The peptide-binding strategy of the MHC class II I-A molecules.
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Animals↗
Biomedical subjects
F Mor
Publications and source records attributed to F Mor.
Stress and autoimmunity: the neuropeptides corticotropin-releasing factor and urocortin suppress encephalomyelitis via effects on both the hypothalamic-pituitary-adrenal axis and the immune system.
Corticotropin-releasing factor (CRF) exerts a major role in the stress response. Both CRF and urocortin, a newly discovered neuropeptide homologous to CRF, suppressed experimental autoimmune encephalomyelitis (EAE). Suppression of paralysis with CRF involved stimulation of the hypothalamic-pituitary-adrenal axis and inhibitory effects on an encephalitogenic T cell line. While CRF increased glucocorticoid production, which is known to block EAE, it also suppressed EAE in adrenalectomized rats, where glucocorticoid stimulation via CRF plays no role. Moreover, the encephalitogenicity of a T cell line exposed to CRF in vitro was reduced. Stress may influence autoimmune disease through the hypothalamic-pituitary-adrenal axis and directly via the immune system.
Animals↗
Peptide binding motifs of the MHC class I molecules (RT1.Al) of the Lewis rat.
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Animals↗
Molecular characterization of the diabetes-associated mouse MHC class II protein, I-Ag7.
The MHC class II molecule of the non-obese diabetic (NOD) mice, I-Ag7, is associated with susceptibility to autoimmune diabetes. To try to understand the molecular basis of this association, we analyzed the peptide binding properties and intracellular behavior of I-Ag7 in comparison with other I-A haplotypes. We found that I-Ag7 molecules manifested normal intracellular trafficking and lifespan, and a small but clearly detectable fraction of I-Ag7 in the cells formed SDS-resistant compact dimers. The binding of an antigenic reference peptide to I-Ag7 was stable and was accompanied by compact dimer formation. Our analysis of the binding specificity of I-Ag7 revealed a peptide binding motif of nine amino acids with a degenerate position at P1 and three conserved anchor positions: P4, P6 and P9. An allele-specific preference for negatively charged residues was found at P9, apparently due to the presence of the rare Ser residue at position 57 of the I-Ag7 beta chain. These findings could have implications for the mechanisms of MHC-mediated susceptibility to autoimmune diabetes in the NOD mice.
Amino Acid Sequence↗
IL-2 and TNF receptors as targets of regulatory T-T interactions: isolation and characterization of cytokine receptor-reactive T cell lines in the Lewis rat.
T cells are considered to be of prime importance in immune regulation of both B and T cell functions. The targets of recognition in T-T cell interactions are not clear. Most recent experimental work has focused on the idiotypic regulatory interactions mediated by TCR peptides. There is experimental evidence that regulatory cells exist that do not recognize the TCR. This type of regulation is selectively induced by activated T cells. Therefore, we designed this study to examine the possible role of cytokine receptors as targets of immune regulation. We tested two peptides of IL-2R alpha-chain, 2 of IL-2R beta-chain, and one of TNFR (p60). All peptides were found to be immunogenic at inducing T cell proliferation and four induced Abs in Lewis rats. We generated T cell lines to these five peptides, and tested them both in vitro and in vivo. We found that the T cells exhibited a proliferative response when cultured with activated, irradiated stimulator cells that were augmented upon addition of the cytokine receptor peptide. The cytokine profile of the lines was characterized as well as the Vbeta gene composition. One of the lines significantly protected against active encephalomyelitis. These results point at cytokine receptors as possible targets of immune regulation and T-T cell interactions.
Amino Acid Sequence↗
The dominant and the cryptic T cell repertoire to myelin basic protein in the Lewis rat.
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Animals↗
IL-2 rescues antigen-specific T cells from radiation or dexamethasone-induced apoptosis. Correlation with induction of Bcl-2.
