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PubMed2000

[Role of the thymus in the pathophysiology of autoimmune diabetes type 1].

The induction of immunological self-tolerance begins in the thymus during fetal life. The random recombination of gene segments coding for TCR is followed by the negative selection of T cells bearing a TCR directed against self-antigens presented by thymic MHC. Insulin-like growth factor type 2 (IGF-2) is the dominant gene of the insulin family that is transcribed and translated in the thymus of different species. Contrary to the other members of the insulin gene family, IGF-2 gene (IGF2) is not transcribed in the thymus of diabetes-prone BB rats. The absence of thymic IGF2 expression is associated with the diabetogenic autoimmune process in BB rats. This defect could not only contribute to the lymphopenia of BB rats, but also to the absence of central self-tolerance of the insulin family in this animal.

Animals↗
PubMed1993

Compartmentalization of the peripheral immune system.

The periphery of the immune system--as opposed to the central lymphoid organs--contains inhomogeneously distributed B and T cells whose phenotype, repertoire, developmental origin, and function are highly divergent. Nonconventional lymphocytes bearing a phenotype that is rare in the blood, spleen, or lymph nodes of undiseased individuals are encountered at high frequency in different localizations, e.g., alpha/beta TCR+CD4-CD8- cells in the bone marrow and gut epithelium, particular invariant gamma/delta TCR+CD4-CD8 alpha+CD8 beta- and gamma/delta TCR+CD4-CD8 alpha-CD8 beta- T cells in various epithelia, or CD5+ B cells in the peritoneum. The antigen receptor repertoire is different in each localization. Thus, different gamma/delta TCR gene products dominant in each site, and the proportion of cells expressing transgenic and endogenous alpha/beta TCR and immunoglobulin gene products follows a gradient, with a maximum of endogenous gene expression in the peritoneum, intermediate values in other peripheral lymphoid organs (spleen, lymph nodes), and minimum values in thymus and bone marrow. Forbidden T cells that bear self-superantigen-reactive V beta gene products are physiologically detected among alpha/beta TCR+CD4-CD8- lymphocytes of the bone marrow, as well as in the gut. Violating previous ideas on self-tolerance preservation, self-peptide-specific gamma/delta T cells are present among intestinal intraepithelial lymphocytes, and CD5+ B cells produce low-affinity crossreactive autoantibodies in a physiological fashion. It appears that, in contrast to the bulk of T and B lymphocytes, certain gamma/delta and alpha/beta T cells found in the periphery, as well as most CD5+ B cells, do not depend on the thymus or bone marrow for their development, respectively, but arise from different, nonconventional lineages. In addition to divergent lineages that are targeted to different organs guided by a spatiotemporal sequence of tissue-specific homing receptors, local induction or selection processes may be important in the diversification of peripheral lymphocyte compartments. Selection may be exerted by local antigens, antigen-presenting cells whose function varies in each anatomical localization, cytokines, and cell-matrix interactions, thus leading to the expansion and maintenance of some clones, whereas others are diluted out or deleted. The spatial compartmentalization of lymphocytes in different microenvironments has major functional consequences and leads to a partial fragmentation of immunoregulatory circuits at the local level. Lymphocytes residing in certain antigen-exposed compartments are likely to combat tissue-specific pathogens or self-proteins.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Characteristics of autoimmunity in type 1 diabetes and type 1.5 overlap with type 2 diabetes.

This presentation is an overview of mechanisms for developing and maintaining self-tolerance in mammalian organisms. Because this meeting is focused on type 1 diabetes and its mechanisms, the discussion deals primarily with mechanisms of T-cell tolerance, since type 1 diabetes in both effector and initiator phases is primarily a T-cell-mediated autoimmune disease. Emphasis is placed on more recently discovered mechanisms of maintaining self-tolerance (autoimmune regulator [AIRE]) and a new defect in T-cell negative selection. The emerging picture is that of a polygenic disease with various combinations of different alleles of many genes with important roles in the normal immune response or normal immune responses.

