Showing papers in "Autoimmunity in 1993"
TL;DR: Human T cell lines specific for an immunodominant region of MBP were shown to have a functional phenotype similar to T helper 1 (Th1) inflammatory cells of the mouse on the basis of their antigen-specific cytotoxic activity and production of interferon-gamma and lymphotoxin/tumor necrosis factor-alpha, but not interleukin-4.
Abstract: Multiple sclerosis (MS) is widely accepted as an autoimmune disease with myelin basic protein (MBP) a candidate autoantigen. In the current report, human T cell lines specific for an immunodominant region of MBP were shown to have a functional phenotype similar to T helper 1 (Th1) inflammatory cells of the mouse on the basis of their antigen-specific cytotoxic activity and production of interferon-gamma and lymphotoxin/tumor necrosis factor-alpha, but not interleukin-4. In experimental allergic encephalomyelitis (EAE), a proposed animal model for MS, MBP-specific T cell lines which mediate disease are of the Th1 subtype. Thus, MBP-specific T cells in humans exist which are phenotypically similar to MBP-specific encephalitogenic T cells in murine EAE.
141 citations
TL;DR: It is demonstrated that IgG prepared from patients with Graves' disease with or without overt ophthalmopathy interact with IGF-1 binding sites on orbital fibroblasts whereas IgG from normal subjects had no significant effect.
Abstract: Graves' disease is an autoimmune disorder but the nature of the association between hyperthyroidism and ophthalmopathy is not yet understood. Serum autoantibodies to orbital tissues have previously been identified and the cross-reactivity with orbital and thyroid antigens has been implicated in the development of thyroid-associated ophthalmopathy (TAO). The ophthalmopathy of Graves' disease is remarkable for the hypertrophy of extraocular muscles and proliferation of fibroblasts within the orbit; features which suggest a possible involvement of growth factors. The present study was therefore undertaken to investigate the interaction of IgGs extracted from the sera of patients with Graves' disease, with or without overt ophthalmopathy, with respect to IGF-1 receptor binding sites on fibroblasts from human orbital tissue. IGF-1 binding sites were demonstrated on human orbital fibroblast monolayers grown from eye muscle explants. These cells exhibited a population of high affinity IGF-1 binding sites (Kd, 0.5nM SEM +/- 0.05). IgG prepared from sera taken from patients with Graves' disease (n = 23) significantly inhibited [125I]IGF-1 binding to orbital fibroblasts when compared to IgGs prepared from normal volunteers (n = 13, p < 0.002). It was found that 12 of 23 (52%) patients' IgG samples gave rise to significant levels of inhibition of [125I]IGF-1 binding to orbital fibroblasts. The IgG preparations did not bind directly to IGF-1. This study demonstrates that IgG prepared from patients with Graves' disease with or without overt ophthalmopathy interact with IGF-1 binding sites on orbital fibroblasts whereas IgG from normal subjects had no significant effect.(ABSTRACT TRUNCATED AT 250 WORDS)
121 citations
TL;DR: In vivo and in vitro results suggest that systemic IFN-Gamma serves as a physiological regulator of a suppressor mechanism in EAE, and the abrogation of this regulatory mechanism by anti-IFN-gamma administration contributes to a more severe form of experimental allergic encephalomyelitis.
Abstract: Interferon-gamma (IFN-gamma) is a cytokine with multiple activities on a variety of cells. Under various circumstances, IFN-gamma can exhibit either pro-inflammatory or inhibitory actions. Treatment of SJL/J mice with a monoclonal antibody (Mab) to IFN-gamma during the afferent limb of the immune response to myelin protein produced an enhancement of acute experimental allergic encephalomyelitis (EAE), with increased morbidity, mortality and earlier onset of disease. Systemic administration of IFN-gamma did not improve or worsen clinical outcome, but delayed disease onset. Passive transfer of immune lymph node cells co-activated with MBP and anti-IFN-gamma Mab resulted in more sever disease than that induced by MBP stimulated cells or MBP and IFN-gamma co-stimulated cells. However, in vitro proliferation of an MBP specific T cell line was not influenced by IFN-gamma nor anti-IFN-gamma treatment. Mab to IFN-gamma inhibited suppressor function, in a non-specific assay. These in vivo and in vitro results suggest that systemic IFN-gamma serves as a physiological regulator of a suppressor mechanism in EAE. The abrogation of this regulatory mechanism by anti-IFN-gamma administration contributes to a more severe form of experimental allergic encephalomyelitis.
115 citations
TL;DR: The evaluation of autoantibody abnormalities in all cases of suspected autoimmune-associated reproductive failure is valuable and will improve clinical care of affected patients, and Clinicians need to adjust their clinical management to the degree and quality of autoantsibody evaluation available to them in their community.
Abstract: Condensation: The diagnosis and treatment of autoantibody-associated forms of reproductive failure is critically reviewed.OBJECTIVE: To critically evaluate the published literature in reference to autoantibody-associated forms of reproductive failure.LOCATION: Medical School-affiliated private Infertility Center.MATERIALS: A review of over 200 published papers reflecting on the topic.RESULTS: Autoantibody associated reproductive failure, characterized by a decrease in fecundity and an increase in the risk of pregnancy loss, appears established. Autoantibody abnormalities, as routinely detected by standard laboratory assays, are, however, neither immunologically nor biologically specific since cross reactivities between autoantibodies are frequent and a specific autoantibody may cause a biological effect in one but not in another affected individual.CONCLUSIONS: The evaluation of autoantibody abnormalities in all cases of suspected autoimmune-associated reproductive failure is valuable and will improve cli...
