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PubMed2006

Dendritic cell apoptosis in the maintenance of immune tolerance.

Apoptosis in the immune system is critical for maintaining self-tolerance and preventing autoimmunity. Nevertheless, inhibiting apoptosis in lymphocytes is not alone sufficient to break self-tolerance, suggesting the involvement of other cell types. We investigated whether apoptosis in dendritic cells (DCs) helps regulate self-tolerance by generating transgenic mice expressing the baculoviral caspase inhibitor, p35, in DCs (DC-p35). DC-p35 mice displayed defective DC apoptosis, resulting in their accumulation and, in turn, chronic lymphocyte activation and systemic autoimmune manifestations. The observation that a defect in DC apoptosis can independently lead to autoimmunity is consistent with a central role for these cells in maintaining immune self-tolerance.

Adoptive Transfer↗
PubMed2006

Increasing donor chimerism and inducing tolerance to islet allografts by post-transplant donor lymphocyte infusion.

Inducing donor chimerism is the most consistently successful approach to achieve transplant tolerance. We found that a low level of donor chimerism, which was induced by a relatively non-toxic approach, induced donor-specific tolerance to islet allografts in chemically induced diabetic mice. However, a similar level of donor chimerism could not protect donor islet allografts in non-obese diabetic (NOD) mice that spontaneously developed autoimmune diabetes. Rejection of donor islet allografts in diabetic NOD mice with a low level of donor chimerism was mediated by recurrent autoimmunity. We used post-transplant donor lymphocyte infusion (DLI) to increase donor chimerism and to induce tolerance to islet allografts. DLI significantly increased donor chimerism and promoted donor-specific tolerance to islet allografts in diabetic NOD mice. Self-tolerance to islet autoantigens was restored and restoring self-tolerance is mediated by immunoregulation. Thus, our data showed that adoptive immunotherapy with post-transplant DLI after establishing a low level of donor chimerism as a platform enhances donor chimerism, induces donor-specific tolerance to islet allografts and restores self-tolerance in the setting of autoimmune diabetes. Our data also showed that central tolerance is not sufficient to induce tolerance and peripheral tolerance through immunoregulation for restoring self-tolerance is required in the setting of autoimmune diabetes.

Adoptive Transfer↗
PubMed1999

The role of apoptosis in autoimmunity: immunogen, antigen, and accelerant.

The immunologic basis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) is complex and multifaceted. Recent advances in the field of apoptosis have suggested new paradigms for the development of autoimmunity. This review examines the role that apoptosis plays in maintaining immunologic tolerance to self-antigens, and how abnormalities in the regulation of apoptosis can lead to a breakdown in self-tolerance. This article also examines the increasing recognition of apoptotic cell antigens as the targets of autoantibodies and discusses the possibility that the autoimmune response characteristic of SLE is specifically directed against apoptotic cells. In addition, we will describe some of the features that distinguish nonpathogenic anti-DNA autoantibodies from those which deposit in the kidney and lead to lupus nephritis. Finally, we will attempt to synthesize the vast body of data connecting apoptosis and SLE into a single hypothesis in which we suggest that apoptotic cells are a primary source of immunogen, and that abnormalities in the handling of apoptotic cells can lead to a breakdown in self-tolerance.

Animals↗
PubMed2000

B cell tolerance and autoimmunity.

Self-tolerance is induced in B cells at various maturational stages by diverse self-antigens B cell tolerance involves multiple mechanisms, ie. clonal deletion, clonal anergy, receptor editing and maturation arrest. The mechanism utilized for self-tolerance depends on both the maturational stage of B cells and the molecular nature of the self-antigens. B cell tolerance is abrogated by various mechanisms such as defects in inhibitory co-receptors, overexpression of CD19, T cell help and defects in the death receptor Fas (CD95). Since all of these molecules regulate B cell apoptosis mediated by either the antigen receptor or Fas, B cell apoptosis may play a role in the induction and maintenance of B cell tolerance. Moreover, environmental factors such as intestinal lipopolysaccharide also play a role in the breakdown of B cell tolerance.