Autoimmune Diseases↗
PubMed2001

Lupus autoantigens: their origins, forms, and presentation.

The immune system has developed a number of mechanisms by which to distinguish self from foreign proteins. These mechanisms are found throughout the ontogeny of B and T cell development and include the deletion of autoreactive cells in central lymphoid organs and the induction of self-tolerance in the periphery. However, any failure of these mechanisms for self-tolerance may result in autoimmune disease. Efforts in our laboratory have been directed at understanding how autoimmunity is initiated and maintained in both the B and T cell compartment, with particular interest in the autoimmunity of systemic lupus erythematosus (SLE). This review will focus on our studies on the forms of self-antigens that may be involved in the original "antigenic sin" of SLE and in the role of B lymphocytes as autoantigen presenting cells. We will also discuss whether costimulation is a formal requirement for the induction and maintenance of autoimmunity. Finally, we have provided a model for how all of these individual elements may contribute to the autoimmune processes leading to pathology.

Animals↗
PubMedDate not supplied

The thymic insulin-like growth factor axis: involvement in physiology and disease.

A repertoire of neuroendocrine-related genes is transcribed in the non-lymphoid compartment of the thymus, transposing the dual physiological role of this organ at the molecular level in T-cell development towards the establishment of central T-cell self-tolerance. The "neuroendocrine self" has been defined as a series of antigen sequences processed from precursors predominantly expressed in the thymus and first encountered by differentiating T-lymphocytes in their early life. All the members of the insulin gene family are expressed in the thymus according to a precise hierarchy and cellular topography, whereby IGF-II (epithelium of the subcapsular cortex and medulla) exceeds IGF-I (macrophages), which in turn far exceeds INS (rare subsets of medullary epithelial cells). This hierarchy in the degree of their respective thymic expression explains why IGF-II is more tolerated than IGF-I, and much more so than insulin. Evidence has been found for significant regulatory/tolerogenic properties in the IGF-II B:11 - 25 sequence after analysis of the cytokine secretion profile in peripheral blood mononuclear cells isolated from ten DQ8+ type 1 diabetic adolescents. In the thymus, IGF ligands and receptors also intervene in the control of T-cell proliferation and differentiation. Here, we also discuss how a disturbance in the intrathymic IGF-mediated signaling could contribute to the pathogenesis of T-cell leukemia.

Animals↗
PubMed2005

Regulation of immunity by self-reactive T cells.

A basic principle of immunology is that lymphocytes respond to foreign antigens but tolerate self tissues. For developing T cells, the ability to distinguish self from non-self is acquired in the thymus, where the majority of self-reactive cells are eliminated. Recently, however, it has become apparent that some self-reactive T cells avoid being destroyed and instead differentiate into specialized regulatory cells. This appears to be beneficial. Subpopulations of self-reactive T cells have a strong influence on self tolerance and may represent targets for therapeutic intervention to control a variety of autoimmune diseases, tumour growth and infection.

Animals↗
PubMed2005

Human cytolytic T lymphocytes expressing HLA class-I-specific inhibitory receptors.

MHC class-1-specific inhibitory receptors were originally described in NK cells, in which they represent an important fail-safe mechanism that induces NK cell tolerance to normal self cells. These inhibitory NK receptors (iNKRs) were subsequently found expressed on different T cell subsets, primarily CD8(+) cytolytic T lymphocytes (CTLs), in which they can inhibit T cell receptor mediated functions. Some iNKR(+) CTLs are HLA-E-restricted, represent oligo- or monoclonal expansions, and can play a defensive role in viral infections. Although T cell activation, in the presence of certain cytokines, can induce the expression of the CD94-NKG2A heterodimeric receptor, the mechanism leading to the expression of killer immunoglobulin-like receptors (KIRs) is still unknown. The expression of iNKRs in T cells might contribute to the prevention of apoptotic cell death, thus allowing their survival and clonal expansion in vivo. In addition, iNKR(+) T cells might contribute to peripheral self-tolerance.