84 citations
TL;DR: The antigenic difference between the native and denatured Ro/SSA isoforms is studied and it is found that the autoanti-Ro/Ssa response to the native 60 kD antigen is quite homogeneous.
Abstract: Recent studies have shown that Ro/SSA autoantigen is heterogeneous and the autoanti-Ro/SSA response is correspondingly heterogeneous. There are two isoform families; the 60 kD forms and the 52 kD forms.We studied the antigenic difference between the native and denatured Ro/SSA isoforms and found that the autoanti-Ro/SSA response to the native 60 kD antigen is quite homogeneous. All anti-Ro/SSA sera recognize the native kD antigen regardless of the reactivities to the 60 kD band on the Western blot. Surprisingly, no anti-Ro/SSA sera without anti-La/SSB reacts with the native 52 kD Ro/SSA, although sera with both precipitating anti-Ro/SSA and anti-La/SSB can immunoprecipitate the native 52 kD antigen.Anti-Ro/SSA sera exist which react exclusively with the native 60 kD Ro/SSA protein (10/43. 232) while no anti-Ro/SSA sera have been found which react exclusively with the denatured 52 kD Ro/SSA antigen. In sera with anti-Ro/SSA precipitins alone, only antibody to the denatured 52 kD Ro/SSA molecule is found! I...
84 citations
TL;DR: The results suggest that the CD45R0+ subset is relatively more sensitive than CD45RA+ subset to the inhibitory effects of 1,25-(OH)2 D3, which may be of pharmacological interest, because these cells have been associated with the pathogenesis of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.
Abstract: 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3), the biologically active form of vitamin D3, has been shown to modulate lymphocyte functions in vitro. These effects are exerted through binding to specific receptors that are expressed in activated, but not in resting lymphocytes. 1,25-(OH)2 D3 inhibits lymphocyte proliferation, immunoglobulin production and the release of cytokines including interleukin-2 (IL-2) and interferon gamma (IFN gamma) by mitogen driven blood mononuclear cells (MNC). A distinction between CD45RA+ and CD45R0+ subsets of T cells has, however, proven extremely relevant in terms of immunoactivation and immunopathology. The present study was undertaken to evaluate effects of 1,25-(OH)2 D3 on proliferation and cytokine production by purified CD45RA+ and CD45R0+ T cells. 1,25-(OH)2 D3 caused a dose- and time-dependent reduction in phytohemagglutinin-(PHA) and poke-weed mitogen (PWM)-driven proliferation of purified CD45R0+ T cells. In contrast, proliferation of the CD45RA+ subset was unaffected by this treatment. Comparable levels of lymphotoxin (LT), IFN gamma and IL-2 were obtained in cultures of both subsets. 1,25-(OH)2 D3 reduced these levels, but the suppressive effect of the hormone was delayed in cultures of CD45RA+ T cells. The results suggest that the CD45R0+ subset is relatively more sensitive than CD45RA+ subset to the inhibitory effects of 1,25-(OH)2 D3. This finding may be of pharmacological interest, because the CD45R0+ subset plays a key role in immune activation and because these cells have been associated with the pathogenesis of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.
81 citations
TL;DR: Results indicate that nitric oxide produced by the inducible isoform of Nitric oxide synthase mediates cytokine induced islet dysfunction and destruction, and that the beta-cell is the islet endocrine cellular source of constitutive nitricoxide synthase.
Abstract: Nitric oxide has recently been implicated as a cellular effector molecule that mediates interleukin-1β (IL-lβ)-induced inhibition of glucose-stimulated insulin secretion by islets of Langerhans. In this study evidence is presented which demonstrates that islets contain both the cytokine inducible and the constitutive isoforms of nitric oxide synthase as determined by NADPH diaphorase staining and immunohistochemical localization. Untreated islets contain NADPH diaphorase activity, and the intensity of NADPH diaphorase staining is dramatically increased after culture for 18 hrs with IL-1β. Both control and IL-lβ-induced NADPH diaphorase staining of islets is inhibited by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (NMMA). Importantly, ~60–70% of islet cells stained positive for NADPH diaphorase (under both IL-1β treated and control conditions), suggesting that a subset of islet cells contain nitric oxide synthase. The β-cell appears to be the endocrine cell type which contains constitutive...
81 citations
TL;DR: Construction of a detailed model for the natural history of autoimmune diabetes is permitted, based on a TH2- and not a TH1-mediated scheme, and questions the more popular concepts currently thought to form the bases of the autoimmune reactions underlying IDD.
Abstract: Type I, insulin-dependent diabetes (IDD) in both man and animals results from a specific autoimmune destruction of the pancreatic beta cells involving both humoral and cellular immune mechanisms. The pathognomonic histologic lesion, termed insulitis, is an inflammatory and immune cell infiltrate of the pancreatic islet cells. While recent histological and flow cytometric analyses have identified the cell composition of the infiltrate, the presence of a cell population may not reflect the functional reactivities important for beta cell destruction. In the present study, we have investigated the possible functional reactivities of islet-infiltrating mononuclear cell populations by measuring increased cytokine mRNA usage. Results indicate that 1) cytokine mRNA profiles exhibited by islet-infiltrating cells of female and male NOD mice were quite similar with the exception of IL-6 expression and the marked differences in the levels of IL-2 receptor and IL-1 alpha mRNA, 2) CD4+ T lymphocytes expressed IL-4, presumably IL-5, and occasionally IL-10 mRNA but no detectable IL-2 mRNA, 3) CD8+ T lymphocytes exhibited TNF-beta, perforin and high levels of IFN-gamma, and 4) IL-7 was expressed in the islet at very high levels. These findings, together with our earlier flow cytometric analyses of the islet-infiltrating cells, have permitted construction of a detailed model for the natural history of autoimmune diabetes. Interestingly, this model, based on a TH2- and not a TH1-mediated scheme, questions the more popular concepts currently thought to form the bases of the autoimmune reactions underlying IDD.
