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PubMed2005

Autoimmune liver disease.

PURPOSE OF REVIEW: This review aims to demonstrate how recent insights into disease behavior and mechanisms and the availability of new drugs can be assimilated into evolving concepts of diagnosis and treatment. RECENT FINDINGS: Autoimmune hepatitis has a global distribution, and its clinical manifestations are similar in different regions. Concurrent immune diseases are common, and immunoglobulin A nephropathy may explain ascites in some patients. Subclinical celiac disease can cause cryptic liver dysfunction or be associated with autoimmune hepatitis. A fulminant presentation that is associated with de novo rather than exacerbated pre-existent disease is possible, and these patients may have centrilobular zone 3 necrosis. Bile duct injury as a background histologic finding should not change the diagnosis or therapy, and the clinical significance of autoantibodies can be determined only by examination of liver biopsy tissue. Molecular mimicry may be important in breaking self-tolerance, and a murine model based on DNA immunization with self-antigens supports this hypothesis. Corticosteroid therapy reduces or prevents hepatic fibrosis, and noninvasive techniques promise to facilitate the development of treatments that enhance this effect. Mycophenolate mofetil is a possible salvage therapy that requires clinical trial, and liver transplantation has a 5-year patient survival of 78% but is frequently followed by recurrent disease and acute rejection. SUMMARY: Autoimmune hepatitis should be considered in all patients with acute or chronic liver disease. Therapy can reduce or prevent fibrosis. The new immunosuppressive drugs should undergo clinical trial before empiric use. Animal models promise to identify key pathogenic sites that can be targeted by therapies.

Hepatitis, Autoimmune↗
PubMed2005

Bone marrow-derived dendritic cells reverse the anergic state of CD4+CD25+ T cells without reversing their suppressive function.

Dendritic cells (DC) are potent inducers of immunity to foreign Ags, but also contribute to self-tolerance by induction of regulatory T cells or deletion/anergy of self-reactive T cells. In this study, we have studied the capacity of DC to activate naturally occurring CD4+CD25+ regulatory T cells as well as the ability of CD4+CD25+ T cells to suppress the DC-mediated activation of CD4+CD25- T cells. Mature bone marrow-derived dendritic cells, but not splenic DC, were able to induce the proliferation of CD4+CD25+ T cells in the presence of a polyclonal stimulus and in the absence of exogenous IL-2. The DC-induced proliferative response of the CD4+CD25+ T cells was partially dependent on IL-2 produced by a small number of contaminating CD25+ effector cells. Because bone marrow-derived dendritic cells induce proliferation of both CD4+CD25+ and CD4+CD25- T cells in vitro, it was impossible to assay the suppressive function of the CD4+CD25+ T cells using [3H]TdR uptake or CFSE dilution. We therefore measured IL-2 production in cocultures of CD4+CD25+ and CD4+CD25- T cells using the IL-2 secretion assay. Surprisingly, CD4+CD25+ T cells markedly suppressed IL-2 secretion by the CD4+CD25- T cells without inhibiting their proliferation. Collectively, these results suggest that Ag presentation by DC can induce the expansion of CD4+CD25+ T cells while simultaneously activating their ability to suppress cytokine secretion by effector T cells.

Animals↗
PubMed1979

Autoimmune disease and the theory of clonal abortion. Is it still relevant?

Explanations for self-tolerance and its failure in autoimmune disease remain conjectural. Earlier deletional theories and the later clonal abortion theory as a basis for central B-cell (and possibly T-cell) tolerance seemed to conflict with various experimental and clinical observations, including those relating to the ability to induce autoimmune reactivity in normal adult animals. Accordingly, immunoregulatory controls have dominated discussions. However, there is recent compelling experimental evidence in favour of clonal abortion of B lymphocytes in the absence of T-cell help. It is proposed that two sets of regulatory systems operate at different stages in life to establish and maintain self-recognition: a central tolerance operates through clonal abortion during embryonic and early postnatal life and during childhood and beyond, ancillary regulatory systems deal with the self-reactive cells which emerge in a milieu in which helper influences interfere with clonal abortion.

Adult↗
PubMedDate not supplied

Efficiency of antigen presentation differs in mice differing at the Mls locus.

