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PubMedDate not supplied

Cell mediated immune regulation in autoimmunity.

Autoimmunity is the term for the immune conditions characterized by a specific humoral or cell mediated response to the body's own tissues. The termination of the natural state of self tolerance may lead to immunopathological manifestations with clinical consequences, i.e. autoimmune diseases. In a very general sense, one may classify autoimmune diseases into two groups with respect to the underlying mechanism: 1. There are autoimmune diseases which develop in the presence of a normal intact regulation mechanism. 2. Another group whose development must be understood on the basis of a cellular dysfunction. In the first case, dequestered or semi-sequestered autoantigens are liberated as a consequence of exogenic influences inducing the sensitization of immunocompetent cells. The immune system then reacts with these autoantigens in the same way as with foreign substances. This kind of autoimmune disease will, however, not be dealt with here. In the second case, autoantigens are normally, i.e. in healthy individuals, accessible to the immunocompetent cells. To understand the reason for the development of an autoimmune reaction one must first clarify the mechanism of self tolerance. Then one must examine the way in which a break of this physiological state takes place. One of the major unanswered questions is the relative importance of antibody-mediated and cell-mediated immune mechanisms in the onset and further development of autoimmune diseases. Recently it has been suggested that a dysfunction at the cellular level might represent the basic cause which induces the termination of selftolerance. Most of the conceptions about the mechanism by which autoimmune diseases are triggered were gained through experiments with animals. It is, however, difficult to use these experimental results to explain human diseases; in humans many questions are still open. Undoubtedly, the mechanisms of induction and maintenance of self tolerance and also the ways in which autoimmune diseases may be induced, are not uniform. In all these cases, cells and cellular interactions as well as the corresponding cellular products are decisive. The majority of autoimmune diseases are mediated by antibodies as can be demonstrated in transfer experiments, for instance. Experimental Autoimmune Thyroiditis (EAT), rather than by sensitized cells. An example of the latter would be Experimental Autoimmune Encephalitis (EAE). In principle the following can be said of all these kinds of autoimmune diseases as well as of selftolerance: 1. Induction of autoantibodies is in principle possible. 2. Self antigens important in autoimmune diseases are T-dependent. 3. Self-reacting lymphocytes (T- and/or B-cells) are present in "normal" individuals.

Antibody Formation↗
PubMed1992

Absence of T cell tolerance to pancreatic islet cells.

To examine whether the lack of self-tolerance to beta cells is responsible for the development of type I diabetes in nonobese diabetic (NOD) mice, we attempted to induce T cell responses to cells from the islets of Langerhans. The data show that all NOD mice, irrespective of age, sex, and disease progression, possess islet cell-specific CD4+, MHC class II-restricted T cells. Both primary and secondary proliferative responses to islet cells were readily induced. The activation of T cells required presentation of islet cell Ag by APC in the responding lymph node cell population. Cells from other tissues, e.g., salivary gland, adrenal gland, and spleen, failed to activate autologous T lymphocytes. T cells specific for other Ag did not respond to islet cells, indicating that the proliferation is not the result of nonspecific stimulation by islet cell products. The presence of islet cell-reactive T cells is, however, not unique to NOD mice, because similar T cell reactivity was also demonstrated in non-diabetes-prone mouse strains. Hence, self-tolerance to islet cells appears to be absent. The results indicate a normal occurrence of islet cell-reactive T cells in both diabetes-prone as well as non-diabetes-prone mice. Thus, the lack of tolerance cannot be the initial cause of diabetes, but the activation of such autoreactive T cells may be important for the development of the disease.

Animals↗
PubMed2006

Autoimmunity: basic mechanisms and implications in endocrine diseases. Part II.