80 citations
TL;DR: The recent findings suggest that while in healthy subjects the majority of natural polyreactive antibodies is encoded in V genes in germline configuration, some polyre active antibodies are encoded in somatically mutated V genes, in a fashion consistent with an antigen-driven process of selection of such mutations.
Abstract: The delineation of distinct subsets committed to the production of antibodies with different antigen-binding activities supports the view of a compartmentalization and specialization of function in the B cell repertoire and is consistent with the hypothesis of a developmentally layered immune system; as originally proposed by Herzenberg and Herzenberg. On the basis of the data by Solvason and Kearney in the human fetus and our data in the adult, and in agreement with the findings of Herzenberg et al. and Hardy et al. in the mouse, we propose that the human B cell repertoire includes at least three distinct B cell subsets: B-1a cells, which develop from progenitors in the fetal splanchnic district, namely the omentum, and are maintained in adult life by virtue of their self-replenishing nature; B-1b cells, progenitors of which can be found in the splanchnic district and, perhaps, adult bone marrow; and, finally, B-2 cells, which arise in the fetal liver and are continuously replenished in adult life by progenitors in the bone marrow (Figure 5). The different B cells types are distinguished by their differential expression of surface CD5 and, perhaps, CD11b and CD14, their differential expression of CD5 mRNA, and the different classes and specificities of the Ig they produce (Figure 5). B-1 lymphocytes play a major role in autoimmunity and constitute the physiological equivalent of the neoplastic forms in various lymphoproliferative disorders, such as CLL and SLL, which are often associated with the production of monoclonal antibodies to self antigens. Human B-1a (CD5+ B) and B-1b (CD5- CD45RAlo B) cells are responsible for the production of natural (polyreactive and monoreactive) antibodies in the fetus, neonate, and adult, and can give rise to the autoantibody-producing cells characteristic of several autoimmune disease states. Our recent findings suggest that while in healthy subjects the majority of natural polyreactive antibodies is encoded in V genes in germline configuration, some polyreactive antibodies are encoded in somatically mutated V genes, in a fashion consistent with an antigen-driven process of selection of such mutations. The nature of the antigen(s) involved in these selection processes remains to be determined. Under possibly different circumstances, the application of an antigen-driven process of clonal selection to B-1a and/or B-1b cells, previously committed to natural antibody production, can result in the generation of monoreactive high affinity and possibly pathogenic autoantibodies (Figures 5A and 5B).(ABSTRACT TRUNCATED AT 400 WORDS)
79 citations
TL;DR: The studies show that the oral administration of CII alters the subsequent immune response to the arthritogenic challenge and indicate that this oral tolerance of C II is due, not to clonal deletion or anergy, but rather to an antigen-driven active suppression mechanism that affects both T cells and B cells, most likely through the action of regulatory cytokines IL-4, IL-10 and TGF beta.
Abstract: The oral administration of CII by gavage to WA/KIR rats before a conventional arthritogenic challenge with bovine CII in FIA reduced the incidence (by 23%) and delayed the onset of collagen-induced arthritis in about 50% of the animals. Selective changes in B cell and T cell responses to CII in animals treated this way are interpreted to indicate a state of tolerance or hyporesponsiveness to CII. Tolerant animals made less serum antibody, to bovine and rat CII, of the IgG2b isotype and more of the IgG1 isotype. Phenotypic and functional analysis of peripheral lymph node cells showed that those from tolerized animals expressed less MHC Class II, proliferated less and secreted less IgG2b anti-CII antibody in response to stimulation in vitro with CII when compared with cells from non-tolerant animals. However, this depression of the immune responses to CII seen in vitro was overcome when the cells were incubated with increasing amounts of CII. Tolerance could be transferred to normal animals. Spleen cells, and nylon wool-filtered splenic T cells (but not mesenteric lymph node cells) adoptively transferred hyporesponsiveness to normal recipients which were then less susceptible to collagen-induced arthritis. Transfer of serum from gavaged animals did not modify the susceptibility of normal recipients to arthritis. Spleen cells from gavaged animals suppressed proliferative and antibody responses in co-cultures in vitro with lymph node cells from animals immunized with CII in FIA. The suppressive spleen cell population contained more cells expressing MHC Class II, in both the CD8+ and CD4+ populations. These studies show that the oral administration of CII alters the subsequent immune response to the arthritogenic challenge and indicate that this oral tolerance of CII is due, not to clonal deletion or anergy, but rather to an antigen-driven active suppression mechanism that affects both T cells and B cells, most likely through the action of regulatory cytokines IL-4, IL-10 and TGF beta.
74 citations
TL;DR: A cDNA encoding the extracellular domain of human TSHr (ETSHr) was expressed in large quantities using the baculovirus expression system and has an apparent molecular weight of 50 kDa and is larger than the predicted size of 44 kDa, suggesting that the protein is glycosylated.