In the mouse, potent primary in vitro proliferation of T cells can be induced by allelic variants of cell-surface glycoproteins, Ia antigens, the genes for which are located in the I region of the major histocompatibility complex (MHC) on chromosome 17. The only other potent primary proliferative response known is induced by mixing MHC-identical lymphocytes from strains that differ at the locus termed Mls (ref. 1) (for mixed lymphocyte stimulating), which has been mapped to chromosome 1. While it is relatively easy to raise antibodies against Ia antigens, and thus determine both their chemical nature and their role in T-cell stimulation, the nature of the product of the Mls locus has remained obscure. It has been proposed that the Mls locus product is a minor antigen recognized in association with self-Ia antigens, a translocated Ia-like element, or a mitogenic molecule found on the surface of antigen presenting cells (APC). Here, we demonstrate that APCs from mice carrying stimulatory Mls locus alleles present antigen more efficiently to cloned, antigen-specific, Ia-restricted T cells than APCs from mice carrying nonstimulating Mls locus alleles. We propose that the Mls locus does not encode a unique cell-surface antigen at all; we suggest instead that the T-cell proliferative response induced by Mls-locus disparate cells reflects recognition of self-Ia molecules on APCs. If our interpretation is correct, it provides further evidence both for the quantitative nature of self tolerance and for the existence of a distinct recognition site for self-Ia molecules on antigen-specific T lymphocytes.

Animals↗
PubMed1996

Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation.

Neonatal thymectomy (NTx), especially around day 3 after birth, causes various organ-specific autoimmune diseases in mice. This report shows that: (a) T cells expressing the interleukin 2 receptor alpha chains (CD25) ontogenically begin to appear in the normal periphery immediately after day 3, rapidly increasing within 2 wk to nearly adult levels (approximately 10% of CD3+ cells, especially of CD4+ cells); (b) NTx on day 3 eliminates CD25+ T cells from the periphery for several days; inoculation immediately after NTx of CD25+ splenic T cells from syngeneic non-Tx adult mice prevents autoimmune development, whereas inoculation of CD25- T cells even at a larger dose does not; and furthermore, (c) similar autoimmune diseases can be produced in adult athymic nu/nu mice by inoculating either spleen cell suspensions from 3-d-old euthymic nu/+ mice or CD25+ cell-depleted spleen cell suspensions from older, even 1-yr-old, nu/+ mice. The CD25- populations from neonates or adults are also similar in the profile of cytokine formation. These results, taken together, indicate that one aspect of peripheral self-tolerance is maintained by CD25+ T cells that sustain potentially pathogenic self-reactive T cells in a CD25- dormant state; the thymic production of the former is developmentally programmed to begin on day 3 after birth in mice. Thus, NTx on day 3 can, at least transiently, eliminate/reduce the autoimmune-preventive CD25+ T cells, thereby leading to activation of the self-reactive T cells that have been produced before NTx.

Age Factors↗
PubMed1991

Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice.

Self-reactive B cells can be regulated by either deletion or inactivation. These manifestations of self-tolerance have been dramatically shown in transgenic mice in which the number of self-reactive cells has been artificially expanded. We have now extended these models to ask if B-cell tolerance as described for non-disease-associated antigens also operates for the targets of autoimmunity. The target we have chosen is DNA. Anti-DNA antibodies are diagnostic of certain autoimmune syndromes in humans and are a characteristic of the murine model of systemic autoimmunity, the MRl/lpr mouse. Antibodies to both single-stranded and double-stranded DNA have been implicated in disease. By generating anti-DNA transgenic mice, we have addressed the question of whether DNA-specific B cells are regulated in normal (non-autoimmune) mice. We indeed found that most transgenic B cells bind DNA, yet we failed to detect secreted anti-DNA. We suggest that as a consequence of their self-reactivity these B cells are developmentally arrested.

Animals↗
PubMed1991

The dominant self and the cryptic self: shaping the autoreactive T-cell repertoire.

Deletion of autoreactive T cells during the induction of self tolerance has been directly demonstrated. However, it is still relatively easy to detect self reactivity in normal healthy animals. In this article, Guy Gammon, Eli Sercarz and Gilles Benichou speculate on which T cells may escape tolerance induction and discuss how these cells could subsequently be involved in autoimmunity.

Animals↗
PubMed2001

An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide.