Regulation of the immune response to self-antigens is a complex process that involves maintaining self-tolerance while preserving the capacity to exert an effective immune response. The primary mechanism that leads to self-tolerance is central tolerance. However, potential pathogenic autoreactive lymphocytes are normally present in the periphery of all individuals. This suggests the existence of mechanisms of peripheral tolerance that prevent the initiation of autoimmune diseases by limiting the activation of autoreactive lymphocytes. If these mechanisms of peripheral tolerance are impaired, the autoreactive lymphocytes may be activated and autoimmune diseases can develop. Several processes are involved in the maintenance of peripheral tolerance: the active suppression mediated by regulatory T cell populations, the different maturation state of antigen-presenting cells presenting the autoantigen to autoreactive lymphocytes, inducing tolerance instead of cell activation, the characteristics of B cell populations. A deeper comprehension of these mechanisms may lead to important therapeutic applications, such as the development of cellular vaccines for organ-specific autoimmune diseases. In addition, autoimmunity does not always have pathological consequences, but may exert a protective function, as suggested by several observations on the beneficial role of autoreactive T cells in central nervous system injury.

Animals↗
PubMed2000

Graves' disease: a host defense mechanism gone awry.

In this report we summarize evidence to support a model for the development of Graves' disease. The model suggests that Graves' disease is initiated by an insult to the thyrocyte in an individual with a normal immune system. The insult, infectious or otherwise, causes double strand DNA or RNA to enter the cytoplasm of the cell. This causes abnormal expression of major histocompatibility (MHC) class I as a dominant feature, but also aberrant expression of MHC class II, as well as changes in genes or gene products needed for the thyrocyte to become an antigen presenting cell (APC). These include increased expression of proteasome processing proteins (LMP2), transporters of antigen peptides (TAP), invariant chain (Ii), HLA-DM, and the co-stimulatory molecule, B7, as well as STAT and NF-kappaB activation. A critical factor in these changes is the loss of normal negative regulation of MHC class I, class II, and thyrotropin receptor (TSHR) gene expression, which is necessary to maintain self-tolerance during the normal changes in gene expression involved in hormonally-increased growth and function of the cell. Self-tolerance to the TSHR is maintained in normals because there is a population of CD8- cells which normally suppresses a population of CD4+ cells that can interact with the TSHR if thyrocytes become APCs. This is a host self-defense mechanism that we hypothesize leads to autoimmune disease in persons, for example, with a specific viral infection, a genetic predisposition, or even, possibly, a TSHR polymorphism. The model is suggested to be important to explain the development of other autoimmune diseases including systemic lupus or diabetes.

Animals↗
PubMed1993

The failure of a combination of thyroid and thymus allografts to prevent the development of autoimmunity in thyroidectomized foetal lambs.

Previous experiments have shown that surgical removal of the thyroid gland from the foetal lamb one third of the way through gestation prevents the development of self tolerance towards thyroid-specific determinants. As a result, self thyroid tissue reintroduced into the foetal lamb after maturation of the immune system is not recognized as self and is subject to autoimmune thyroiditis. Furthermore, the transplantation of a thyroid allograft into a foetal lamb immediately after extirpation of its own gland has been shown not to direct the development of self tolerance to thyroid determinants. In the present experiment, foetal lambs were submitted to removal of the entire thyroid gland and the majority of the thymus gland, at 51-54 days of gestation followed by the immediate implantation of thyroid and thymic allografts. The additional implantation of thymus tissue did not affect the previously observed incapacity of a thyroid allograft to facilitate induction of organ-specific tolerance by the thyroid allograft. It was inferred that any T lymphocytes generated within the thymus graft and tolerant of thyroid-specific determinants had not had the capacity to suppress the activity of autoreactive cells generated in the host's thymus.

Animals↗
PubMed2001

T cell studies in a peptide-induced model of systemic lupus erythematosus.