Abstract: A cDNA encoding the extracellular domain of human TSHr (ETSHr) was expressed in large quantities using the baculovirus expression system. Maximum level of protein was produced at 60 hr post-infection and represented approximately 20% of the total cellular protein. The identity of the protein as ETSHr was confirmed by Western blot using antibodies to synthetic peptides derived from the TSHr. The protein has an apparent molecular weight of 50 kDa and is larger than the predicted size of 44 ma, suggesting that the protein is glycosylated. Polyclonal antibodies raised in rabbits against gel purified ETSHr blocked the binding of 125I-TSH to native TSHr in solubilized porcine thyroid membranes in a radioreceptor assay. The availability of this antigenically active protein will facilitate further characterization of the protein and analysis of immune response against TSHr in experimental animals as well as in patients with autoimmune Graves' disease.
TL;DR: It is suggested that this imbalanced cytokine production may well account for the pattern of immune response which may be observed in elderly, i.e. a normal or increased humoral response in face of a low T cell immune responsiveness.
Abstract: It is well known that ageing is associated with various alterations of the lymphoid cell functions. Although both B and T cell are affected, the last appear to be more sensitive to ageing process. During the past years, to gain insight into the mechanism(s) of this impairment, effort has been centered on the helper T cells specifically engaged in the production of interleukin-2 (IL-2) because of the pivotal role played by this cytokine in the activation of several immune functions. The results have demonstrated that the ability to produce IL-2 declines with age. In this paper we report the results of a study performed to determine the influence of age on the capacity to produce γ-interferon (γ-IFN), interleukin-4 (IL-4) and interleukin-6 (IL-6). Mononuclear cells from young and old subjects were assessed for cytokine producing capacity in response to phytohaemoagglutinin stimulation. A significant decrease of γ-IFN production by old subjects has been observed. No significant difference was instead observe...
TL;DR: It appeared that a widespread infiltration of the exocrine pancreas with single dendritic-like cells, and T-cells, and little clusters of these cells were normal features of fetal and neonatal pancreases, but in the diabetic case these infiltrative patterns were more pronounced.
Abstract: Lymphoid cell infiltrates were analyzed using immunohistochemical techniques on 5 normal fetal and 6 normal neonatal pancreases. Data were compared to data obtained analyzing the lymphoid cell infiltrates in the pancreas of an 8 months old diabetic infant. In the normal fetal and neonatal pancreases islets were intact and not infiltrated. In the diabetic infant beta-cells had vanished in almost all islets, the remaining islets showed a minor infiltration with primarily T-cells, a few B-cells, and some classical macrophages. It appeared that a widespread infiltration of the exocrine pancreas with single dendritic-like cells, and T-cells, and little clusters of these cells were normal features of fetal and neonatal pancreases. In the diabetic case these infiltrative patterns were more pronounced. Larger accumulations of such lymphoid cells could also be detected in the normal fetal and neonatal pancreases and these consisted mainly of T-cell zones, sometimes containing HEV's, with intermingled interdigitating dendritic cells and a few macrophages. This architecture is reminiscent of peripheral lymphoid tissue, such as bronchus-or gut-associated lymphoid tissue. The function of this fetal/neonatal intrapancreatic lymphoid tissue (which disappears in later life) is unknown. Various possibilities are suggested such as a yet unknown ubiquitous fetal/neonatal microbial infection, tolerance induction towards islet cell antigens, an endocrine regulatory function of infiltrated lymphoid cells, and a normal ontogenetic process.
TL;DR: It is suggested that microbes may act to modulate the immunological status or immune repertoire of an individual genetically programmed for IDDM away from an autoimmune response.
Abstract: For some time now, microbial agents have been implicated in the etiology of autoimmune diseases, including insulin dependent diabetes mellitus (IDDM). Recent studies, however, have revealed that exposure of genetically diabetes-susceptible animals to certain microbes or microbial agents at an early age prevents the induction and progression of disease. This suggests that microbes may act to modulate the immunological status or immune repertoire of an individual genetically programmed for IDDM away from an autoimmune response. Immunization with microbial agents at an early age may offer an important new direction for the immunotherapy of IDDM.
TL;DR: Reactivity of anti- parietal cell autoantibodies with the 95 kDa α subunit is optimal when the SDS-PAGE is carried out with samples which are reduced but not boiled, whereas reactivity with the 60-90 kDa β sub unit is optimal with samplesWhich are boiled but not reduced.
Abstract: We have previously shown that parietal cell autoantibodies predominantly react with a 60-90 kDa gastric autoantigen, subsequently identified as the beta subunit of the gastric H+/K(+)-ATPase (EC 3.6.1.3) (proton pump) whereas Karlsson et al showed that these autoantibodies primarily target the 95 kDa alpha subunit of the pump. In view of these discordant results, we have reassessed the reactivity of parietal cell autoantibodies with the two subunits of the gastric H+/K(+)-ATPase. We show here that all 26 parietal cell autoantibody-positive sera immunoblot both subunits under appropriate, but mutually exclusive, conditions. Thus, reactivity of anti-parietal cell autoantibodies with the 95 kDa alpha subunit is optimal when the SDS-PAGE is carried out with samples which are reduced but not boiled. Whereas reactivity with the 60-90 kDa beta subunit is optimal with samples which are boiled but not reduced. Autoantibody reactivity with the beta subunit is critically dependent on the presence of a full complement of N-linked glycans since partially deglycosylated protein, and recombinant beta subunit expressed in COS cells, bearing high mannose N-glycans, failed to bind to the autoantibody. These studies also suggest that B cell auto-epitopes are located on the lumenal domain of the beta subunit. Reactivity of parietal cell autoantibodies with a bacterial fusion protein incorporating the catalytic cytoplasmic domain of the alpha subunit suggests the presence of auto-epitopes in this region of the molecule.
