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PubMed1985

Recessive T cell response to poly (Glu50Tyr50) possibly caused by self tolerance.

The proliferative T cell response of inbred mouse strains to the random copolymer poly(Glu50Tyr50) (GT) was found to fall into two categories. Some strains responded only marginally (delta cpm values less than 10,000 and stimulation indices less than 3), whereas other strains mounted a substantial response (delta cpm 10,000 to 80,000, SI 3 to 30). The response is controlled by the A alpha and A beta loci of the major histocompatibility complex (MHC), as well as by genes not linked to the MHC. Because the response is selectively inhibited by monoclonal antibodies specific for the A alpha A beta molecule, we assume that its control by A loci is manifested as an A-restriction of the participating T (Ly-1high, Ly-2-) cells. It is of interest that the responsiveness is recessive in F1 hybrids of responder and nonresponder strains that are H-2-identical, but differ at their genetic background. Nonresponsiveness of these F1 mice is caused neither by a defect of antigen presentation, nor the result of immune suppression on priming or at the effector phase of the response. It is most likely the consequence of clonal deletion during the establishment of self-tolerance.

Animals↗
PubMed1990

Thymus: a direct target tissue in graft-versus-host reaction after allogeneic bone marrow transplantation that results in abrogation of induction of self-tolerance.

Graft-versus-host reaction (GVHR) following allogeneic bone marrow (BM) transplantation was investigated by analyzing expression of antigen receptors on T cells specific for recipient antigens. GVHR chimeras were prepared by transplanting mixtures of splenic T cells and T-cell-depleted BM cells from B10 (I-E-, Mls-1b) or B10.AQR (I-E+, Mls-1b) mice into lethally irradiated AKR/J (I-E+, Mls-1a) recipients. Increased proportions of V beta 6+ T cells reactive to recipient antigens (I-E and Mls-1a) were observed in thymuses from such chimeras 1 or 5 wk after BM transplantation. V beta 6+ T cells observed 1 wk after BM transplantation were derived from mature T cells that had been inoculated into recipients. These cells responded to recipient antigens expressed in the thymus. After 5 wk, thymocytes brightly positive for V beta 6+ were shown not to descend from mature T cells but to differentiate from precursor cells present in the BM inocula. Since V beta 6+ T cells were eliminated in thymuses from non-GVHR chimeras 5 wk after BM transplantation using T-cell-depleted BM cells alone, it appears that GVHR occurring in the thymus at an early stage abrogates thymic stromal functions essential to induction of self-tolerance in the T-cell repertoire. These findings propose a mechanism (autoimmunity) to explain in part the pathogenesis of chronic GVHR.

Animals↗
PubMed1994

Spontaneous reestablishment of self-tolerance in BB/Pfd rats.

We describe a substrain of BB rats, BB/Pfd, characterized by a loss of autoimmune potential soon after onset of diabetes. When fresh syngeneic (BB/Pfd) islets (6 islets/g body weight) were transplanted under the kidney capsule of diabetic BB/Pfd rats 1-2 weeks after diabetes onset (n = 14), no recurrence of diabetes occurred. When, however, islets were transplanted on the day of diabetes diagnosis (n = 16), 10 animals were able to destroy the transplant (P < 0.005 vs. previous group). Pancreatic biopsies taken at the moment of transplantation in both groups showed an almost complete disappearance of beta cells and also insulitis in the pancreata of the 1- to 2-week diabetic rats, while the acutely diabetic rats still conserved a certain amount of beta cells and a florid insulitis. The development of a general immune defect was not the cause of this nonrecurrence, since allogeneic islet grafts were easily rejected (7 of 8), nor was there a general defect in mounting immune memory, since second set skin grafts could be rejected in an accelerated manner (9.7 vs. 15.8 days). The development of suppressor mechanisms as cause for nonrecurrence could not be demonstrated, since transfer of lymphocytes taken from 1- to 2-week diabetic rats into acutely diabetic rats at the moment of syngeneic islet transplantation was unable to prevent recurrence of disease (6 recurrences in 10 animals). We conclude that in the BB/Pfd substrain, the autoimmune capacity wanes rapidly after the onset of diabetes. This loss of autoimmune potential is parallelled by a disappearance of insulitis in the native pancreas, but the exact mechanisms of the spontaneous reestablishment of self-tolerance remain unclear.

