Mercury-induced anti-nucleolar autoantibodies can transgress the membrane of living cells in vivo and in vitro.
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Treatment with HgCl2 induces a systemic autoimmune disease in certain mice and rats. The major characteristic of this disease in mice with H-2s genotype is the production of anti-nucleolar autoantibodies (ANoIA). The exact mechanism(s) for the production and the functional role of mercury-induced ANoIA are not known. We have studied the ability of mercury-induced ANoIA to enter the living cells in vivo and in vitro. We found that in highly susceptible mice, treatment with mercury induced ANoIA capable of localizing in the nucleoli of kidney and liver cells in vivo. No detectable nucleoli localization of ANoIA were found in the cells of the heart, stomach, intestine and spleen. Consistent with the in vivo studies, mercury-induced ANoIA were also able to enter and translocate in the nucleoli of certain cells in vitro. The highest degree of antibody penetration was found in A-498 cells (a human kidney cell line) followed by 3T3 cells (a mouse fibroblast cell line), whereas the cells of lymphoid origin exhibited a very low degree of antibody penetration. Penetrated ANoIA could be recovered from the nucleoli of live 3T3 cells previously treated with ANoIA. The in vitro nucleolar translocation by ANoIA did not affect the DNA synthesis, but was found to be an active process dependent on time and temperature. Furthermore, pre-treatment of living cells with trypsin markedly inhibited both cell entry and nucleolar accumulation of ANoIA. Thus, mercury-induced ANoIA have a unique ability to transgress the membrane of certain living cells in vivo and in vitro, and to localize in the nucleoli. (+info)
Activation of microvascular pericytes in autoimmune Raynaud's phenomenon and systemic sclerosis.
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OBJECTIVE: To determine the temporal and spatial relationship between platelet-derived growth factor beta (PDGFbeta) receptors, PDGF-AB/BB, and activated pericytes across the Raynaud's phenomenon (RP) and systemic sclerosis (SSc; scleroderma) disease spectrum. METHODS: Monoclonal antibodies against PDGFbeta receptors, PDGF-AB/BB, and high molecular weight-melanoma-associated antigen (HMW-MAA), a marker for activated pericytes, were used to immunohistochemically analyze serial sections of skin biopsy tissue from patients with RP and from scleroderma patients. To delineate cell-specific PDGFbeta receptor expression, double immunofluorescence-stained sections were analyzed using computer-aided image analysis and confocal microscopy. RESULTS: PDGFbeta receptor-expressing cells and HMW-MAA-expressing pericytes were found in biopsy samples from autoimmune RP patients and in both early fibrotic and early nonfibrotic scleroderma skin, but not in normal or primary RP or late-stage scleroderma skin. PDGF-AB/BB was expressed within the epidermis, at the epidermal/dermal junction, and by dermal macrophages. Analysis of juxtaposed serial sections revealed an increased frequency of receptor expression in microvessels from autoimmune RP and early scleroderma skin (P < 0.01). Double-labeling studies using confocal microscopy showed that, in vivo, PDGFbeta receptors were predominantly expressed by microvascular pericytes from both autoimmune RP and early scleroderma skin. CONCLUSION: PDGFbeta receptors are expressed by activated microvascular pericytes in patients with autoimmune RP and in early SSc patients, but not in those with primary RP or late-stage scleroderma. These findings suggest that features of autoimmune RP are distinct from those of primary RP, and that microvascular pericytes may be an important link between chronic microvascular damage and fibrosis. (+info)
Combined analysis of long-term anti-beta-cell humoral reactivity in type 1 diabetes with and without thyroid disease.