Animals↗
PubMed2002

Implications of CD94 deficiency and monoallelic NKG2A expression for natural killer cell development and repertoire formation.

Natural killer (NK) cells are believed to achieve self-tolerance through the expression of self-MHC-specific inhibitory receptors, such as members of the Ly49 and CD94/NKG2 families. Individual Ly49 genes are stochastically expressed by NK subsets and are expressed in a monoallelic fashion, but little is known about the mechanisms underlying CD94/NKG2A expression. We show here that, like Ly49 genes, mouse Nkg2a is stochastically and monoallelically expressed. Thus, a single general mechanism controls expression of all known MHC-specific receptors by mouse NK cells. In addition, we find that DBA/2J mice are naturally CD94-deficient and do not express cell-surface CD94/NKG2A receptors, even on neonatal NK cells. Thus, self-tolerance of neonatal NK cells cannot be attributed to CD94/NKG2A expression. Taken together, the results lead to a reconsideration of current models of NK cell development and self-tolerance.

Alleles↗
PubMedDate not supplied

Identity of cells that imprint H-2-restricted T-cell specificity in the thymus.

The thymus has two important roles in controlling the specificity of T lymphocytes. First, T cells differentiating in the thymus are rendered tolerant of 'self' antigens, particularly antigens encoded by the major histocompatibility complex, the H-2 complex in mice. Second, the thymus imbues T cells with the property of H-2-restricted recognition of antigen, that is, the capacity of T cells to react with foreign antigens presented in association with self H-2 gene products. Until recently it has generally been assumed that self-tolerance and H-2-restricted specificity both reflect early T-cell contact with self H-2 determinants expressed on thymic epithelial cells. Recent evidence suggests, however, that intrathymic cells of the macrophage/dendritic cell (Mphi/DC) lineage also have a role in shaping T-cell specificity. In particular, it has been found that the tolerance to graft-type H-2 determinants which normally ensues when T cells differentiate in an H-2-different thymus fails to occur when the thymus is pretreated with deoxyguanosine (dGuo), a procedure that selectively destroys Mphi/DC but spares epithelial cells. In contrast to these findings on tolerance induction, evidence is presented here that dGuo-treated thymus grafts do imprint T cells with H--2-restricted specificity for antigen. It appears, therefore, that induction of tolerance and H--2 restriction are controlled by different cells in the thymus.

Animals↗
PubMed2006

Germs, hosts, and the origin of Frank Macfarlane Burnet's concept of "self " and "tolerance," 1936-1949.

In the early twentieth century, the living organism's ability to distinguish its "self" from foreign entities such as bacteria, viruses, transplanted tissue, or transfused blood was a major problem in medical science. This article discusses how the Australian immunologist Frank Macfarlane Burnet arrived at a satisfactory explanation of this problem through his 1949 theory of "self" and "tolerance." Burnet's theoretical work began from his study of diverse factors affecting the conditions of the host and the germ for the occurrence of infectious diseases. Among them, the host's age came to receive his attention as a crucial factor. This understanding was facilitated by his acceptance of cytoplasm inheritance theories, which emphasized the importance of the embryonic host's changing conditions according to its age. Based on this idea, he claimed in 1949 that the "self" of the organism was defined during its embryogenesis. Peter B. Medawar and his colleagues' demonstration of Burnet's claim became the basis for awarding Burnet and Medawar the Nobel Prize in Physiology and Medicine in 1960. While previous histories have focused on Burnet's "inductive reasoning" or "ecological perspective" to explain his conception of the theory of "self" and "tolerance," this article finds the origin of his ideas within an important line of modern medical research engendered through the development of germ theories--the studies of the host body and its relationship with parasites.