Most studies of apoptosis on T lymphocytes have examined the effects of various stimuli on immature T cells from the thymus. Previous work has indicated that apoptosis of mature memory T cells may be an important pathophysiologic mechanism in diseases such as AIDS, cancer, and autoimmunity. The effect of IL-2 on apoptosis of T cells is not clear. Therefore, we studied the ability of IL-2 to rescue Ag-specific T cells from apoptosis. We found that IL-2, in a dose-dependent manner, prevented T cells from entering apoptosis induced by gamma-irradiation, mitomycin C, or dexamethasone. This effect was specific for IL-2; IL-1 beta, IL-6, or IFN-gamma could not reproduce it. In contrast to Ag-specific T cells, immature T cells and naive mature peripheral T cells could not be rescued by IL-2 from radiation-induced apoptosis. Apoptosis rescue by IL-2 was associated with the induction of bcl-2 mRNA and protein. This induction could not be attributed to the effects of IL-2 on the cell cycle, as T cells that were prevented from cell cycle progression by irradiation showed a similar induction of bcl-2. Rescued cells retained their Ag-specific proliferative capacity and in vivo functions. These findings demonstrate that the apoptotic death of Ag-specific T cell lines, cells which can be regarded as a model for memory T cells, can be prevented with IL-2. This effect may have important therapeutic implications for patients receiving chemotherapy or radiotherapy, and for patients with AIDS who develop immunodeficiency primarily as a result of loss of Ag-specific memory T cells.
Amino Acid Sequence↗
Suppressive vaccination with DNA encoding a variable region gene of the T-cell receptor prevents autoimmune encephalomyelitis and activates Th2 immunity.
A variable region gene of the T-cell receptor, V beta 8.2, is rearranged, and its product is expressed on pathogenic T cells that induce experimental autoimmune encephalomyelitis (EAE) in H-2u mice after immunization with myelin basic protein (MBP). Vaccination of these mice with naked DNA encoding V beta 8.2 protected mice from EAE. Analysis of T cells reacting to the pathogenic portion of the MBP molecule indicated that in the vaccinated mice there was a reduction in the Th1 cytokines interleukin-2 (IL-2) and interferon-gama. In parallel, there was an elevation in the production of IL-4, a Th2 cytokine associated with suppression of disease. A novel feature of DNA immunization for autoimmune disease, reversal of the autoimmune response from Th1 to Th2, may make this approach attractive for treatment of Th1-mediated diseases like multiple sclerosis, juvenile diabetes and rheumatoid arthritis.
Amino Acid Sequence↗
The peptide binding specificity of the MHC class II I-A molecule of the Lewis rat, RT1.BI.
The specificity of peptide binding to MHC molecules is defined by binding motifs composed of several relatively conserved anchor positions. The peptide binding motifs of murine MHC class II I-A molecules are functionally important but poorly characterized. Here we use peptide binding studies and isolation of naturally presented peptides to characterize the peptide binding motif of the MHC class II I-A molecule, RT1.BI, a molecule that is involved in experimental autoimmunity in the Lewis rat. We now report that, similar to other class II motifs, the RT1.BI motif consists of a nonamer sequence with four major anchor positions (P1, P4, P6 and P9). Residues at P4 and P9, rather than at P1, appeared to be particularly important for binding. Negatively charged residues were favored at P9, consistent with the presence of a serine at position 57 of the RT1.BI beta chain. This RT1.BI motif could be observed in the dominant autoantigenic T cell epitopes mapped previously in the Lewis rat. These results highlight a general similarity and some important differences in the organization of MHC class II peptide binding motifs. The reported RT1.BI motif should facilitate the prediction and design of T cell epitopes for the induction and control of experimental autoimmune diseases in Lewis rat models.
Amino Acid Sequence↗
Pathogenicity of T cells responsive to diverse cryptic epitopes of myelin basic protein in the Lewis rat.