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The prevalence and levels of islet-cell antibodies (ICA) decrease in the years following diabetes onset but may persist, particularly in patients with concomitant autoimmune disease. The aim of this cross-sectional study was to investigate the frequencies, associations and levels of the major anti-beta-cell antibodies in long-standing diabetic patients (median duration: 14 years; range 5-47 years) with and without autoimmune thyroid disease (ATD) in order to consider the specific antipancreatic immunologic features associated with endocrine autoimmunity. Both ICA and glutamic acid decarboxylase (GAD) antibody (GAD-A) frequencies were increased in diabetic patients with ATD (38 vs 23%, p = 0.03 and 70 vs 21%, p < 10(-4) respectively). Although IA2-A frequency tended to be higher in diabetic patients with ATD, no significant difference was seen (37 vs 26%, p = 0.14). GAD median level was significantly higher in the diabetic group with ATD (15 vs 5 units, p < 10(-4)). IA2-A and ICA median levels were similar in both groups. Regardless of the combined analysis performed (ICA/GAD-A, ICA/IA2-A or GAD-A/IA2-A), the prevalence of combined antibody positivity was higher in diabetic patients with than without ATD. In both diabetic populations, ICA and GA-DA were significantly associated (p < 10(-4), and their levels were correlated (r = 0.42, p < 10(-4) and r = 0.584, p < 10(-4) respectively). No significant correlation was seen between IA2-A levels and either ICA or GAD-A titres. It is concluded that Type 1 diabetes mellitus with ATD is characterised by increased persistent humoral islet-related reactivity, particularly directed towards GAD. (+info)
The role of environmental antigens in the spontaneous development of autoimmunity in MRL-lpr mice.
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It has been proposed that the "normal" stimulation of the immune system that occurs from interactions with environmental stimuli, whether infectious or dietary, is necessary for the initiation and/or continuation of autoimmunity. We tested this hypothesis by deriving a group of MRL-lpr mice into a germfree (GF) environment. At 5 mo of age, no differences between GF and conventional MRL-lpr mice were noted in lymphoproliferation, flow cytometric analysis of lymph node cells (LN), or histologic analysis of the kidneys. Autoantibody levels were comparably elevated in both groups. A second experiment tested the role of residual environmental stimuli by contrasting GF mice fed either a low m.w., ultrafiltered Ag-free (GF-AF) diet or an autoclaved natural ingredient diet (GF-NI). At 4 mo of age, both groups showed extensive lymphoproliferation and aberrant T cell formation, although the GF-AF mice had approximately 50% smaller LNs compared with sex-matched GF-NI controls. Autoantibody formation was present in both groups. Histologic analysis of the kidneys revealed that GF-AF mice had much lower levels of nephritis, while immunofluorescence analysis demonstrated no difference in Ig deposits but did reveal a paucity of C3 deposition in the kidneys of GF-AF mice. These data do not support a role for infectious agents in the induction of lymphoproliferation and B cell autoimmunity in MRL-lpr mice. Furthermore, they suggest that autoantibodies do not originate from B cells that were initially committed to exogenous Ags. They do suggest a possible contributory role for dietary exposure in the extent of lymphoproliferation and development of nephritis in this strain. (+info)
De novo autoimmunity to cardiac myosin after heart transplantation and its contribution to the rejection process.
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Allograft rejection is initiated by an immune response to donor MHC proteins. We recently reported that this response can result in breakdown of immune tolerance to a recipient self Ag. However, the contribution of this autoimmune response to graft rejection has yet to be determined. Here, we found that after mouse allogeneic heart transplantation, de novo CD4+ T cell and B cell autoimmune response to cardiac myosin (CM), a major contractile protein of cardiac muscle, is elicited in recipients. Importantly, CM is the autoantigen that causes autoimmune myocarditis, a heart autoimmune disease whose histopathological features resemble those observed in rejected cardiac transplants. Furthermore, T cell responses directed to CM peptide myhcalpha 334-352, a known myocarditogenic determinant, were detected in heart-transplanted mice. No responses to CM were observed in mice that had received an allogeneic skin graft or a syngeneic heart transplant, demonstrating that this response is tissue specific and that allogeneic response is necessary to break tolerance to CM. Next, we showed that sensitization of recipient mice with CM markedly accelerates the rejection of allogeneic heart. Therefore, posttransplant autoimmune response to CM is relevant to the rejection process. We conclude that transplantation-induced autoimmune response to CM represents a new mechanism that may play a significant role in cardiac transplant rejection. (+info)
Cyclosporin A-induced autologous graft-versus-host disease: a prototypical model of autoimmunity and active (dominant) tolerance coordinately induced by recent thymic emigrants.