Allergy and Immunology↗
PubMed1995

Self-reactive T cell hybridomas and tolerance. Same range of antigen dose dependence but higher numbers of self-reactive T cell hybridomas from mice in which self-tolerance has been broken by antiserum treatment.

Mechanisms of self-tolerance of 4-hydroxyphenylpyruvate dioxygenase (HPPD) are explored. It is well established that negative selection based on TCR affinity occurs in the thymus. We have investigated the frequency with which self-reactive T cell hybridomas can be obtained in relation to self-tolerance. Mice immunized with the self-form of HPPD gave rise to T cell hybridomas that were able to recognize self-protein and a synthetic peptide representing the T cell epitope, at higher Ag concentration than was necessary for recognition of allo-protein. The efficiency of negative selection was then reduced by treating neonatal mice with anti-HPPD antiserum. This reduced T cell tolerance of the self-protein, as judged by in vitro proliferation, and enabled self-reactive T cell hybridomas to be generated at a higher frequency. However, the Ag concentration requirements of these hybridomas for the self-protein and the self-peptide remained unaltered. The possibility that these findings reflect an auxiliary mechanism of self-tolerance based on frequencies of self-reactive T cells is discussed.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed2004

Long-distance pollen flow and tolerance to selfing in a neotropical tree species.

Outcrossing rates, pollen dispersal and male mating success were assessed in Dicorynia guianensis Amshoff, a neotropical tree endemic to the Guiana shield. All adult trees within a continuous area of 40 ha (n = 157) were mapped, and were genotyped with six microsatellite loci. In addition, progenies were genotyped from 22 mature trees. At the population level, the species was mostly outcrossing (tm = 0.89) but there was marked variation among individuals. One tree exhibited mixed mating, confirming earlier results obtained with isozymes that D. guianensis can tolerate selfing. A Bayesian extension of the fractional paternity method was used for paternity analysis, and was compared with the neighbourhood method used widely for forest trees. Both methods indicated that pollen dispersal was only weakly related to distance between trees within the study area, and that the majority (62%) of pollen came from outside the study stand. Using maximum likelihood, male potential population size was estimated to be 1119, corresponding to a neighbourhood size of 560 hectares. Male mating success was, however, related to the diameter of the stem and to flowering intensity assessed visually. The mating behaviour of D. guianensis is a combination of long-distance pollen flow and occasional selfing. The species can still reproduce when it is extremely rare, either by selfing or by dispersing pollen at long distances. These results, together with the observation that male mating success was correlated with the size of the trees, could be implemented in management procedures aiming at regenerating the species.

Bayes Theorem↗
PubMed1991

Control of self-reactivity in the intestine.

In the intestine maintenance of self-tolerance may involve tissue-specific self-Ags, APCs, 'second signals', and extrathymic pathways of T cell maturation. These factors combine to create a unique environment where autoimmune tissue destruction is prevented despite local inflammatory influences. In this review we summarize our findings using a TCR-gamma delta transgenic model where self-tolerance was maintained by clonal deletion for cells localizing to peripheral lymphoid tissue and by clonal anergy for cells localizing to the intraepithelial compartments. Several possible explanations exist for these results but in general, these findings have implications for the maintenance of self-tolerance of normal TCR-alpha beta and TCR-gamma delta IELs in epithelial tissues such as the intestine.

Animals↗
PubMed2002

Tolerance to self gangliosides is the major factor restricting the antibody response to lipopolysaccharide core oligosaccharides in Campylobacter jejuni strains associated with Guillain-Barré syndrome.