EAE can refer either to experimental autoimmune encephalomyelitis or experimental allergic encephalomyelitis. Although EAE is classically a prototypic T helper 1 (TH1) cell-mediated autoimmune disease, it can also be induced by TH2 cells. Characteristically, the most severe manifestation of allergy, anaphylaxis, is associated with exposure to a foreign antigen that is often derived from medication, insect venom or food. We report here that, after self-tolerance to myelin is destroyed, anaphylaxis may be triggered by a self-antigen, in this case a myelin peptide. "Horror autotoxicus", which was initially described by Ehrlich, may not only include autoimmunity to self, it may also encompass immediate hypersensitivity to self, which leads to shock and rapid death.

Allergens↗
PubMed1991

T cells that recognize peptide sequences of self MHC class II molecules exist in syngeneic mice.

T cell reactivity toward self MHC class II molecules has been recognized in syngeneic MLR in a number of studies, where the T cells are believed to recognize the combination of self/nonself peptide and self MHC molecule. We investigated the stimulation of T cell proliferation by synthetic peptides of sequences corresponding to the first polymorphic amino terminal domain of alpha- and beta-chains of self I-A molecules. Both unprimed and primed T cells responded to a number of peptides of alpha 1 and beta 1 domains of self I-Ad molecules. The response was dependent on the presentation of I-Ad peptides by syngeneic APC and was blocked by anti-class II MHC mAb. Upon further investigation it was observed that I-Ad peptides could inhibit the stimulation of Ag-specific MHC class II-restricted T cell hybridoma due to self presentation of peptides rather than to direct binding of free peptides to the TCR, further supporting their affinity/interaction with intact self MHC class II molecules. The peptide I-A beta d 62-78 showed high affinity toward intact self MHC II molecule as determined by the inhibition of Ag-specific T cell stimulation and yet was nonstimulatory for syngeneic T cells, therefore representing an MHC determinant that may have induced self tolerance. Thus we have shown that strong T cell proliferative responses can be generated in normal mice against the peptides derived from self MHC class II molecules and these cells are part of the normal T cell repertoire. Therefore complete tolerance toward potentially powerful immunodominant but cryptic determinants of self Ag may not be necessary to prevent autoimmune diseases.

Amino Acid Sequence↗
PubMed1996

Anergy-associated T cell antigen presentation. A mechanism of infectious tolerance in experimental autoimmune encephalomyelitis.

CD4+ T cells promote immune responses against foreign Ags while actively suppressing responses against self Ags. To address how CD4+ T cells ensure self-tolerance, we focused on two CD4+ T helper cells specific for myelin basic protein (MBP). GP2.E5/R1 T cells recognized rat MBP (RMBP) as a partial agonist and mediated mild experimental autoimmune encephalomyelitis (EAE), whereas R2 T cells recognized RMBP with full efficacy and mediated severe EAE. GP2.E5/R1 T cells were more susceptible to anergy induction than R2 T cells. Anergic GP2.E5/R1 T cells lacked proliferative reactivity, but expressed both I-A glycoproteins and high levels of radioresistant APC activity. During induction of anergy, these T cells acquired the ability to present MBP. In a separate subsequent culture without further addition of Ag, anergic GP2.E5/R1 T cells elicited full proliferative and IL-2 production responses by R2 T cells. Unlike activations induced via irradiated splenocytes, irradiated anergic T cells elicited anergy in R2 T cells in the form of a postactivational phase of nonresponsiveness. Anergic GP2.E5/R1 T cells not only transferred anergy to pathogenic R2 T cells in vitro, but these anergic T cells also transferred resistance to EAE in Lewis rats subsequently challenged with guinea pig MBP in CFA. Antagonistic signaling by autologous RMBP was more tolerogenic than that of guinea pig MBP in both in vitro and in vivo models of infectious anergy. We conclude that in the presence of tolerogenic mAb, antagonistic signaling by a self protein elicited the coordinate expression of anergy and T cell-mediated APC activity as a mechanism for the genesis and spread of infectious tolerance.

Animals↗
PubMed2006

A unified theory of central tolerance in the thymus.

Non-deletional tolerance resulting in the generation of regulatory T cells within the thymus is a key mechanism for the establishment of immunological self-tolerance. How the high-affinity self-reactive regulatory T cells escape negative selection and what type of antigen-presenting cells positively select them within the thymus are unsolved questions. Previous studies suggest that thymic epithelial cells are crucial for the positive selection of regulatory T cells in thymus. A recent study from my group shows that a subset of dendritic cells (that have been "educated" by the thymic stromal lymphopoietin molecule produced by a thymic cell type known as Hassall's corpuscles) positively select regulatory T cells within the medulla of human thymus. Here, I discuss the implications and historical context of this new result and suggest that a subset of mature dendritic cells within the thymic medulla protects the medium- to high-affinity self-reactive T cells from negative deletion and induces their differentiation into regulatory T cells in the thymus.