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Cyclosporin A (CSA)-induced autologous graft-vs-host disease (autoGVHD) is an autoimmune syndrome initiated by autoeffector T cells presumed to be exported from the thymus during CSA treatment. The appearance of noncytotoxic immunoregulatory T cell activity after cessation of CSA treatment is also thymus dependent. In the present study, we have tested the hypothesis that both autoeffector and immunoregulatory T cells in CSA-treated rats are recent thymic emigrants (RTEs). Local syngeneic graft-vs-host reaction (synGVHR) and timed thymectomy (Tx) assays revealed that autoeffector T cells appear initially in the thymus and are promptly exported to lymph nodes (LN) during the first week of CSA treatment. In contrast, immunoregulatory thymocytes are first detectable by local synGVHR inhibition assays during the second week of CSA treatment but are not exported to LN until approximately 4 days post-CSA. Both the autoeffector and immunoregulatory T cells in LN express Thy-1, a selective marker for RTEs in the rat. However, the autoeffector RTEs have a CD4+8+ phenotype, whereas the immunoregulatory RTEs have a CD4+8- phenotype. Thus, the coordinate formation in and release from the thymus cortex and medulla of autoeffector and immunoregulatory T cells in CSA-treated rats directly demonstrates that centrally induced, nondeletional tolerance can serve as a fail-safe mechanism by which clones of autoeffector T cells that have escaped intrathymic negative selection for self-MHC class II Ag can be suppressed postthymically. (+info)
A shared TCR CDR3 sequence in NOD mouse autoimmune diabetes.
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T cells involved in autoimmune diseases have been characterized by the genetic elements used to construct their autoimmune TCR. In the present study, we sequenced the alpha and beta chains of the TCR expressed by a CD4(+) T cell clone, C9, functional in NOD mouse diabetes. Clone C9 can adoptively transfer diabetes or, when attenuated, C9 can be used to vaccinate NOD mice against diabetes. Clone C9 recognizes a peptide epitope (p277) of the 60 kDa heat shock protein (hsp60) molecule. We now report that the C9 TCR beta chain features a CDR3 peptide sequence that is prevalent among NOD mice. This CDR3 element is detectable by 2 weeks of age in the thymus, and later in the spleen and in the autoimmune insulitis. Thus, a TCR CDR3beta sequence appears to be a common idiotope associated with mouse diabetes. (+info)
Activation-induced apoptosis of autoreactive and alloreactive T lymphocytes in the target organ as a major mechanism of tolerance.
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Normal individuals have mature T lymphocytes that are capable of reacting to self-antigens and can be activated by cross-reacting environmental antigens. The mechanism that maintains immune tolerance and prevents these activated autoreactive T cells from causing autoimmune disease is unclear. We have previously hypothesized that activation-induced apoptosis of previously activated autoreactive T cells in the target organ is a major mechanism for maintaining tolerance. Here I review the current evidence to support this hypothesis. It is proposed that when activated autoreactive T cells enter the target organ, they are reactivated mainly by non-professional antigen-presenting cells (APC) and deleted by activation-induced apoptosis through the Fas (CD95) pathway before producing significant target organ damage. This apoptosis occurs because the reactivated T cells do not receive sufficient costimulation from the non-professional APC to up-regulate their expression of Bcl-2-related anti-apoptotic proteins, which inhibit the CD95 pro-apoptotic pathway. This is in contrast to the situation in peripheral lymphoid organs, where reactivation of T cells by professional APC results in sufficient costimulation-induced up-regulation of Bcl-2-related proteins to inhibit the CD95 pathway and allow T cell proliferation and survival as memory T cells. Activation-induced apoptosis of alloreactive T cells in allografts can similarly account for spontaneous allograft acceptance, as occurs after MHC-mismatched liver transplantation. (+info)