗
PubMed1989

Tolerance induction in the organ-cultured thymus lobes upon intimate contact with allogeneic thymus lobes.

In an organ-cultured murine fetus thymus, precursor cytotoxic T lymphocytes (pCTL) specific for alloantigens developed successfully but those reactive with self antigens were eliminated. In attempting to dissect the mechanism of self tolerance, intrathymic chimera was made by culturing two genetically disparate thymuses in close contact with each other (parabiosis of thymuses). This maneuver resulted in the induction of specific and mutual CTL tolerance. It seems that CTL tolerance was induced by clonal deletion but not by active suppression. Since 2'-deoxyguanosine treatment abolished the tolerogenic capability of the thymus, hemopoietic cells capable of migrating to and fro in the parabiotic thymuses are thought to be responsible for tolerance induction. Induction of CTL tolerance was dependent on the maturation stages of T cells in the thymus: T cells in 5-day-, but not in 7-day-cultured thymuses were susceptible to tolerance induction, indicating that T cells expressing T cell receptors at low density are susceptible to tolerance induction.

Age Factors↗
PubMed2001

Overexpression of glutathione S-transferase II and multidrug resistance transport proteins is associated with acquired tolerance to inorganic arsenic.

Recent work shows that long-term exposure to low levels of arsenite induces malignant transformation in a rat liver epithelial cell line. Importantly, these chronic arsenic-exposed (CAsE) cells also develop self-tolerance to acute arsenic exposure. Tolerance is accompanied by reduced cellular arsenic accumulation, suggesting a mechanistic basis for reduced arsenic sensitivity. The present study examined the role of xenobiotic export pumps in acquired arsenic tolerance. Microarray analysis of CAsE cells showed increased expression of the genes encoding for glutathione S-transferase Pi (GST-Pi), multidrug resistance-associated protein genes (MRP1/MRP2, which encode for the efflux transporter Mrp1/Mrp2) and the multidrug resistance gene (MDR1, which encodes for the efflux transporter P-glycoprotein). These findings were confirmed at the transcription level by reverse transcription-polymerase chain reaction and at the translation level by Western-blot analysis. Acquired arsenic tolerance was abolished when cells were exposed to ethacrynic acid (an inhibitor of GST-Pi), buthionine sulfoximine (a glutathione synthesis inhibitor), MK571 (a specific inhibitor for Mrps), and PSC833 (a specific inhibitor for P-glycoprotein) in dose-dependent fashions. MK571, PSC833, and buthionine sulfoximine markedly increased cellular arsenic accumulation. Consistent with a role for multidrug resistance efflux pumps in arsenic resistance, CAsE cells were found to be cross-resistant to cytotoxicity of several anticancer drugs, such as vinblastine, doxorubicin, actinomycin-D, and cisplatin, that are also substrates for Mrps and P-glycoprotein. Thus, acquired tolerance to arsenic is associated with increased expression GST-Pi, Mrp1/Mrp2 and P-glycoprotein, which function together to reduce cellular arsenic accumulation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2007

Frequency, function and CLA expression of CD4+CD25+FOXP3+ regulatory T cells in bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease associated with autoantibodies to collagen XVII and tissue-separation along the dermo-epidermal junction. We addressed the question whether the loss of tolerance in BP patients is associated with a reduction and/or functional impairment of CD4+CD25+FOXP3+ regulatory T cells, which are essential for the active maintenance of self tolerance. The relative and absolute frequency of CD4+CD25+ and CD4+CD25(high) regulatory T cells in the peripheral blood of newly diagnosed, untreated patients was similar to that of healthy controls. Interestingly, more than 50% of circulating CD4+CD25(high) regulatory T cells from both patients as well as healthy controls expressed cutaneous lymphocyte-associated antigen. Considerable numbers of FOXP3+ cells were detected in lesional skin of patients. CD4+CD25+ regulatory T cells of patients were functionally intact as assessed by their ability to suppress allogeneic as well as antigen-specific T-cell proliferation. These data argue against a general defect of CD4+CD25+FOXP3+ regulatory T cells in patients with BP.

