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PubMed1992

Self tolerance to human A and B histo-blood group antigens exists at the B cell level and cannot be broken by potent polyclonal B cell activation in vitro.

It is generally considered that tolerance to self antigens is less complete in B than in T lymphocytes. However, B cell tolerance through either functional inactivation (anergy) or clonal deletion has been demonstrated in transgenic mice. In the present study, we investigated whether B cells specific for self A/B histo-blood group antigens can be detected in normal humans. It is a key feature of the ABO system that all normal individuals make natural antibodies against those A or B carbohydrates which are not present in their organism. To detect B cells by the limiting dilution approach we used a specific enzyme-linked immunosorbent assay for the quantitation of anti-A/B antibodies, and a culture system in which polyclonal B cell activation occurs through cell contact with EL4 thymoma cells. As was reported for other B cell studies, we frequently detected "polyreactive" immunoglobulin (Ig)M (but not IgG) with apparent autoreactivity but of uncertain significance regarding physiologic conditions. However, A- or B-specific B cell responses occurred with selective patterns in agreement with classical blood group serology in 14 individuals with A, B, AB or 0 blood group phenotypes: 1/11,600 B cells made anti-allo A/B IgM and 1/26,500 B cells such as IgG, while only 1/104,000 B cells apparently made anti-self A/B IgM and 1/350,000 B cells such as IgG. This shows self tolerance at the B cell level. Since anergy of B cells can frequently be broken by polyclonal B cell activation in vitro, and EL4 cells are potent B cell stimulators, the present results argue for either a highly resistant anergic state or for clonal deletion of self-A/B histo-blood group-specific human B cells.

ABO Blood-Group System↗
PubMed2002

Post-liver transplant Crohn's disease: graft tolerance but not self-tolerance?

Inflammatory bowel disease (IBD) rarely occurs de novo after liver transplantation, and when it does usually presents as ulcerative colitis in patients transplanted for primary sclerosing cholangitis. We present two patients who developed de novo Crohn's colitis two and three years after liver transplant for primary biliary cirrhosis (PBC) and chronic hepatitis B infection, respectively. Both were on maintenance immunosuppression with a calcineurin inhibitor and azathioprine with no evidence of allograft rejection. Investigations for enteric and opportunistic infection were negative. In the nontransplant setting, the development of IBD is likely multifactorial with an immune origin. In our cases, the immunosuppression was titrated to minimal levels when IBD developed. Clearly, although a significant degree of allograft tolerance can occur, autoimmune diseases can still develop elsewhere, suggesting selective immune tolerance.

Colon↗
PubMed2001

Cross-presentation in viral immunity and self-tolerance.

T lymphocytes recognize peptide antigens presented by class I and class II molecules encoded by the major histocompatibility complex (MHC). Classical antigen-presentation studies showed that MHC class I molecules present peptides derived from proteins synthesized within the cell, whereas MHC class II molecules present exogenous proteins captured from the environment. Emerging evidence indicates, however, that dendritic cells have a specialized capacity to process exogenous antigens into the MHC class I pathway. This function, known as cross-presentation, provides the immune system with an important mechanism for generating immunity to viruses and tolerance to self.

Animals↗
PubMed2004

Learning from panel boards: T-lymphocyte and B-lymphocyte self-tolerance game.

Immunology is a vast, complex and challenging subject. To facilitate students' understanding, the authors have created a T-lymphocyte and B-lymphocyte self-tolerance game. The T-lymphocyte self-tolerance game consisted of 24 cardboard pieces with illustrations and statements about self-tolerance mechanisms and one large panel board. The B-lymphocyte panel board consisted of 11 cardboard pieces with illustrations and statements about self-tolerance mechanisms, and two large panels. Students had to associate mechanisms of self-tolerance with the corresponding cardboard pieces. In total, 120 students attended the session. Of these, 95.8% considered that the panel board facilitated their understanding; 95% affirmed they understood how T- and B-lymphocyte self-tolerance worked. Students' grades improved significantly. The good results obtained show the value of using a panel board when approaching a subject that is vast and complex.