TL;DR: A human-mouse hybridoma has been produced by fusion of Hashimoto thyroid lymphocytes with the mouse myeloma line X63-Ag8, and the cloned hybridoma secreted an IgG kappa thyroid peroxidase (TPO) autoantibody with high affinity and specificity for human TPO.
Abstract: A human-mouse hybridoma has been produced by fusion of Hashimoto thyroid lymphocytes with the mouse myeloma line X63-Ag8.653. The cloned hybridoma secreted 2.5 µg per 106 cells per day of an IgG kappa thyroid peroxidase (TPO) autoantibody (2G4) with high affinity (2.5×109 molar−1) and specificity for human TPO. 2G4 did not react with lactoperoxidase, horseradish peroxidase or human myeloperoxidase or with porcine TPO or with human thyroglobulin. Plastic tubes coated with 2G4 bound about 50% of 125I-labelled human TPO added and the binding was inhibited by IgGs prepared from 18/18 TPO autoantibody-positive sera. This indicated that all 18 sera contained autoantibodies which recognised the same (or closely related) epitope as 2′ 34. Plastic tubes coated with IgGs from different TPO autoantibody-positive patient sera also bound 125I-labelled TPO but inhibition by 2G4 in this system was not complete. This suggested that the sera contained at least 2 types of TPO autoantibodies. with only one type of autoantib...
TL;DR: The presence of IgG autoantibodies to the protein core of vHSPG in sera from patients with systemic lupus erythematosus demonstrates that the entire vH SPG proteoglycan is the target of autoimmunity in SLE.
Abstract: Vascular heparan sulfate proteoglycan (vHSPG) has an important role in the normal vasculature, including hemostasis, lipolysis and other vascular functions. These functions are mediated by both the glycosarninogly-can and protein core moieties of vHSPG. Autoimmunity to vHSPG has been demonstrated to play a role in vascular injury in animal models, and is present in patients with autoimmune vascular disease. However, most previous studies of human autoimmunity to vHSPG have only investigated heparan sulfate glycosaminoglycan epitopes. In the current investigations. autoantibodies to the protein core of vHSPG in sera from patients with systemic lupus erythematosus (SLE) were investigated. vHSPG protein core was prepared by chemical deglycosylation. Competitive immunoinhibition ELISA and immunoblotting imrnuno-assays were established employing monoclonal antibodies to vHSPG protein core. SLE sera were demonstrated to contain IgG autoantibodies reactive with the vHSPG protein core by immunoblotting. Human aut...
TL;DR: CD5+ B lymphocytes and TCR gamma-delta T lymphocytes, phenotypes implicated in the pathogenesis of autoimmune disease, were isolated from the vitreous in a case of acute sympathetic ophthalmitis using a method which allows the selective maintainance in vitro of in vivo activated T lymph cells.
Abstract: CD5+ B lymphocytes and TCR gamma-delta T lymphocytes, phenotypes implicated in the pathogenesis of autoimmune disease, were isolated from the vitreous in a case of acute sympathetic ophthalmitis. These cells were obtained using a method which allows the selective maintainance in vitro of in vivo activated T lymphocytes. Dual colour flow cytometry showed that after 3 days culture in IL-2 containing medium 61% of cells were CD5/CD19 + ve and 41% CD3/TCR gamma delta + ve. Of the total CD3 + ve population, 15% were gamma/delta negative. These cells formed a population which also responded in a proliferation assay to retinal antigens. Histologically the eye showed a marked mononuclear cell infiltration of the retina, ciliary body and choroid. Granulomatous lesions within the choroid contained lymphocytes, plasma cells and multinucleate giant cells. Immunocytochemistry showed lymphocyte populations to be predominantly CD2 + ve CD3 + ve T lymphocytes of the CD4 sub-set. Distribution of monocytes/macrophages throughout the lesions and restriction of B-lymphocytes to granulomata were all consistent with a DTH type reaction. Despite immunosuppressive therapy, the expression of activation antigens HLA-DR and ICAM-1 on infiltrating and resident ocular tissue cells was high, although IL-2 receptor (CD25) expression was virtually absent. Flow cytometric analysis of peripheral blood cells prior to treatment with Cyclosporin-A showed systemic activation of lymphocytes, with high levels of HLA-DR and CD25 expression and a raised CD4/CD8 ratio.
TL;DR: It is demonstrated that some Guillain-Barre syndrome patients produce autoantibodies to various phospholipid and nuclear antigens, however, these autoantibia are probably produced as a result of the myelin damage rather than cause the demyelination.
Abstract: Guillain-Barre syndrome (GBS) is a transient neurological disorder characterized by an inflammatory demyelination of peripheral nerves Although the pathogenesis of GBS has not been elucidated, there is increasing evidence pointing to an autoimmune etiology We have studied the reactivity of GBS sera with various phospholipids which are known to be important constituents of myelin, and serve as autoantigens in other autoimmune conditions Sixteen Guillain-Barre syndrome (GBS) sera were studied for the presence of autoantibodies to ssDNA, dsDNA, cardiolipin (CL), phosphatidyl-ethanolamine (PE), phosphatidyl-choline (PC), phosphatidyl-serine (PS), and brain extract Six of the 16 GBS sera had autoantibodies to one or more of the antigens studied Three of the sera contained autoantibodies to brain extract (p < 005), two of the sera had autoantibodies to dsDNA, ssDNA, CL and PE, and one serum had autoantibodies to PC, and PS As expected a significant proportion of the lupus sera contained autoantibodies to ssDNA and dsDNA, while the frequency of autoantibodies to different phospholipids was significantly high in sera of patients with systemic lupus erythematosus (SLE) and cerebritis Absorption of GBS sera with cardiolipin, phosphatidyl-choline, or brain extract inhibited the binding of the sera to cardiolipin Our results demonstrate that some GBS patients produce autoantibodies to various phospholipid and nuclear antigens However, these autoantibodies are probably produced as a result of the myelin damage rather than cause the demyelination
TL;DR: It was found that one daily intraperitoneal injection of AG failed to prevent the development of diabetes as well as insulitis following the streptozotocin injections, which raises concerns about the use of testing AG as therapeutic agent in IDDM.