The cellular immunology of experimental autoimmune encephalomyelitis, a model for multiple sclerosis, has been studied, for the most part, using T cells directed to dominant epitopes of the Ag myelin basic protein (MBP). To characterize T cells reactive to cryptic epitopes of MBP, we immunized Lewis rats with each of 17 overlapping peptides of the 18.5-kDa isoform of rat MBP. We found that, in addition to the known 71-90 epitope, six other peptides induced active encephalomyelitis in the majority the injected rats. T cell lines raised to six different MBP epitopes were encephalitogenic upon adoptive transfer to naive rats. In contrast to the T cells specific for the dominant 71-90 peptide, the T cell lines reactive to cryptic epitopes were not restricted in their TCR genes to V beta 8.2, and some of the lines caused prolonged disease. Thus, T cells of different specificities and TCR usage can be pathogenic.
Amino Acid Sequence↗
Differential effects of polysulfated polysaccharide on experimental encephalomyelitis, proliferation of autoimmune T cells, and inhibition of heparanase activity.
The extravasation of activated T lymphocytes through blood vessel walls and their migration to inflammatory loci are associated with secretion of extracellular matrix (ECM)-degrading enzymes, such as heparanase, which degrades heparan sulfate (HS) moieties of the ECM. The HS-degrading activity of heparanase was found to be inhibited by HS and heparin. Since induction of experimental autoimmune encephalomyelitis (EAE) requires extravasation and migration of autoimmune T cells, degradation of ECM by heparanase is expected to be involved in induction of the disease. Herein, we examined whether laminarin sulfate, a polysulfated polysaccharide (PSS) isolated from the cell walls of seaweeds and subjected to chemical sulfation, could inhibit ECM degradation by mammalian heparanase, and could prevent EAE. PSS was a more potent inhibitor of heparanase-mediated degradation of ECM than heparin. In-vivo, PSS, injected once a week, inhibited the severity of actively-induced EAE in rats. However, inhibition of EAE was not due to an overall suppression of autoimmune T cells, since PSS enhanced the proliferation of myelin basic protein (MBP)-specific, encephalitogenic T cells. PSS-activated autoimmune T cells, but not MBP-activated cells, failed to induce EAE in recipient rats. Moreover, rats injected with PSS-activated T cells were resistant to induction of EAE by anti-MBP CD4+ T cells. Thus, PSS may have potential clinical applications in the treatment of autoimmune diseases.
Animals↗
Functional activation of encephalitogenic T cells in the absence of antigen-presenting cells.
Co-stimulatory signals provided by surface receptors of antigen-presenting cells (APC) are crucial for the activation of CD4+ T cells, classically measured by cell proliferation or IL-2 secretion. The contribution of APC co-stimulatory signals to the acquisition of various effector functions by activated T cells is not fully understood. We have now examined the importance of surface-mediated co-stimulation by APC for activation of the effector potential of T cell clones mediating experimental allergic encephalomyelitis (EAE). We now report that T cell clones can be activated to produce EAE not only with APC but also by antibody-mediated TCR cross-linking in the presence of a mixture of T cell growth factors. Without activation, the T cell clones did not cause EAE. Therefore, at least some types of T cells can be activated to express their effector potential in the absence of any surface co-stimulatory signals requiring intact APC.
Animals↗
Vaccines to prevent and treat autoimmune diseases.
The current therapy for human autoimmune disease is based on nonselective immunosuppression achieved by corticosteroids or cytotoxic drugs. This form of therapy is toxic and frequently not effective in curing the disease. The study of experimental autoimmune disease models indicates that the pathogenic population of immune cells is restricted in terms of T-cell receptor gene usage and peptide epitopes recognized in the self-antigens. The recent developments in understanding of the pathophysiology of autoimmune disease point to the crucial role of the pathogenic T cell, the autoantigenic peptide, and the major histocompatibility complex molecules as well as the regulatory T-cell population in the disease process. The purpose of this review is to describe the use of vaccines to prevent and treat autoimmune disease. Encouraging results in animal models using vaccines based on the pathogenic T cell or the autoantigen have prompted the design of novel and selective immune-based therapies for human autoimmune disease.
Animals↗
Expression of major histocompatibility complex class II molecules in rat T cells.