Guillain-Barré syndrome following Campylobacter jejuni infection is frequently associated with anti-ganglioside autoantibodies mediated by molecular mimicry with ganglioside-like oligosaccharides on bacterial lipopolysaccharide (LPS). The regulation of antibody responses to these T-cell-independent antigens is poorly understood, and only a minority of Campylobacter-infected individuals develop anti-ganglioside antibodies. This study investigates the response to gangliosides and LPS in strains of mice by using a range of immunization strategies. In normal mice following intraperitoneal immunization, antibody responses to gangliosides and LPS are low level but can be enhanced by the antigen format or coadministration of protein to recruit T-cell help. Class switching from the predominant immunoglobulin M (IgM) response to IgG3 occurs at low levels, suggesting B1-cell involvement. Systemic immunization results in poor responses. In GalNAc transferase knockout mice that lack all complex gangliosides and instead express high levels of GM3 and GD3, generation of anti-ganglioside antibodies upon immunization with either complex gangliosides or ganglioside-mimicking LPS is greatly enhanced and exhibits class switching to T-cell-dependent IgG isotypes and immunological memory, indicating that tolerance to self gangliosides is a major regulatory factor. Responses to GD3 are suppressed in knockout mice compared with wild-type mice, in which responses to GD3 are induced specifically by GD3 and as a result of polyclonal B-cell activation by LPS. The anti-ganglioside response generated in response to LPS is also dependent on the epitope density of the ganglioside mimicked and can be further manipulated by providing secondary signals via lipid A and CD40 ligation.

Animals↗
PubMed2004

The role and mechanisms of double negative regulatory T cells in the suppression of immune responses.

Accumulating evidence has demonstrated that regulatory T (Treg) cells play an important role in the maintenance of immunologic self-tolerance and in down-regulating various immune responses. Thus, there has recently been an increasing interest in studying the biology of Treg cells as well as their potential application in treating immune diseases. Many types of Treg cell subsets have been reported in a variety of disease models. Among these subsets, alpha beta TCR(+)CD3(+)CD4(-)CD8(-) double negative (DN) Treg cells are defined by their capability of inhibiting immune responses via directly killing effector T cells in an antigen specific fashion. Furthermore, DN Treg cells have been shown to develop regulatory activity after encountering specific antigens, partially mediated by the acquisition of MHC-peptide complexes from antigen presenting cells (APCs). The presentation of acquired alloantigens on DN T cells allows for the specific interaction between DN Treg cells and alloantigen reactive effector T cells. Once the DN Treg and target cells have come into contact, killing is then mediated by Fas/Fas-ligand interactions, and perhaps through other unidentified pathways. Further characterization of the functions, molecular expression and mechanisms of activation of DN Treg cells will help in the development of novel therapies to induce antigen specific tolerance to self and foreign antigens.

Animals↗
PubMed1989

Elimination of self-tolerogen turns nonresponder mice into responders.

Two sets of genes control the immune response of H-2d mice to the synthetic antigen poly(Glu50Tyr50) (GT). One set involves class II major histocompatibility complex (Mhc) loci encoding an Ad product that serves as a recognition context to GT-reactive helper T cells (Th). The other one is a background gene, the product of which, in association with the same Mhc-restricting element, mimics the GT/Ad complex. Mice expressing the GT-mimicking background-encoded structure (Imgt), which is preferentially displayed on B lymphoblasts, do not respond to GT as a consequence of self-tolerance. On the other hand, elimination of cells bearing Imgt renders these mice responsive to GT, demonstrating that tolerance to self can impoverish the immune system. Imgt is probably not identical to GT, but resembles it in the way it forms complexes with Ad molecules of Mhc.

Animals↗
PubMed1994

T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in thymus.

Transgenic mice expressing T antigen (Tag) in pancreatic beta cells establish systemic tolerance toward this self-protein. The self-tolerance in two families of rat insulin promoter (RIP)-Tag mice, expressing different levels of Tag protein, has been characterized. These mice have impaired antibody responses to Tag, show diminished Tag-specific T-cell proliferation, and evidence an inability to generate Tag-specific cytotoxic T cells. The existence of systemic tolerance toward a beta-cell-specific protein motivated examination of transgene expression in the thymus. Indeed, low levels of Tag mRNA were detected intrathymically. Remarkably, this expression is a valid property of the insulin gene regulatory region, since insulin RNA was also expressed in the thymus of nontransgenic mice. RNA for other pancreatic genes was also detected in the thymus, thus raising the possibility that many tissue-specific genes could be expressed intrathymically during immunological development and induction of self-tolerance. These results raise important questions for future research into the role of the thymus in tolerance induction toward so-called tissue-specific antigens.