Abstract: It has been suggested that pancreatic beta-cell destruction occurring during the process leading to insulin-dependent diabetes mellitus (IDDM) involves formation of nitric oxide (NO). We have presently studied the effect of aminoguanidine (AG), which has recently been reported to inhibit generation of NO induced by the cytokine interleukin-1 beta. AG currently counteracted IL-1 beta induced impairment of the glucose oxidation rate in rat pancreatic islets. Then we studied the effect of AG on the development of hyperglycemia and pancreatic insulitis in mice treated with multiple low dose injections of streptozotocin (40 mg/kg body-weight for five consecutive days). It was found that one daily intraperitoneal injection of AG (50 mg/kg body-weight) for 14 days failed to prevent the development of diabetes as well as insulitis following the streptozotocin injections. Furthermore, the mice treated with streptozotocin plus AG showed an increased mortality compared to mice treated with streptozotocin plus saline. Although the present data do not exclude a role for NO in IDDM, it raises concerns about the use of testing AG as therapeutic agent in IDDM.
TL;DR: Macrophages from autoimmune diabetes prone BB rats were found to produce radical oxygen intermediates (ROI) at an enhanced rate when compared to diabetes resistant BB or normal Wistar rats.
Abstract: Macrophages from autoimmune diabetes prone BB rats were found to produce radical oxygen intermediates (ROI) at an enhanced rate when compared to diabetes resistant BB or normal Wistar rats. The release of ROI was determined by chemiluminescence using in parallel luminol and lucigenin as detector molecules. In diabetes prone BB rats the spontaneous release of ROI was upregulated in macrophages from different compartments, i.e. peritoneum and spleen. Also, maximal output of ROI after activation of macrophages either in vivo by injection of Corynebacterium parvum or in vitro by LPS and IFN was highest for cells from diabetes prone BB rats. This macrophage abnormality was seen in animals prior to recognizable islet inflammation and also was present at the level of macrophages grown in vitro from precursor cells of diabetes prone BB rats. Hypersecretion of oxygen radicals may contribute to Beta cell loss and diabetes development in BB rats.
TL;DR: IL-1 activated thyrocyte may participate directly in the immunological process by reacting to and producing immunoinflammatory cytokines.
Abstract: The inhibitory effect of interleukin (IL)-1 on thyroid cell functions, including cAMP and thyroglobulin production, is well documented. Recently, IL-1 was shown to enhance the production of IL-6 from thyrocytes, and IL-1 receptors were demonstrated on normal thyroid cells. The origin of IL-1 could be from infiltrating monocytes/-macrophages, endothelial cells as well as from the thyrocytes themselves. Thus, IL-1 activated thyrocyte may participate directly in the immunological process by reacting to and producing immunoinflammatory cytokines.
TL;DR: The increased knowledge about the role of adhesion receptors in the pathogenesis of RA and other inflammatory diseases will allow the introduction of a new therapeutic approach by: the use of specific blocking reagents designed to interfere with the function ofAdhesion molecules.
Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by infiltration of mononuclear cells, mainly T lymphocytes, into the synovial membrane (SM). The interaction of peripheral blood T cells with the different components of the rheumatoid synovium is mediated by cell surface proteins such as selectins, integrins, members of the immunoglobulin superfamily and homing receptors. T lymphocytes infiltrating the rheumatoid SM show an activated phenotype and display an increased avidity of their adhesion receptors that results in an enhanced interaction of these cells with both extracellular matrix proteins (ECM) and cellular ligands (VCAM-1, ICAMs). The interaction of T cell integrins with their ligands, besides an additional antigenic stimulus, could trigger a mitogenic response on these cells, a phenomenon that can contribute to increased cellularity observed into the rheumatoid SM. Moreover, cell attachment to ECM through integrins induces the secretion of several proteases that can contr...
TL;DR: Data suggest that MAM's capacity to induce B cell differentiation correlates with its induction of a relatively weak proliferative response by unselected human T cells, and may result in a significant perturbation of the human immune system and potentially contribute to clinical syndromes characterized by immunostimulation and hypergammaglobulinemia.