Histocompatibility Antigens Class I↗
PubMed2004

Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches.

The role of BAFF in B cell self tolerance was examined by tracking the fate of anti-HEL self-reactive B cells in BAFF transgenic mice using four different models of self-reactive B cell deletion. BAFF overexpression did not affect the development of self-reactive B cells normally deleted in the bone marrow or during the early stages of peripheral development. By contrast, self-reactive B cells normally deleted around the late T2 stage of peripheral development were rescued from deletion, matured, and colonized the splenic follicle. Furthermore, self-reactive B cells normally selectively deleted from the marginal zone repopulated this compartment when excess BAFF was present. Self-reactive B cells rescued by excess BAFF were not anergic. BAFF overexpression therefore rescued only self-reactive B cells normally deleted with relatively low stringency and facilitated their migration into otherwise forbidden microenvironments. This partial subversion of B cell self tolerance is likely to underlie the autoimmunity associated with BAFF overexpression.

Animals↗
PubMed2002

The natural killer cell -- friend or foe in autoimmune disease?

Autoimmune diseases are chronic conditions resulting from a loss of immunological tolerance to self-antigens. Recent observations have supported an ever-broader role for innate immune responses in directing and regulating adaptive immunity, including responses to self. This review summarizes recent findings supporting important functions of natural killer (NK) cells in regulating autoimmunity. A close survey of the current literature reveals multiple steps where NK cells can regulate inflammation and intervene in loss of self-tolerance. Importantly, the findings also caution against inferring a similar role for NK cells in all autoimmune phenomena or during separate stages of the same disease. Indeed, NK cells may have different influences during the priming and the effector phases of disease. Hence, an increased understanding of the involvement of NK cells in inflammation and infection should provide new insights into the pathogenesis of autoimmune disease.

Animals↗
PubMed1983

Suppressor T cell memory. II. The role of memory suppressor T cells in tolerance to human gamma globulin.

The transient presence of suppressor T cell (Ts) activity in high-dose tolerance to human gamma globulin (HGG), and its (apparent) absence in low-dose tolerance, have been advanced as strong evidence against the concept that Ts play an important role in maintenance of immunological unresponsiveness. To analyze this question, CBA mice were exposed to high or low doses of deaggregated HGG (dHGG) and later challenged with HGG in immunogenic form (aHGG); their capacity to mount a primary or secondary suppressive response was assessed in an adoptive hapten-carrier system. Primary suppression reached a maximum 7 d after high-dose tolerance induction and gradually waned thereafter, being no longer detectable by day 30-35. Subsequent challenge of tolerant mice with aHGG, however, led to a rapid reactivation of suppression that bore the hallmarks of an anamnestic secondary response, and this effect was still demonstrable 135 d after tolerance induction. It was also shown that a single low dose of dHGG was capable of generating memory for suppression despite the absence of detectable primary suppression, indicating that the latter is not a prerequisite for induction of memory cells. The results were interpreted as indicating that tolerance, like immunity, is a manifestation of specific immunological memory. If tolerance to self-antigens is maintained by a similar mechanism, it would be expected that memory Ts could be induced during the early stages of fetal development. Mice were therefore exposed to tolerogen in utero by injection of their mothers with dHGG at day 7 of gestation, and were assessed at various times after birth for the capacity to exhibit primary or secondary suppression in adoptive transfer. Nonspecific suppression masked any specific effects during the first 5 wk of life. Antigen-specific, primary suppression was demonstrable subsequently until 10-12 wk of age, and if the animals were challenged with aHGG before transfer an anamnestic secondary suppressive response could be elicited up to 6 mo of age. These observations are consistent with the notion that memory Ts may play an important role in the maintenance of self-tolerance.

Animals↗
PubMedDate not supplied

CD4+CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2.