Allergy and Immunology↗
PubMed2005

2B4 (CD244)-CD48 interactions provide a novel MHC class I-independent system for NK-cell self-tolerance in mice.

Natural killer (NK) cells must be able to eliminate infected and transformed cells while remaining tolerant of normal cells. NK-cell self-tolerance is thought to be maintained by self-major histocompatibility complex (MHC) class I recognition; however, there are examples where NK cells are not regulated by MHC class I and yet remain self-tolerant. Here, we show that 2B4 (CD244) and CD48 represent a second system for murine NK-cell self-recognition. 2B4 and MHC class I receptors act nonredundantly to inhibit NK lysis of syngeneic tumor cells. NK cells from beta2 microglobulin (beta2m)-deficient mice and NK cells that lack expression of self-MHC-binding inhibitory receptors are inhibited by 2B4. Moreover, we provide the first in vivo evidence for MHC-independent NK self-recognition in a bone marrow rejection assay. These data suggest that NK-cell self-tolerance can be mediated by molecules other than MHC.

Animals↗
PubMed1998

The study of self-tolerance using murine haemoglobin as a model self antigen.

T cell tolerance to self proteins involves both thymic and peripheral mechanisms. We have used allotypic differences in murine haemoglobin (Hb) to study the development of tolerance to the abundantly expressed self-protein. In Hb beta s/H-2k mice, the response to Hb beta d is directed against Hb beta d (64-76) presented by I-Ek molecules. Using T cell hybridomas and clones specific for this epitope, we have demonstrated that Hb(64-76)/I-Ek complexes and present on antigen-presenting cells in all lymphoid organs including dendritic cells, B cells and macrophages. In the thymus, the presence of these complexes results in negative selection of transgenic T cells with high levels of Hb(64-76)/I-Ek-specific receptor. However, cells with intermediate levels of specific receptor escape negative selection and can be found in the periphery. Under normal circumstances these cells remain tolerant, but can be activated by mechanisms which increase the number of Hb(64-76)/I-Ek complexes.

Animals↗
PubMed1989

Interception of the development of self tolerance in fetal lambs.

Investigation of the nature of immunological self tolerance has usually relied upon experimental protocols in which the tolerant state is interrupted in mature animals with the production of autoimmune disease. While such research has improved the understanding of those processes operative in overt autoimmunity, it has not been informative in relation to events associated with the establishment of self tolerance. Any description of this state which is to be based on observation will necessitate the use of experimental systems that permit observation of animals during the development of self tolerance. The present experiment entailed intervention approximately one third of the way through the gestation period of fetal lambs. An earlier experiment had established that 54-day fetal lambs would accept allografts of adult skin. This indicated that the capacity to discriminate between self and non-self had not been acquired at that age. Fetuses at this stage of gestation were submitted to either partial or total removal of the thyroid gland. The excised tissue was then implanted in nude mice for periods of 5 to 9 weeks. It was subsequently replaced subcutaneously, either in the original donor or in another fetus at a comparable stage of gestation. At postmortem examination, several weeks later, self implants in lambs from which the thyroid gland had been completely removed displayed autoimmune thyroiditis of varying degrees of severity. However, self implants in partially thyroidectomized animals were uniformly free from autoimmune manifestations. This implied that these reactions had not been directed against contaminating murine tissues in the implants replaced in completely thyroidectomized lambs. All allogeneic implants were subject to vey heavy lymphocytic infiltration, usually with accompanying necrosis consistent with allograft rejection. This was taken as an indication that hypothyroid fetal lambs had become immunocompetent by the time of thyroid reimplantation. Spontaneous immunological reactivity against reimplanted self thyroid tissue by thyroidectomized lambs was interpreted as a failure to acquire the capacity for self recognition as a result of antigen deprivation.

Animals↗
PubMed2005

Regulatory T cells in the establishment and maintenance of self-tolerance: role of the thymic epithelium.