Animals↗
PubMed2002

T-regulatory cells: are we re-discovering T suppressors?

Regulatory T cells are shown to originate form the thymus and their role is to maintain self-tolerance to intra-thymic as well as extra-thymic self-antigens. Their mode of action, using in vivo and in vitro systems, has led to different conclusions as to the need of cell-cell interactions or regulation upon suppressive cytokines. The more we study regulatory T cells the more we find similarities to the old notion of the suppressor T cell network. The limited knowledge in molecular technology in the early 70s and 80s discouraged investigators to further scrutinize the issue and the terms T suppressors and contra-suppressors that were coined back then have been forgotten over the years. It is now time to remember the work of these investigators and attempt to explain their findings using the current knowledge and technology.

Animals↗
PubMed2005

Receptor editing in peripheral B cell tolerance.

Receptor editing or secondary Ig gene rearrangement occurs in immature, autoreactive B cells to maintain self-tolerance. Here we show that nonspontaneously autoimmune mice immunized with a peptide mimetope of DNA develop peptide- and DNA-reactive antibodies. Antigen-specific B cells display a follicular B cell phenotype. As these cells move into the memory compartment, many express RAG protein and acquire expression of both kappa and lambda light chains. Thus, this study provides evidence for receptor editing occurring in a mature, antigen-activated B cell population. Because the receptor editing observed here occurred in an autoreactive response to antigen, it may function to maintain peripheral tolerance.

Animals↗
PubMed1993

Intrathymic and extrathymic tolerance in bone marrow chimeras.

Parent-->F1 bone marrow (BM) chimeras provide a useful model for studying self tolerance induction. When prepared with supralethal irradiation (1300 cGy) and conditioned with anti-T cell antibodies, parent-->F1 BM chimeras are devoid of host BM-derived cells; host H-2 expression is apparent in both the intrathymic and extrathymic environments but is limited to non BM-derived cells. When parent-->F1 chimeras are injected with T cells from normal parental strain mice, the expression of host H-2 antigens on nonprofessional APC might be expected to induce tolerance through induction of clonal anergy. In practice, this does not occur. Instead, a small proportion of the injected T cells is induced to proliferate and differentiate into effector cells. Tolerance is not seen. Similarly, tolerance is not apparent when thymectomized parent-->F1 chimeras are given parental strain thymus grafts. These findings suggest that the expression of host H-2 antigens in the post-thymic environment of chimeras is not intrinsically tolerogenic for mature T cells or recent thymic emigrants. Interestingly, post-thymic tolerance does occur when parental strain T cells differentiate in the endogenous thymus of chimeras. Thus, when mature CD8+ cells are prepared from thymus vs lymph nodes (LN) of parent-->F1 chimeras, tolerance to host class I antigens is more marked in LN than thymus; this applies to cytotoxic T lymphocyte (CTL) precursors, generated by limiting dilution analysis. It would appear therefore that many of the host-reactive CTL precursors generated in the thymus of chimeras undergo tolerance induction (deletion or irreversible inactivation) in the post-thymic environment. We suggest that such tolerance is a reflection of a covert form of tolerance induced in the thymus: intrathymic contact with host antigens on thymic epithelial cells (TEC) in chimeras does not delete typical CTL precursors, but these cells are rendered "semi-tolerant". When cultured in vitro in the presence of lymphokines, the cells are able to recover and differentiate into CTL. In vivo, however, the cells recognize antigen in the periphery in the relative absence of lymphokines and the cells die. Although host class I expression on TEC in chimeras deletes only a small proportion of CTL precursors, contact with TEC induces strong tolerance of CD8+ cells in terms of helper-independent proliferative responses in vitro and induction of lethal graft-versus-host disease in vivo. We postulate that these latter responses are controlled by high-affinity T cells, whereas typical CTL generated in LDA are predominantly low-affinity cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

The self and the nonself: immunorecognition and immunologic functions.