We have previously reported that immunization with a peptide mimetope of dsDNA on a branched polylysine backbone (DWEYSVWLSN-MAP) induces a systemic lupus erythematosus-like syndrome in the nonautoimmune BALB/c mouse strain. To understand the mechanism underlying this breakdown in self tolerance, we examined the role of T cells in the response. Our results show that the anti-foreign and anti-self response induced by immunization is T cell dependent and is mediated by I-E(d)-restricted CD4(+) T cells of the Th1 subset. In addition, generation of the critical T cell epitope requires processing by APCs and depends on the presence of both DWEYSVWLSN and the MAP backbone. The breakdown in self tolerance does not occur through cross-reactivity between the T cell epitope of DWEYSVWLSN-MAP and epitopes derived from nuclear Ags. In this induced-model of SLE, therefore, autoreactivity results from the activation of T cells specific for foreign Ag and of cross-reactive anti-foreign, anti-self B cells. Despite the fact that tissue injury is mediated by Ab, the critical initiating T cell response is Th1.

Animals↗
PubMed1991

Sequences of the mouse F protein alleles and identification of a T cell epitope.

F protein is found predominantly in the liver and is of unknown function. The protein has been of interest to immunologists in the areas of self tolerance and the immunogenetics of the anti-F protein response. In the mouse there are two alleles (F1 and F2), and although mice are completely tolerant to the self form of the protein, mice of responder strains make a good antibody response to immunization with the non-self form. This response cross-reacts with the self form, implying firstly, that autoreactive B cells are present and that tolerance is therefore maintained at the T cell level, and secondly, that the difference between the two allelic products defines a T cell epitope. Primers based on the published sequence for rat F protein were used in the polymerase chain reaction to amplify the cDNA for the two mouse alleles. Subsequent sequencing shows a high degree of sequence identity between the rat and mouse cDNA. The two mouse cDNA are identical apart from a single A to G base change which predicts an asparagine (F1 protein) to aspartate (F2 protein) amino acid residue change. Using allele-specific oligonucleotide probes we confirmed that this base change has the same strain distribution as the previously determined F protein type. Isoelectric focusing shows that F1 protein migrates in a more basic position than F2 protein, as predicted by the asparagine to aspartate change. Finally, a synthetic peptide from the allovariable site of F2 protein will successfully restimulate T cells in vitro from an F1 type mouse primed in vivo with whole F2 protein, whereas the corresponding peptide from F1 protein will not. This is evidence that, as predicted, the allovariable site does indeed define a T cell epitope. Peptides covering the rest of the F2 protein molecule were not stimulatory.

Alleles↗
PubMed1989

Positive selection of CD4+ T cells mediated by MHC class II-bearing stromal cell in the thymic cortex.

T lymphocytes differentiate in the thymus, where functionally immature, CD4+CD8+ (double positive) thymocytes develop into functionally mature CD4+ helper cells and CD8+ cytotoxic (single positive) T cells. The thymus is the site where self-reactive T cells are negatively selected (clonally deleted) and where T cells with the capacity to recognize foreign antigens in association with self-proteins encoded by the major histocompatibility complex (MHC) are positively selected. The net result of these developmental pathways is a T-cell repertoire that is both self-tolerant and self-restricted. One unresolved issue is the identity of the thymic stromal cells that mediate the negative and positive selection of the T-cell repertoire. Previous work has pointed to a bone-marrow-derived macrophage or dendritic cell as the inducer of tolerance, whereas a radiation-resistant, deoxyguanosine-resistant thymic cell seems to mediate the positive selection of self-MHC restricted T cells. Thymic stromal cells in the cortex interact with the T-cell antigen receptor on thymocytes. Using several strains of transgenic mice that express the class II MHC molecule I-E in specific regions of the thymus, we show directly that the positive selection of T cells is mediated by an I-E-bearing cell in the thymic cortex.

Animals↗
PubMed2000

T lymphocytes of allophenic mice do not reject spleen colony-forming units of the parental genotypes.