Animals↗
PubMed2001

Regulation by phagic T-lymphocytes of a (pluripotent?) organ stem cell present in adult human blood. A beneficial exception to self-tolerance.

Stem cells isolated from adult human blood are able to give rise to several different kinds of cell types such as mesenchymal cells, including striated muscle cells, hepatocytes, and endothelial-cells. Because independently studied by authors whose interests focused on particular tissue types, these stem cells have been described as different. However, they might well represent one unique population of pluripotent stem cells in homeostatic equilibrium with the 'reserve' stem cells buried in organs. In the blood, these stem cells have a monocytic phenotype. In in vitro culture, once they have adhered, they spontaneously differentiate into diverse types of cells reminiscent of embryonic stem cells in culture. Normally, they are almost quiescent cells. But under precise circumstances such as wound-healing, they may proliferate and migrate to the right organ to give rise there to the right type of cells, in order to participate in the repair process. Indeed, such a powerful stem cell needs to be tightly controlled. We illustrate here, by time-lapse videocinematography, how a special subpopulation of T-lymphocytes, for which we coined the name 'phagic T-lymphocytes' (PTLs), destroys these stem cells as soon as they differentiate in vitro, i.e., without the purpose of a repair. These stem cells express constitutively HLA-DR molecules and therefore can act as antigen-presenting cells able to activate phagic T-lymphocytes. The targets of these activated phagic T-lymphocytes are the differentiated stem cell themselves. Phagic T-lymphocytes are attracted by the stem cells, circulate around them, then penetrate and circulate inside them until the latter 'explode'. This mechanism of destruction by phagic T-lymphocytes is unique and seems to be normally restricted to stem cells. It represents a beneficial exception in self-tolerance since it avoids the accumulation of these stem cells out of healing purposes. Interestingly, in disorders such as fibrosis and/or some malignant proliferations, these stem cells proliferate, escape destruction by phagic T-lymphocytes and, as a consequence, accumulate, giving rise to a 'tissue' when cultured in vitro.

Adult↗
PubMed2003

Reduced thymic expression of islet antigen contributes to loss of self-tolerance.

Type 1 diabetes (T1DM) results from a failure of central and peripheral tolerance to islet cell antigens. ICA69 belongs to a group of molecules expressed predominantly in neuroendocrine tissues (including pancreatic islets), which are targets of autoimmune responses in T1DM. These molecules are also expressed in the thymus and peripheral lymphoid organs by dendritic cells. The aim of the present study was to evaluate possible variation in thymic ICA69 expression, comparing diabetes-resistant controls to T1DM-prone NOD mice. Thymic tissue was retrieved from 3- to 6-week-old female B6, NOD-H2(b), and NOD mice. Paraffin-embedded sections were stained with an ICA69-specific antibody in an immunoperoxidase assay. ICA69 staining of thymic sections from B6 and NOD.H2(b) showed strong and continual staining, yet the sections from the NOD mice showed significantly reduced staining for ICA69. Corroboration of the reduced level of ICA69 in the thymus of NOD mice has been obtained via analysis for the expression of ICA69 versus other candidate autoantigens (glutamic acid decarboxylase 65, glutamic acid decarboxylase 67, and insulin 2) in the thymus. Real-time PCR analysis, using cDNA generated from the thymus, displayed that the expression of GAD65, GAD67, and INS2 were equivalent when comparing NOD at any age to B6, BALB/cJ, and ALR/LtJ. In marked contrast, the level of ICA69 in the thymus of the NOD mice examined was significantly reduced when compared to the controls. In fact, the real-time PCR analysis strongly suggested that ICA69 was not expressed in the thymus of NOD mice. These findings support the hypothesis that the level of thymic ICA69 expression may be of importance in regulating self-tolerance in T1DM.

Animals↗
PubMed1990

A peripheral mechanism preserves self-tolerance to a secreted protein in transgenic mice.