For almost a century self-nonself discrimination has been considered the driving force of the immune system and the dogma of self-tolerance (horror autotoxicus) the essential issue for understanding protective immunity and pathologic autoreactivity. This classical picture has been recently challenged by the discovery that the immune system is influenced by internal activation (amor autocognitus) and autoreactive clones are both present and activated in healthy individuals. Central to the concepts of reactivity and tolerance, in other terms, to physiology and pathology, is the analysis of structures involved in immunorecognition and as they contribute to the outcome of the immune response. The capacity of the immune system to recognize nonself structures and eventually react to them developed during evolution probably before the generation of clonally distributed antigen receptors. The high level of autoreactivity that characterizes the immune system seems to suggest that immunocompetent cells never learned to ignore the self, but rather that, sometime during evolution, they specialized in the function of self-identification, one of the most basic activities of all living cells. Autoimmune diseases would result from a pathologic deviation of a physiologic function, just as many other diseases do.

Animals↗
PubMed1995

Immunological function of a defined T-cell population tolerized to low-affinity self antigens.

In the thymus there are two major mechanisms of T-lymphocyte tolerance: clonal deletion and clonal inactivation. One important problem underlying the mechanism of clonal inactivation is why unresponsive cells are maintained in the mature peripheral T-cell repertoire. Here we report that transgenic alpha beta T-cells may be tolerized to a self antigen Mls-1a, but still retain proliferative responses for alternative peptide antigens and superantigens. These self-tolerant T cells can also provide immunopathological and memory cytotoxic function in vivo. We propose that high-affinity/avidity self-reactive T cells are deleted in the thymus, whereas lower-affinity/avidity interactions lead to unresponsiveness and define the 'resting threshold' for a given T cell. These low-affinity self-tolerant T cells remain functionally competent for high-affinity foreign antigens, and efficiently eliminate natural pathogens in vivo.

Animals↗
PubMed1976

Lack of neonatal susceptibility to induction of tolerance by polysaccharide antigens.

Susceptibility to tolerance induction by polysaccharides during the neonatal period has been studied with the alpha-1.3 and alpha-1.6 glucosyl epitopes of dextran B1355 in BALB/c mice and the beta-2.6 fructosyl epitope of levan in CBA mice. Acquisition of responsiveness, as measured by plaque-forming cell (PFC) assays, is relatively late - taking more than 14 days to appear and 2 - 3 months to attain maturity in the case of alpha-1.6 glucosyl and beta-2.6 fructosy. The mice responded well to sheep red blood cells and 2,4-dinitrophenylated (DNP) keyhole limpet hemocyanin (KLH) by 14 days, but were refractory to another thymus-independent antigen DNP-Ficoll. Nonresponsiveness of 2-week-old spleen cells to the polysaccharides was stable on transfer and could not be attributed to suppressor cells. Despite this long post-natal phase of immaturity, no evidence was obtained of concomitant susceptibility to tolerance induction by textran and levan. Response curves in mice injected at birth with weight-adjusted doses revealed similar or even higher "high-zone" thresholds to those tolerized at 3 months. Only partial alpha-1.3 glucosyl tolerance is inducible in adults but this was no greater after neonatal exposure, which led also to short-lived alpha-1.6 tolerance. Repeated injections of B1355 and levan during the first 10 days was no more tolerogenic and PFC appeared spontaneously with maturity in mice given these antigens neonatally. Thus, the recognized neonatal susceptibility to thymus-dependent antigens does not extend to these thymus-independent antigens. It is therefore considered that tolerance studied with polysaccharides has little relevance to the mechanism of self-tolerance acquired in the embryo and, in vivo, is determined by interaction with a relatively mature B cell rather than by "clonal abortion" of a tolerance-sensitive precursor stage.

Age Factors↗
PubMed1983

A spleen-thymus interaction is involved in the tolerization of thymocytes to xenogeneic erythrocytes.

Previous work has shown that thymocytes of rats receiving two i.v. injections, 4 days apart, of large numbers of xenogeneic erythrocytes become tolerant of the injected cells whereas peripheral T cells in the same recipients make a vigorous response to the injected antigen. Results are herein presented of experiments on the effect of splenectomy on the induction of thymocyte tolerance produced in this way. Splenectomy performed either immediately before the first injection of erythrocytes, or between the two injections, completely prevented tolerance induction and tolerance was still incomplete when splenectomy was performed as late as a few hours after the second injection of tolerogen. Sham splenectomy had no effect on the erythrocyte-induced thymocyte tolerance. The results demonstrate an essential role for the spleen in the tolerization of thymocytes in this system. Possible mechanisms and the implications for self tolerance are discussed.

Animals↗