Aged↗
PubMed2006

Regulatory T-cells: immunomodulators in health and disease.

Regulation of immune responses is crucial in order to maintain immunological self-tolerance. This is maintained in the periphery by a number of cell types that have the capacity to control and regulate immune responses, thus preventing reactivity to self while monitoring appropriate, non-exuberant responses to non-self-antigens. The various mechanisms of regulation will be discussed in this review together with how this knowledge could be used to develop better drugs and treatments for various diseases.

Animals↗
PubMed1991

Autoimmunity, microbial immunity and the immunological homunculus.

Clonal deletion and anergy are believed by many immunologists to be the fundamental mechanisms responsible for self tolerance. Nevertheless, as Irun Cohen and Douglas Young point out, such notions of nonreactivity cannot explain certain key features of immune behaviour: the immunological dominance of microbial antigens that mimic self, the uniformity of autoimmune diseases and the prevalence of natural autoimmunity among the healthy. The theory of the immunological homunculus is presented here as a unifying principle.

Animals↗
PubMedDate not supplied

CD8+ T cell tolerance and cancer immunotherapy.

To provide protection against all foreign pathogens one can possibly encounter during their lifetime, the T cell repertoire has to be as diverse as possible. At the same time, it is desirable that the T cell repertoire remains unresponsive towards healthy tissues. To realize this self/nonself discriminatory property, T cells undergo tightly controlled selection processes during maturation in the thymus. The key parameter determining the outcome of these selection processes is the avidity of the T cells for self-MHC/self-peptide complexes expressed in the thymus; low avidity interactions result in positive selection, whereas high avidity interactions lead to negative selection. Despite the selection processes, self-tolerance is far from absolute. In many cases, this is due to the presence of self-antigen in the thymus at a level that is too low to induce thymic deletion. In addition, T cells with a low avidity for ubiquitously expressed self-antigens can escape clonal deletion and enter the periphery. A thorough understanding of the self-specific T cell repertoire is important because many potential targets for cancer immunotherapy are self-proteins. In this review, the authors discuss the impact of self-antigen expression on the CD8+ T cell repertoire. An overview of the fate and functional capacities of self-specific T cells with specificity for tissue-restricted self-antigens and for ubiquitously expressed self-antigens is provided. Furthermore, the authors discuss the influence of negative selection on the antitumor reactivity of the mature T cell repertoire.

Animals↗
PubMed1992

Cross tolerance between cromakalim and RP49356 in the uterus of the rat in vivo and in vitro.

We investigated tolerance to the potassium (K+) channel openers, cromakalim and RP49356 and cross tolerance between them in the uterus of the rat. Continuous infusion of RP49356 in vivo produced 5.2-fold (200 or 300 micrograms/kg per h) and 7.2-fold (600 micrograms/kg per h) desensitization of the uterus to RP49356. Uterine sensitivity to RP49356 was reduced 7.4-fold in cromakalim-tolerant rats and sensitivity to cromakalim was reduced 7.9-fold in RP49356-tolerant rats. Incubation of isolated uterus with 10 microM cromakalim for 4 h reduced uterine sensitivity to cromakalim by about 45-fold and to RP49356 by 2.1-fold but did not alter sensitivity to salbutamol. Incubation with 10 microM RP49356 for 4 h reduced sensitivity to RP49356 by 2.5-fold and to cromakalim by 3.8-fold. Occurrence of uterine tolerance to K+ channel openers in vitro suggests that tolerance in vivo has a pharmacodynamic basis. Cross tolerance between cromakalim and RP49356 provides evidence that these two K+ channel openers possess common binding sites and/or mechanism(s) of action. However, the greater extent of self-tolerance to cromakalim than to RP49356 suggests a difference in their actions.

Animals↗