We have examined mechanisms of tolerance to circulating self-proteins in mice that are transgenic for human insulin. Normal, nontransgenic mice develop serum antibody responses when injected with human insulin in CFA; syngeneic transgenic mice do not. B cell responsiveness was assessed by immunizing with human insulin coupled to a T-independent Ag, Brucella abortus. No differences were found in the numbers of insulin-specific splenic plaque-forming cells between transgenic and nontransgenic mice suggesting that insulin-specific B cells are not tolerant in transgenic mice. Similarly, APC from transgenic and nontransgenic mice display no differences in their ability to process and present human insulin to human insulin-specific T cells in vitro. However, marked differences were detected between transgenic and nontransgenic T cells. Lymph node T cells from transgenic mice primed with human insulin provided no detectable helper activity for secondary antibody responses to human insulin whereas, lymph node T cells from nontransgenic mice did. Nevertheless, lymph node T cells from transgenic mice developed significant proliferative responses to human insulin. Lymph node T cells obtained from transgenic and nontransgenic mice were fused to BW5147 and human insulin-specific T cell hybridomas were generated. The fact that human insulin-specific T cell hybridomas were obtained from the transgenic mice suggests that these T cells were not clonally deleted. In addition, APC from transgenic mice did not stimulate human insulin-specific hybridomas from normal mice in the absence of exogenous insulin. We suggest that T cells specific for human insulin are not deleted in the thymus of transgenic mice because APC in the thymus do not bear the requisite levels of endogenous human insulin/Ia complexes. Therefore, we conclude that tolerance in the transgenic mice is preserved by peripheral mechanisms.

Animals↗
PubMed1989

Induction of self-tolerance in mature peripheral B lymphocytes.

In transgenic mice, mature peripheral B lymphocytes in lymphoid follicles, like immature B cells, are rendered tolerant by encounter with self-antigen, provided receptor occupancy by self-antigen exceeds a critical threshold. The tolerant state of the B cell is closely correlated with down-regulation of membrane IgM but not IgD antigen-receptors. Identical changes in antigen-receptor expression occur in a subset of follicular B cells in nontransgenic mice, suggesting that clonally silenced self-reactive cells are common in the peripheral B-cell repertoire.

Animals↗
PubMed1981

Microbial parasitism cross-reactive with host antigen: implications concerning loss of "self" tolerance and development of autoimmune disease.

The implications of inserting eukaryotic genetic material coding for human "self" antigens into prokaryotic microbe vectors that parasitize humans are discussed against the background of contemporary concepts of immunologic tolerance to "self" constituents and the types of host autoreactive immune responses that might occur. The injurious potential of autoreactive immune responses elicited by infecting microbes which share antigenic constituents with host "self" antigens is carefully weighed. The risk of similar cross-reacting microbial vectors arising as a consequence of ongoing recombinant DNA technology and experimentation and posing public health concerns for humans is examined. On balance, the risk would appear to be extraordinarily low.

Antigens↗
PubMed2005

A new self: MHC-class-I-independent natural-killer-cell self-tolerance.

A fundamental tenet of the immune system is the requirement for lymphocytes to respond to transformed or infected cells while remaining tolerant of normal cells. Natural killer (NK) cells discriminate between self and non-self by monitoring the expression of MHC class I molecules. According to the 'missing-self' hypothesis, cells that express self-MHC class I molecules are protected from NK cells, but those that lack this self-marker are eliminated by NK cells. Recent work has revealed that there is another system of NK-cell inhibition, which is independent of MHC class I molecules. Newly discovered NK-cell inhibitory receptors that have non-MHC-molecule ligands broaden the definition of self as seen by NK cells.

Animals↗
PubMed2005

In vivo assessment of the relative contributions of deletion, anergy, and editing to B cell self-tolerance.

In normal B cell development, a large percentage of newly formed cells bear receptors with high levels of self-reactivity that must be tolerized before entry into the mature B cell pool. We followed the fate of self-reactive B cells expressing high affinity anti-hen egg lysozyme (HEL) Ag receptors exposed in vivo to membrane HEL in a setting in which the anti-HEL L chain was "knocked-in" at the endogenous L chain locus. These mice demonstrated extensive and efficient L chain receptor editing responses and had B cell numbers comparable to those found in animals lacking membrane Ag. BrdU labeling indicated that the time required for editing in response to membrane HEL was approximately 6 h. In mice transgenic for soluble HEL, anti-HEL B cells capable of editing showed evidence for both editing and anergy. These data identify receptor editing as a major physiologic mechanism by which highly self-reactive B cells are tolerized to membrane and soluble self-Ags.