The expression of major histocompatibility complex (MHC) class II molecules in murine T cells has been controversial. We therefore reexamined the transcription, synthesis and surface expression of MHC class II determinants in rat T cells both in vivo and in vitro. In naive rats, a large proportion of small CD4+8+ and mature CD4+8-/CD4-8+ thymocytes was found to be MHC class II positive. At least some of the MHC class II molecules found on thymocytes were actively synthesized. The synthesis of MHC class II proteins was detected in peripheral T cells activated in vivo during induction of experimental allergic encephalomyelitis (EAE). A proportion of T cells from the inflammatory lesion of EAE exhibited MHC class II on the surface. A panel of helper T cell lines and clones was shown to synthesize MHC class II proteins. In a prototypic clone, a weak constitutive expression of MHC class II was observed. During activation, the rate of endogenous MHC class II synthesis increased and passive absorption of surface MHC class II from other cells occurred. Our data demonstrate the expression of MHC class II molecules in rat T cells in both the thymus and periphery. Since the primary function of MHC class II molecules is the presentation of peptide epitopes to T cells, these results call attention to the possible role of MHC class II molecules in T-T interactions during T cell maturation and activation.
Animals↗
T cell immunity to myelin basic protein induces anterior uveitis in Lewis rats.
Uveitis of unknown etiology is known to occur in association with various systemic disorders. We now report that anterior uveitis (AU) can be produced by T cell immunity to myelin basic protein (BP) and accompanies experimental autoimmune encephalomyelitis (EAE). EAE with AU was induced in Lewis rats by immunization to BP in CFA or by immunization to various BP peptides including the encephalitogenic 71-90 peptide. Slit-lamp biomicroscopy of BP-immunized Lewis rats revealed AU, characterised by inflammation of the iris, in 73% of the eyes. The onset of AU in actively immunized rats varied between days 12 and 26, often appearing after spontaneous remission of the paralysis, the hallmark of EAE. The course of AU was progressive, affecting more than 50% of the surface of the iris in 16 of 29 diseased eyes. Like the paralysis, the AU was self-limiting: within 2 weeks the disease remitted. In addition, AU could be adoptively transferred to naive and irradiated rats by a T cell clone specific for BP peptide 71-90. The present observations are compatible with the idea that AU may be triggered by BP-reactive T cells. The myelinated nerves present in the iris have been shown to contain BP. However, these peripheral nerves would now appear to be the only peripheral nerves susceptible to acute EAE.
Amino Acid Sequence↗
T cell vaccines for autoimmune diseases.
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Animals↗
Shifts in the epitopes of myelin basic protein recognized by Lewis rat T cells before, during, and after the induction of experimental autoimmune encephalomyelitis.
An epitope present in the 71-90 sequence of basic protein (BP) has been identified as the dominant epitope recognized by most Lewis rat encephalitogenic T cells isolated during experimental autoimmune encephalomyelitis (EAE). In the present study, we investigated the BP epitopes recognized by Lewis rat T cells in naive rats, in rats suffering from acute EAE, and in recovered rats. T cells isolated from the spinal cord lesions and from the lymph nodes were studied using T cell lines and bulk cultures. Virulence of the T cells was assayed by adoptive transfer. We now report that naive and recovered Lewis rats are populated with T cells reactive to a variety of BP epitopes and only a minority are specific for the 71-90 epitope. In contrast, the induction of EAE was associated with a predominance of T cells reactive to the 71-90 epitope. T cells recovered from naive, diseased, or recovered rats were found to be virulent upon passive transfer. Some of these virulent T cells were specific to BP epitopes other than the 71-90 epitope. There was no major difference in the BP specificities of T cells isolated from the lesions and from the lymph nodes. Thus, natural T cell reactivity to BP is heterogeneous and pathogenicity is not confined to one particular epitope, active disease is characterized by a dominant response to the 71-90 epitope, and recovery is marked by a return to heterogeneity.
Acute Disease↗
On the regulation of EAE.
This paper describes some of the factors involved in the regulation of EAE and of autoimmunity in general. The immunological homunculus is discussed.
Adjuvants, Immunologic↗