CD4+CD25+ T regulatory (Treg) cells control immunologic tolerance to self-antigens and play a role in suppressing antitumor immune responses, but the mechanism of suppression in vivo remains uncertain. Recently, signaling through the high-affinity interleukin-2 (IL-2) receptor has been shown to be critical for Treg cell differentiation and survival in vivo. Mice deficient in IL-2 or its receptor (CD25 or CD122) or deficient in downstream signaling molecules, including JAK-3 and STAT-5, do not develop a stable population of Treg cells and subsequently acquire lymphoproliferative disease and autoimmunity. in vitro, IL-2 is required to expand Treg cells and to induce their suppressive characteristics. Conversely, IL-2-based regimens can activate cellular antitumor immunity and are the mainstay of immunotherapies directed against melanoma and kidney cancers. Given the seemingly disparate effects of IL-2, the authors discuss the possibility that IL-2 may not be the optimal T-cell growth factor in vivo, but rather an inducer of self-tolerance. The authors propose that other gamma c-signaling cytokines, including IL-15, may be alternative choices for the immunotherapy of cancer.

Adoptive Transfer↗
PubMed2004

Complement receptor 2 and autoimmunity.

Complement receptor 2 (CR2/CD21) plays a major role in the immune response by linking innate and adaptive immunity to foreign pathogens and proteins. In addition, several lines of evidence strongly support a role for CR2 in the maintenance of tolerance to self-antigens. Both the absence of CR2 expression (along with the alternatively spliced gene product CR1) and the presence of a dysfunctional CR2 protein are tightly associated with the development of autoreactivity to nuclear antigens. Altered levels of expression of CR2 in patients with systemic lupus erythematosus support a clinically relevant role for this phenotype. Several possible mechanisms could underlie the loss of self-tolerance related to CR2, but the effect is most likely related to the failure of one or more specific checkpoints that limit autoreactivity during B cell development and immune reactions.

Animals↗
PubMed1998

A pathogenetic role for the thymoma in myasthenia gravis. Autosensitization of IL-4- producing T cell clones recognizing extracellular acetylcholine receptor epitopes presented by minority class II isotypes.

Myasthenia gravis (MG) is caused by helper T cell-dependent autoantibodies against the muscle acetylcholine receptor (AChR). Thymic epithelial tumors (thymomas) occur in 10% of MG patients, but their autoimmunizing potential is unclear. They express mRNAs encoding AChR alpha and epsilon subunits, and might aberrantly select or sensitize developing thymocytes or recirculating peripheral T cells against AChR epitopes. Alternatively, there could be defective self-tolerance induction in the abundant maturing thymocytes that they usually generate. For the first time, we have isolated and characterized AChR-specific T cell clones from two MG thymomas. They recognize extracellular epitopes (alpha75-90 and alpha149-158) which are processed very efficiently from muscle AChR. Both clones express CD4 and CD8alpha, and have a Th-0 cytokine profile, producing IL-4 as well as IFN-gamma. They are restricted to HLA-DP14 and DR52a; expression of these minority isotypes was strong on professional antigen-presenting cells in the donors' tumors, although it is generally weak in the periphery. The two clones' T cell receptor beta chains are different, but their alpha chain sequences are very similar. These resemblances, and the striking contrasts with T cells previously cloned from non-thymoma patients, show that thymomas generate and actively induce specific T cells rather than merely failing to tolerize them against self antigens.

Amino Acid Sequence↗
PubMedDate not supplied

Autoimmune chronic liver disease as a model of human autoimmunity.

Although clonal deletion and clonal energy have been demonstrated in transgenic mice, the findings that autoreactive B or T cells are present in healthy subjects suggest that they are not the sole mechanisms of tolerance. As regards helper T lymphocytes, tolerance to self-antigens can arise by preventing class II MHC expression on non-lymphoid cells and autoantigen presentation to helper T cells initiating the autoimmune response. Autoimmune chronic active hepatitis (CAH) seems to be a good model of self-tolerance bypass. Hepatocytes are able to express class II molecules and can perform accessory cell functions with respect to T cell clones generated from lymphocytes infiltrating the liver in autoimmune CAH patients. The class II antigen expression on hepatocytes may be modulated by IFN-gamma released by infiltrating T lymphocytes; thus, the activated liver cells can present autoantigens to autoreactive T cell clones. On the other hand, these findings may occur only when the upregulation of IFN-gamma or other lymphokines permits the expression of rare class II antigens on hepatocytes capable of binding particular residues of a liver-autoantigen which are recognized by specific autoreactive T cell clones binding different residues on the same epitope.