Animals↗
PubMed2006

Involvement of NFAT1 in B cell self-tolerance.

B cells from anti-lysozyme Ig/soluble lysozyme double-transgenic mice are chronically exposed to self-Ag in the periphery, resulting in an anergic phenotype. Chronic exposure to self-Ag leads to nuclear translocation of NFAT1 and NFAT2, suggesting that they are involved in anergy. To directly test a role for NFAT1 in B cell anergy, NFAT1-deficient mice were crossed with anti-lysozyme Ig transgenic mice. As expected, B cell anergy was evident in the presence of self-Ag based on reduced serum anti-lysozyme levels, percentage and number of mature B cells, and reduced B cell responsiveness. By contrast, B cell anergy was relieved in NFAT1(-/-) mice expressing soluble self-Ag. Bone marrow development was equivalent in NFAT1-sufficient and -deficient mice, suggesting that loss of anergy in the latter is due to selection later in development. Taken together, these studies provide direct evidence that the transcription factor NFAT1 is involved in B cell anergy.

Animals↗
PubMed1998

Homeostasis and self-tolerance in the immune system: turning lymphocytes off.

The immune system responds in a regulated fashion to microbes and eliminates them, but it does not respond to self-antigens. Several regulatory mechanisms function to terminate responses to foreign antigens, returning the immune system to a basal state after the antigen has been cleared, and to maintain unresponsiveness, or tolerance, to self-antigens. Here, recent advances in understanding of the molecular bases and physiologic roles of the mechanisms of immune homeostasis are examined.

Animals↗
PubMed2006

Induction and maintenance of self tolerance: the role of CD4+CD25+ regulatory T cells.

The immune system responds vigorously to invading pathogens (non-self, foreign), while remaining unresponsive (tolerant) to the body's own components and circulating constituents (self). This indifference to self components is a result of finely orchestrated events of thymic negative selection (central tolerance) of developing T cells that are autoaggressive combined with those operative in the periphery (peripheral tolerance) to control the activity of potentially autoreactive T cells that escaped thymic tolerance. Recently, autoimmune regulator expressed in the thymus has been identified as a critical mediator of central tolerance towards tissue-specific antigens. In the periphery, a variety of regulatory T cells are involved in effecting tolerance. There is immense interest and excitement about the newly identified subset of CD4(+)CD25(+) T cells. This is a unique subset of CD4(+) T cells that bear CD25 (IL-2Ralpha chain) on the cell surface in the naïve state and express FoxP3 as a unique marker. These cells suppress the activity of autoreactive effector T cells primarily via cell-cell contact. The deficiency and/or altered function of CD4(+)CD25(+) T cells is associated with autoimmunity. Mice deficient in FoxP3 (scurfy mice) bear an autoimmune phenotype, and human males with mutations in the corresponding gene express the phenotype of wide-spread autoimmunity, the immune dysregulation, polyendocrinopathy and enteropathy, and X-linked syndrome. In vitro expansion of antigen-specific CD4(+)CD25(+) T cells and their adoptive transfer into patients suffering from autoimmunity is emerging as a promising new therapeutic approach for these debilitating disorders.

Animals↗
PubMed1993

Tolerance to self and the processing and presentation of self antigens.

Antigen processing and presentation is critical to the generation and maintenance of self tolerance. The hemoglobin system has provided important data on self antigen processing and presentation in vivo. Hemoglobin/Ia complexes were detectable in the thymus before the time of positive and negative selection. In addition, thymic epithelial cells were shown to lack the costimulatory factors necessary to trigger T cell clone proliferation. We have extended these findings to the renal proximal tubule. This class II MHC-expressing epithelial cell was demonstrated to process and present foreign as well as self antigens to T cell hybridomas. Current studies are examining whether this epithelial cell possesses the costimulatory factors required to fully stimulate T cell clones, or whether the proximal tubule may play an important role in the maintenance of self tolerance. In addition we describe the exciting model of murine autoimmune myocarditis. We have demonstrated that this is a T cell mediated disease and believe that cardiac antigen presenting cells constitutively process and present the inciting self antigen, myosin. These studies may provide important insights into autoimmunity and self tolerance.

Animals↗