Self-tolerance in BALB/c<-->C57BL/6 and BALB/c<-->B10.SM (SM) allophenic mice is examined in this study. Chimerism was determined by coat mosaicism, using electrophoresis of allozyme variants at the glucose phosphate isomerase-1 (GPI-1) in peripheral blood erythrocytes and a cytotoxity test for lymph node (LN) lymphocytes and blood nucleated cells. An age-dependent increase in the percent content of BALB/c erythrocytes was observed in both types of chimeras. The immunological status of chimeras was assessed by T cell interactions with spleen colony-forming cells (SFU-S) able to form colonies in the recipient spleens. LN lymphocytes of the chimeras, together with bone marrow cells (BMC) of the parental genotype, were transplanted to lethally irradiated F1 hybrids. Chimera T lymphocytes did not inactivate CFU-S of the parental genotype and colonies formed in the spleens of F1 hybrids. The absence of splenic colonies in (C x B6)F1 hybrids, in which BMC from B6 had been transplanted (either in combination with chimera lymphocytes or alone), was due to the reaction of host natural killer (NK) cells. The results obtained testify to the permanent immunological tolerance of chimera T lymphocytes to BMC antigens of the both parental genotypes. The chimeric shift in the erythrocyte population is not coupled to disturbances in self-tolerance of chimeric mice.

Animals↗
PubMed1989

Thymic requirement for clonal deletion during T cell development.

During T cell differentiation, self tolerance is established in part by the deletion of self-reactive T cells within the thymus (negative selection). The presence of T cell receptor (TCR)-alpha beta + T cells in older athymic (nu/nu) mice indicates that some T cells can also mature without thymic influence. Therefore, to determine whether the thymus is required for negative selection, TCR V beta expression was compared in athymic nu/nu mice and their congenic normal littermates. T cells expressing V beta 3 proteins are specific for minor lymphocyte stimulatory (Mlsc) determinants and are deleted intrathymically due to self tolerance in Mlsc+ mouse strains. Here it is shown that V beta 3+ T cells are deleted in Mlsc+ BALB/c nu/+ mice, but not in their BALB/c nu/nu littermates. Thus, the thymus is required for clonal deletion during T cell development.

Animals↗
PubMed1998

Activation of low avidity CTL specific for a self epitope results in tumor rejection but not autoimmunity.

To determine how self-tolerance can alter the ability of the immune system to respond against tumor-associated Ags that are also expressed by normal tissue, we designed experiments in which the same protein was expressed both as a tumor Ag and as a transgene product. Unlike conventional BALB/c mice that rejected renal carcinoma cells transfected with the influenza virus hemagglutinin (Renca-HA), transgenic mice that are tolerant of HA due to its expression as a self-Ag on pancreatic islet beta cells, (Ins-HA mice) supported progressive growth of these tumor cells. However, when Ins-HA mice were immunized with a recombinant strain of vaccinia virus expressing the dominant H-2Kd peptide epitope of HA before receiving Renca-HA cells, they too were able to reject the tumor cells. Rejection of Renca-HA cells by immunized Ins-HA mice was found to be associated with the generation of CTL having much lower avidity for target cells presenting the KdHA epitope than CTL from immunized conventional BALB/c mice. Significantly, we show that self-tolerance to the HA Ag is quantitative rather then absolute, and that vaccination of Ins-HA mice can activate low avidity KdHA-specific CD8+ T cells that are able to reject tumor cells expressing high levels of HA, yet these mice remain tolerant of pancreatic islet beta cells expressing HA.

Animals↗
PubMed2001

Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs.