Animals↗
PubMed1989

T cell tolerance to self antigens in New Zealand hybrid mice with lupus-like disease.

We determined if self-reactive T cells are able to escape thymic tolerance in autoimmune New Zealand mice. T cells utilizing V beta 17a and V beta 11 encoded receptors have been shown to be clonally eliminated in nonautoimmune mice expressing I-E because of their potential self-reactivity. Similarly, V beta 8.1+ and V beta 6+ T cells are tolerized in the thymus of nonautoimmune mice that express Mls-1a. These T cell subsets were quantitated in the lymph nodes and spleens of (NZB x NZW)F1 and (NZB x SWR)F1 mice. In young mice from both autoimmune strains, deletion was similar to that observed in control animals matched for I-Ed and Mls-1a expression. Furthermore, older female autoimmune mice with elevated levels of IgG antinuclear antibodies and severe lupus-like renal disease did not demonstrate evidence of a global tolerance defect. We also found that the levels of residual V beta 17a+ cells in MHC-matched control F1 strains were further reduced by up to 80% in autoimmune (NZB x SWR)F1 mice. The greater in vivo elimination corresponded to an enhanced ability of NZB spleen cells, compared with other H-2d spleen cells, to stimulate V beta 17a+ hybridomas in vitro. The increased stimulation in culture could not be attributed to quantitative differences in I-E Ag expression. The results suggest that autoreactive T cells have been eliminated in these autoimmune mice by normal mechanisms of self-tolerance. Furthermore, the data demonstrate the existence of an NZB minor locus not present in other H-2d strains that influences T cell repertoire and enhances stimulation of T cells potentially reactive to self class II MHC Ag.

Animals↗
PubMed1992

In vivo administration of interleukin-2 turns on anergic self-reactive T cells and leads to autoimmune disease.

One major mechanism of self tolerance involves the deletion of T cell clones in the thymus. In athymic mice, tolerance to self antigens must be generated extrathymically. T cells with self-reactive receptors undergo either peripheral clonal deletion or become unresponsive (i.e. anergic). The unresponsive state of human and mouse T cell clones in vitro can be reversed by the addition of exogenous interleukin (IL)-2, thus transforming anergic T cells to an activated state. Here it is shown that the in vivo delivery of IL-2 to athymic BALB/c nu/nu mice abrogates the anergic state of self-reactive V beta 3+ and V beta 11+ T cells [which are normally deleted in the minor lymphocyte stimulatory (Mls)-1b-, I-E(+)-expressing euthymic counterparts]. Thus, V beta 3+ and V beta 11+ T cells from IL-2-treated nude mice proliferate in response to T cell receptor cross-linking and acquire effector functions as measured by their ability to deliver aid to B cells upon specific stimulation. This activation correlates with the development of autoimmune manifestations (DNA autoantibodies, rheumatoid factors, erythroleukopenia and minimal change nephritis) in these IL-2-treated mice.

Animals↗
PubMed1976

Immunosuppression by fetal liver as a model for tolerance to self.

The embryonic liver chimera system was used as a model to study the development of tolerance to self antigens. It was found that the permanent tolerant state which was induced in (C3H/eb x C57BL/6)F1 irradiated hosts following reconstitution with parental C57BL liver cells could be due to the development of suppressor cells within the liver cell inoculum, which specifically prevent reactivity of immunocompetent cells. General suppressor activity could be found in embryonic liver cells at early stages of gestation. However, the differentiation of such cells into specific suppressor of "self" antigens is dependent on the presence of the thymus.

Animals↗