The thymus constitutes the microenvironment for T lymphocyte differentiation and acquisition of self-tolerance. Aiming to specify the contributions of the two essential parts of the thymus, namely hemopoietic and epithelial, we have devised experimental models in birds and mice. Chimeric thymuses, xenogeneic in birds and allogeneic in mice, were constructed early in development. In both models we could demonstrate a critical role of the epithelial component of the thymic stroma in induction and maintenance of self-tolerance. These experiments showed that suppression mechanisms are also implicated in these events, strongly suggesting the existence of regulatory T cells in both models. Before these experiments the control of self-tolerance was usually attributed to suppressive cells. However, as the cell phenotypes were not identified, the role of these cells was disregarded. Numerous studies since our investigations argue in favour of regulatory mechanisms. The work we initiated several years ago represents a contribution to our understanding of the two linked and opposite aspects of immune-responded control, namely self-tolerance and autoimmunity.

Animals↗
PubMed2001

Immunologic self tolerance maintained by T-cell-mediated control of self-reactive T cells: implications for autoimmunity and tumor immunity.

T-cell-mediated dominant control of self-reactive T cells is one mechanism for maintaining immunologic self tolerance. It also hampers the generation of immunity to autologous tumor cells. Abrogation of the control can evoke potent tumor immunity as well as autoimmunity in normal animals. This common regulatory mechanism for autoimmunity and tumor immunity can be exploited to devise a novel immunotherapy against cancer.

Animals↗
PubMed2000

How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis.

Therapy for transplant rejection, autoimmune disease and allergy must target mature lymphocytes that have escaped censoring during their development. FK506 and cyclosporin are immunosuppressants which block three antigen-receptor signalling pathways (NFAT, NFkappaB and JNK), through inhibition of calcineurin, and inhibit mature lymphocyte proliferation to antigen. Neither drug induces long-lived tolerance in vivo, however, necessitating chronic use with adverse side effects. Physiological mechanisms of peripheral tolerance to self-antigens provide an opportunity to emulate these processes pharmacologically. Here we use gene-expression arrays to provide a molecular explanation for the loss of mitogenic response in peripheral B-cell anergy, one aspect of immunological tolerance. Self-antigen induces a set of genes that includes negative regulators of signalling and transcription but not genes that promote proliferation. FK506 interferes with calcium-dependent components of the tolerance response and blocks an unexpectedly small fraction of the activation response. Many genes that were not previously connected to self-tolerance are revealed, and our findings provide a molecular fingerprint for the development of improved immunosuppressants that prevent lymphocyte activation without blocking peripheral tolerance.

Animals↗
PubMed1980

Is self tolerance H-2 restricted?

An individual's immune system must be capable of responding to a wide variety of antigens, but must not react against tissues of the individual itself. The specificity of this 'self tolerance' is determined early in life and recent work has dealt with the mechanisms by which self tolerance is maintained. We report here a study designed to determine whether products of the major histocompatibility complex are involved in the induction of self tolerance; in particular, whether the induction of self tolerance in the mouse is H-2 restricted. H-2 restriction refers to the finding that mouse T cells generally recognize foreign antigens only when presented in association with the products of H-2 alleles. We questioned whether T-cell precursors are made tolerant directly by antigen alone, or whether the antigen must be associated in the cell membrane with an appropriate H-2 molecule. We find that T-cell tolerance to 'self' membrane components does not seem to be H-2 restricted and discuss the possibility that this apparent lack of H-2 restriction is due to antigen processing.

Animals↗
PubMed1991

Maintenance of self tolerance in CD4+ T lymphocytes by antigen presentation on resting B cells--a hypothesis.

Self tolerance in the immune system is established by clonal deletion or induction of clonal anergy in immature lymphocytes. In addition, repair mechanisms for self tolerance working in the mature immune system may exist to take care of self-reactive lymphocytes eventually leaking through the central mechanisms. Two possible repair mechanisms for self tolerance, both capable of self/nonself discrimination, are discussed in this article. The first is the so-called veto function, which works on CD8+ T cells. The second is a new hypothesis suggesting that CD4+ T cells may be anergized by recognizing antigen on self-specific, anergic B cells.