Recent reports indicate that genes with tissue-restricted expression, including those encoding the type 1 diabetes autoantigens insulin, glutamic acid decarboxylase (GAD), and the tyrosine-phosphatase-like protein IA-2 (or ICA512), are transcribed in the thymus. The reported modulation of diabetes susceptibility by genetically determined differences in thymic insulin levels and studies in transgenic mice provide correlative and functional evidence that thymic expression of peripheral proteins is crucial for immunological self-tolerance. However, there are no specific data about the existence, tissue distribution, phenotype, and function of those cells that express insulin and other self-antigens in the human thymus. We find that the human thymus harbors specialized cells synthesizing (pro)insulin, GAD, and IA-2, mainly localized in the medulla, and we demonstrate such cells also in peripheral lymphoid organs (spleen and lymph nodes). Phenotypic analysis qualifies these cells as antigen-presenting cells (APCs), including both dendritic cells and macrophages. These cells often appear surrounded by apoptotic lymphocytes, both in thymus and spleen, and may therefore be involved in the deletion of autoreactive lymphocytes. Our findings demonstrate the existence of, and define the tissue distribution and phenotype of, a novel subset of APCs expressing self-antigens in human lymphoid organs that appear to be involved in the regulation of self-tolerance throughout life.

Adolescent↗
PubMed2001

Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer.

We identified a tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the widely expressed human MDM2 oncoprotein and were able to bypass self-tolerance to this tumor antigen in HLA-A*0201 (A2.1) transgenic mice and by generating A2.1-negative, allo-A2.1-restricted human T lymphocytes. A broad range of malignant, as opposed to nontransformed cells, were killed by high-avidity transgenic mouse and allogeneic human CTLs specific for the A2.1-presented MDM2 epitope. Whereas the self-A2.1-restricted human T cell repertoire gave rise only to low-avidity CTLs unable to recognize the natural MDM2 peptide, human A2.1+ T lymphocytes were turned into efficient MDM2-specific CTLs upon expression of wild-type and partially humanized high-affinity T cell antigen receptor (TCR) genes derived from the transgenic mice. These results demonstrate that TCR gene transfer can be used to circumvent self-tolerance of autologous T lymphocytes to universal tumor antigens and thus provide the basis for a TCR gene transfer-based broad-spectrum immunotherapy of malignant disease.

Animals↗
PubMed1999

In vivo T-lymphocyte tolerance in the absence of thymic clonal deletion mediated by hematopoietic cells.

Thymic negative selection renders the developing T-cell repertoire tolerant to self-major histocompatability complex (MHC)/peptide ligands. The major mechanism of induction of self-tolerance is thought to be thymic clonal deletion, ie, the induction of apoptotic cell death in thymocytes expressing a self-reactive T-cell receptor. Consistent with this hypothesis, in mice deficient in thymic clonal deletion mediated by cells of hematopoietic origin, a twofold to threefold increased generation of mature thymocytes has been observed. Here we describe the analysis of the specificity of T lymphocytes developing in the absence of clonal deletion mediated by hematopoietic cells. In vitro, targets expressing syngeneic MHC were readily lysed by activated CD8(+) T cells from deletion-deficient mice. However, proliferative responses of T cells from these mice on activation with syngeneic antigen presenting cells were rather poor. In vivo, deletion-deficient T cells were incapable of induction of lethal graft-versus-host disease in syngeneic hosts. These data indicate that in the absence of thymic deletion mediated by hematopoietic cells functional T-cell tolerance can be induced by nonhematopoietic cells in the thymus. Moreover, our results emphasize the redundancy in thymic negative selection mechanisms.

Animals↗
PubMed2004

Peripheral antigen-expressing cells in type 1 diabetes.

Studies in both humans and rodent models provide new insight into key mechanisms regulating tolerance to self-molecules. There is evidence that tissue-specific molecules are expressed in the thymus and peripheral lymphoid tissues (PLTs) by specialized antigen-presenting cells (APCs), and that such expression is critical for self-tolerance. Insulin, a key hormone exclusively produced by pancreatic beta cells and a critical autoantigen in type 1 diabetes, provides an excellent example of a molecule with tissue-restricted expression that is ectopically expressed by APCs in both thymus and PLTs. APCs may play a role in insulin presentation in both the central and peripheral immune system. Functional data from several transgenic and knockout mouse models, some specific for the expression of insulin, help dissect the significance of self-molecule presentation by APCs and its role in autoimmune diabetes.

Animals↗