Abstract: Microbial superantigens (SA) activate a significant portion of the T cell repertoire based on their dual avidity for MHC class II antigens and T cell receptor (TCR) epitopes common to products of one or several TCR beta chain variable gene families. While SA that induce massive T cell proliferation and cytokine secretion have been implicated in clinical syndromes characterized by shock and generalized immunosuppression, SA activation of a more restricted T cell response may also have significant, perhaps immunostimulatory, effects on the immune system. To investigate this issue, we measured 3H-thymidine incorporation and polyclonal IgM and IgG secretion by normal human peripheral blood mononuclear cells (PBMC) cultured with a panel of microbial SA, including the Staphylococcus aureus-derived SA, SEA, SEB, SEC-1, SEC-2, SEC-3, SEE, TSST-1, and the Mycoplasma arthritidis-derived SA, MAM. The S. aureus-derived SA induce vigorous proliferation by PBMC, while optimal MAM-induced proliferation is significantly lower in magnitude. In all 12 subjects tested, mitogenic concentrations of MAM reproducibly stimulate unselected PBMC to secrete polyclonal IgM and IgG. In contrast, the S. aureus-derived SA induce Ig production only in cultures containing isolated B cell populations and either very low numbers of untreated autologous T cells, larger numbers of X-irradiated autologous T cells, or very low concentrations of the SA. No difference in the activation of helper (CD4) versus suppressor/cytotoxic (CD8) T cells by MAM and the S. aureus-derived SA was noted. Taken together, these data suggest that MAM's capacity to induce B cell differentiation correlates with its induction of a relatively weak proliferative response by unselected human T cells. MAM-like SA, when encountered in vivo, may result in a significant perturbation of the human immune system and potentially contribute to clinical syndromes characterized by immunostimulation and hypergammaglobulinemia.
TL;DR: Since 1939 Wegener’s granulomatosis has been considered a clinical and histopathologic entity characterized by generalized or local small vessel vasculitis with epithelioid and giant cell granulomas commonly involving upper airways, lungs and kidneys.
Abstract: The M-2 autoantigen in primary biliary cirrhosis was summarized by E. Gershwin (UCD, USA). Primary biliary cirrhosis (PBC) is thought to result from autoimmune mediated destruction of intrahepatic bile ducts with progressive inflammatory scarring that is followed by liver failure. The association of PBC with high titer autoantibodies to mitochondriaI antigens has been long recognized. In 1985, three groups used immunoblotting to show that some five mitochondrial autoantigens could be identified with molecular weights ranging from 74 to 36 kd. In 1987, a cDNA for the 74 kd mitochondrial autoantigen was cloned and sequenced leading to identification of the PBC autoantigen as the mitochondrial pyruvate dehydrogenase complex (PDC)’. The M2 autoantigens of PBC have been identified with the functionally related enzyme family, of which PDC is the most prominent antigenic component. Each of the 2-0x0-acid-dehydrogenase complexes (2-OADC) are located on the mammalian inner mitochondrial membrane and include PDC, the 2-oxoglutarate dehydrogenase complex (OGDC), and the branchedchain 2-0x0-acid dehydrogenase (BCOADC). Each of the three enzymes consist of three subunits, E l , E2, and E3; all are nuclear-encoded proteins that are separately imported into mitochondria by a leader sequence for assembly into high molecular weight multimers of the inner membrane. Cloned antigens have been reliably employed in assays for presence of autoantibodies*; the use of cloned recombinant antigens should replace that of traditional immunofluorescence for AMA assay. Finally, there is increasing evidence that PDC-E2 is located on the cell membrane of biliary epithelial cells. A similar rapid progress was achieved deciphering the enigma of the enzymes proteinase-3 and myeloproxidase as target autoantigens in Wegener’s granulomatosis. Allan Wiik (Copenhagen, Denmark) depicted the major revelations in the field: Since 1939 Wegener’s granulomatosis (WG) has been considered a clinical and histopathologic entity characterized by generalized or local small vessel vasculitis with epithelioid and giant cell granulomas commonly involving upper airways, lungs and kidneys. The diagnosis largely relied on biopsy findings in inflammed tissues, showing focal necrotizing vasculitis with granulomas and glomerulitis. In 1985 autoantibodies directed to granule content of neutrophils were found in the large majority of patients with active WG but only in a minority of WG patients with inactive disease-’. The antineutrophil cytoplasmic antibodies (ANCA), now caIled classical ANCA (c-ANCA) as detected by indirect immunofluorescence (IIF) technique were found to be very specific for this vasculitic entity, and the titers of c-ANCA correlated with disease activity. ANCA’s targeting the azurophil granule enzyme, myeloperoxidase in patients with different forms of focal necrotizing glomerulitis were reported, however, these antibodies were found to be rare in WG patients. Studies from several groups indicated that the c-ANCA recognize a 29 kD serine protease present in azurophil granules most likely identical to the leucocyte proteinase-3. N-terminus amino acid sequence data indicated close identity between proteinase-3, myeloblastin, azurophil granule protein-7 and neutrohpil protease-4 described by other investigators not working with a~toimmunity*-~. c-ANCA’s are mainly contained in the IgG class, especially in the subclasses 1 and 4, which may indicate antibody production through prolonged antigen driven mechanisms. IgM c-ANCA have been found in some WG patients manifesting pronounced plumonary haemorrhage as a result of necrotizing capillaritis. As patients with WG have been successfully treated some investigators find that the patients produce anti-idiotypic antibodies to c-ANCA. Such anti-idiotypic antibodies seem to be common even in healthy blood donors, and intravenous y-globulin
TL;DR: Risk factors that may increase the peripheral need for insulin (infectious diseases, cold environment, a high growth rate and stressful life events) may act as promoters of the Beta-cell destruction but also disclose the beta-cell impairment and make the disease clinically overt.