Animals↗
PubMed2006

Missing self recognition and self tolerance of natural killer (NK) cells.

Natural killer cells express inhibitory receptors specific for polymorphic MHC molecules, which enables them to mediate "missing self recognition", the capacity to attack self cells that extinguish expression of MHC class I molecules. A key question is: how are NK cells rendered self-tolerant? It was proposed that all NK cells express at least one inhibitory receptor specific for self MHC, but we recently identified an NK cell subset that does not. Instead, these NK cells, like anergic B and T cells, are hyporesponsive to stimulation. These findings indicate that NK cell activity can be modulated independently of inhibitory receptors specific for MHC molecules, and that such modulation may contribute to self tolerance. This review summarizes current understanding of NK cell recognition and self tolerance.

Animals↗
PubMed1990

Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance.

During development in the thymus, T cells are rendered tolerant to self antigens. It is now apparent that thymocytes bearing self-reactive T cell receptors can be tolerized by processes that result in physical elimination (clonal deletion) or functional inactivation (clonal anergy). As these mechanisms have important clinical implications for transplantation and autoimmunity, current investigations are focused on understanding the cellular and molecular interactions that generate these forms of tolerance.

Animals↗
PubMed1989

A nondeletional mechanism of thymic self tolerance.

T cells become tolerant of self antigens during their development in the thymus. Clonal deletion of thymocytes bearing self-reactive T cell receptors is a major mechanism for generating tolerance and occurs readily for antigens expressed by bone marrow-derived cells. Tolerance to antigens expressed on the radioresistant thymic stromal elements is demonstrated here to occur via a nondeletional mechanism. For minor lymphocyte stimulatory (Mls-1a) and major histocompatibility complex (MHC) antigens, this alternate form of tolerance induction results in clonal anergy.

Animals↗
PubMed1979

Role of prethymic cells in acquisition of self-tolerance.

The sequential character of T-lymphocyte development as it pertains to the stage at which self-tolerance is acquired was investigated. Three phases were studied, defined here as prethymic, intrathymic, and postthymic as determined by the timing of thymus implantation. The model utilized was the temporal pattern of skin graft rejection in thymusless BALB/c nude mice implanted with allogeneic, C57BL/6J, or syngeneic thymuses before or after skin grafting; in some instances, F(1) hybrid spleen cells were also given to newborns or young adults. These experiments in nude mice showed that, (a) self-tolerance could be established despite the absence of the host's own haplotype in the implanted thymus; (b) recently emigrated postthymic cells could already discriminate self from non-self; (c) specific neonatal tolerance could be induced in nudes by inoculation of F(1) hybrid cells; (d) nudes showed a higher capacity for induction of neonatal tolerance than did normal littermates. These findings indicate that the process of self-tolerance in the T cell's lineage begins during the prethymic state early in ontogeny.

Animals↗
PubMed1992

Mechanisms of self tolerance.

The redundancy of biological systems minimizes the probability that isolated molecular and cellular defects entail deleterious consequences. This notion also applies to the establishment and maintenance of tolerance to self antigens. Thus, immune homeostasis is attributed to multiple distinct safety valves that are connected in series and intervene at defined control points of the life cycle of the developing lymphocyte to guarantee the physical elimination, functional inactivation, or regulated inhibition of self-reactive, potentially autoaggressive, B and T cells.

Animals↗
PubMed1988

Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex.

In mice the product of the Mlsa locus is an unusual antigen capable of interaction with certain products of the major histocompatibility locus (MHC) to form a ligand for a large portion of the T-cell alpha/beta receptor repertoire, including nearly all receptors that use V beta 8.1. The presence of Mlsa/MHC during T-cell development results in the deletion of T cells that express V beta 8.1, documenting the importance of clonal deletion in establishing tolerance to self antigens.

Animals↗