Autoimmune Diseases↗
PubMed2005

Telomerase reverse transcriptase as target for anti-tumor T cell responses in humans.

Human telomerase reverse transcriptase, a ribonucleoprotein intimately connected with the process of cell immortalization, is overexpressed in the vast majority of cancer cells, irrespective of their histological origin. Telomerase is currently viewed as the first antigen with the characteristics of common tumor antigen in humans, and it constitutes a potentially valuable target for attempts to control tumors through CD8 T cell immunity. Telomerase is a self antigen, making it possible that self tolerance imposes severe restrictions on our ability to generate effective anti-tumor immune responses in humans. In this article we review current studies on the antigenic and immunogenic properties of the human telomerase reverse transcriptase, placing them in the context of self tolerance and the size of the available CD8 T cell repertoire restricted by the HLA A2 molecule.

Antigens, Neoplasm↗
PubMed1998

Mycobacterial Cpn10 promotes recognition of the mammalian homologue by a mycobacterium-specific antiserum.

Self-tolerance, a key feature of the immune system, is still a matter of intense debate. We give here evidence for a peculiar behavior of an antiserum against Mycobacterium tuberculosis chaperonin 10 (m-Cpn10), which could have implications for the mechanism of self-recognition by antibodies against non-self. We show that this antiserum can interact in terms of both inhibition of biological activity and physical association (immunoprecipitation), with the mammalian homologue of m-Cpn10, but only if the bacterial protein is present. Several lines of evidence led us to exclude that the two proteins physically associate to form heterocomplexes: (1) the behavior of the antiserum was not shared by a monoclonal antibody against m-Cpn10; (2) a matrix selective for human Cpn10 (h-Cpn10) did not co-purify m-Cpn10; (3) the distribution pattern in non-denaturing isoelectric focusing of labeled m-Cpn10 was not altered by the presence of the unlabeled h-Cpn10. We conclude therefore that the antiserum against M. tuberculosis Cpn10 also recognizes mammalian Cpn10, with an affinity/avidity regulated by the mycobacterial protein, or by the promotion of hetero-oligomerization. This emergence of self-recognition in the presence of M. tuberculosis Cpn10 could imply a breaking of self-tolerance in situations of infection or vaccination.

Animals↗
PubMed1992

Antigen-induced apoptotic death of Ly-1 B cells responsible for autoimmune disease in transgenic mice.

Studies on transgenic mice expressing immunoglobulins against self-antigens have shown that self-tolerance is maintained by active elimination (clonal deletion), functional inactivation (clonal anergy) of self-reactive B cells, or a combination of both. We have established and characterized a transgenic mouse line expressing an anti-erythrocyte autoantibody. In contrast to other autoantibody transgenic lines, about 50% of the animals of this transgenic line suffer from autoimmune disease, indicating a loss of self-tolerance. Here we show that peritoneal Ly-1 B cells (also known as B-1 cells) are responsible for this autoimmune disease in our transgenic mice. A few self-reactive Ly-1 B cells that have somehow escaped the deletion mechanism expand in the peritoneum because of the absence of self-antigen. These Ly-1 B cells are eliminated in vivo by apoptosis once exposed to self-antigen. On the basis of these results we propose a novel autoantibody production mechanism whereby self-reactive B cells sequestered in compartments free of self-antigens may survive, proliferate and be activated for generation of pathogenic autoantibodies in autoimmune diseases.

Anemia, Hemolytic, Autoimmune↗