Abstract: The mechanism of beta-cell destruction leading to insulin dependent diabetes is probably a cell mediated auto-immune process occurring in genetically susceptible individuals Since 50-70% of monozygotic twins will not get the disease non-genetic risk factors must play an important role in the etiology of the disease During the past decade population based epidemiological studies have identified several risk determinants for insulin dependent diabetes Based on these studies a multifactorial hypothesis of causation is proposed Some risk determinants (maternal child blood group incompatibility, fetal viral infections, early exposure to cow's milk proteins, a high exposure level of nitrosamines) may independently initiate the autoimmune process by causing the initial damage of the beta-cell, leading to antigen release Other risk determinants may promote an already ongoing autoimmune destructive process through induction of lymphokine release or by causing an increased work load on the beta-cell Risk factors that may increase the peripheral need for insulin (infectious diseases, cold environment, a high growth rate and stressful life events) may act as promoters of the beta-cell destruction but also disclose the beta-cell impairment and make the disease clinically overt Possibilities of different risk profiles in different age groups and of synergism between different risk factors are also discussed
TL;DR: Investigation of immunohistochemical changes in lesional biopsies of seven patients with severe recalcitrant chronic plaque psoriasis receiving systemic FK 506 therapy revealed a significant fall in the numbers of activated mononuclear cells expressing CD25 (IL-2 receptor alpha-chain), HLA-DR, or CD11a (lymphocyte function-associated antigen-1, LFA-1 alpha chain).
Abstract: FK 506 is a new immunosuppressive agent with a similar molecular action to cyclosporin A. We have investigated immunohistochemical changes in lesional biopsies of seven patients with severe recalcitrant chronic plaque psoriasis receiving systemic FK 506 therapy. Within 4 weeks of start of treatment, there was a striking reduction in psoriasis area and severity index (mean reduction 87.4%), accompanied by marked reductions in dermal and epidermal CD4+ and CD8+ cells. Investigation of biopsies obtained 4–8 weeks after start of treatment revealed a significant fall in the numbers of activated mononuclear cells expressing CD25 (IL-2 receptor α-chain), HLA-DR, or CDlla (lymphocyte function-associated antigen-1, LFA-lα chain). In contrast, the number of epidermal CD1+ (Langerhans) cells increased in response to FK 506 therapy. Study of leukocyte adhesion-related epitopes in active disease revealed strong expression of CD54 (intercellular adhesion molecule-1, ICAM-1) and E-selectin (previously known as endotheli...
TL;DR: The effect of iodine excess on thyroid function and on the immunological sequence of events leading to lymphocytic thyroiditis was studied in the NB subline of BB/W rats to determine the mechanisms by which the level of iodine intake influences the development of LT in this animal model.
Abstract: The effect of iodine excess on thyroid function and on the immunological sequence of events leading to lym-phocytic thyroiditis (LT) was studied in the NB subline of BB/W rats to determine the mechanisms by which the level of iodine intake influences the development of LT in this animal model. Iodine supplemented water (500 μg/l, Group I or 500 mg/l. Group 2) or non-iodine supplemented tap water (Group 3) was given to breeding pairs and their offspring ad libitum. A Wistar rat group, also given tap water (Group 4) served as controls. To determine the immunological sequence of events, the phenotypic nature of the infiltrating thyroid lymphocytes was examined by specific immunoperoxidase staining in BB/W and Wistar rats at 6, 9. 12, and 15 weeks. Antigen-presenting cells and class II (Ia) antigen expression on thyrocytes were also examined.The first immunological event apparent in the iodine-treated BB/W rats was a sharp increase in the number of la positive dendritic cells at 9 weeks compared with control ...
TL;DR: The increased adherence observed in patients with acute relapsing MS during an exacerbation would modulate the migration of lymphocytes across the blood-brain barrier (BBB).
Abstract: To investigate the factors regulating the entry of lymphocytes into the brain, we assessed the adhesion in vitro of 51Cr labelled lymphocytes from peripheral blood of patients with multiple sclerosis (MS) to human cerebral endothelial cells, and evaluated the effect on the adhesion of endothelium activated by interferon-γ (IFN-γ). lipopolysaccharides (LPS), interleukin-1 (IL-1) and tumor necrosis factor (TNF). Patients with acute relapsing MS during an exacerbation showed significant increase in MNC adherence to cerebral. endothelial cells as compared with controls (p<0.001). MNC adherence to cerebral endothelial cells activated by IFN-γ or LPS, was significantly increased as compared to the controls (p<0.01). MNC adherence to endothelial cells was not blocked by antibodies against the intercellular adhesion molecule-1 (ICAM-1), but was blocked by lymphocyte function-associated antigen-1 (LFA-1). The increased adherence observed in patients with acute relapsing MS during an exacerbation would modulate the...
TL;DR: Sera patients with systemic lupus erythematosus and antiphospholipid syndrome were tested for antibodies to phosphatidylethanolamine (aPE), as well as to cardiolipin (aCL) and compared to healthy blood donors and it is suggested that the high IgM-aPE antibodies may be viewed as a thymus independent process.
Abstract: The sera patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) were tested, by ELISA, for antibodies to phosphatidylethanolamine (aPE), as well as to cardiolipin (aCL) and compared to healthy blood donors (HBD). Both, SLE and APS patients presented a higher titre of IgM-aPE antibodies than normals, while the IgG and IgA aPE reactivity did not differ. APS patients were characterized by higher IgM-aPE antibody titres than SLE patients. In contrast, the predominant isotype of aCL antibodies in APS patients was IgG. The IgM aPE reactivity was correlated with IgM aCL reactivity, while no correlation was observed between the total IgM values and IgM-aPE binding units of sera tested. Since it was shown that β2-glycoprotein-I (β2-GPI) contributes to a complex antigen by binding to phospholipids and that this antigen is recognized by antiphospholipid antibodies from autoimmune patients, sera β2-GPI levels were measured and correlated to aCL and APE activity. Although APS patients had...