摘要:

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 eitherin vivoby injection ofCorynebacterium parvumorin vitroby 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 grownin vitrofrom precursor cells of diabetes prone BB rats. Hypersecretion of oxygen radicals may contribute to Beta cell loss and diabetes development in BB rats.

ISSN:0891-6934    

DOI:10.3109/08916939309043883

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Functions of B cells from (NZW x BXSB)F1 (W/BF1) mice are investigated. The W/BF1 mouse, which is an animal model for systemic lupus erythematosus (SLE) and immune thrombocytopenic purpura (ITP), produces anti-DNA and anti-platelet antibodies; W/BF1 mice show hypergammaglobulinemia (particularly increases in lgG2a and IgG2b). The ratio of small resting B cells to large activated B cells in W/BF1 mice is low compared to normal mice, suggesting that B cells in W/BF1 mice are already activated in vivo. Furthermore, small resting B cells separated by a Percoll density gradient technique show hyper-responsiveness to lipopolysaccharide (LPS) or anti-μplus IL-4. This suggests that B cells in W/BF1 mice are genetically programmed to be easily activated, resulting in the overproduction of autoantibodies. A significant number of CD5+B cells are found in the lymph nodes of old W/BF1 mice. These findings indicate that all cells in the B cell lineage of W/BF1 mice are already activatedin vivo.

ISSN:0891-6934    

DOI:10.3109/08916939309043884

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Restimulation of autoreactivity in two different BB rat sublines of the same origin (Ottawa, Canada) was investigated by syngeneic islet transplantation into diabetic animals. Despite identical methods and conditions recurrence of hyperglycaemia was observed in BB/OK rats (Karlsburg, Germany) but not in BB/Pfd rats (Leuven, Belgium). Pancreatic morphology at the time of transplantation revealed significant differences in islet volume density and the degree of insulitis. Additionally, marked differences in the phenotypical composition of cells infiltrating the islets were observed. A loss of autoimmune memory in BB/Pfd rats is discussed as a probable reason for the lack of disease recurrence in those animals.

ISSN:0891-6934    

DOI:10.3109/08916939309043885

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Type 1, 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 forβcell 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-1αmRNA, 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-β, perforin and high levels of IFN-γ, 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.

ISSN:0891-6934    

DOI:10.3109/08916939309043886

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Type I, insulin-dependent diabetes (IDD) results from an autoimmune response against the insulin producing pancreaticβcells. This autoimmune reaction involves both humoral and cell-mediated factors; nevertheless, the relative role of each remains unresolved. Furthermore, while adoptive transfer experiments have provided evidence for the role of T cells inβcell destruction, the specific events which initiate leukocyte migration into the islets (insulitis) are unknown. Earlier studies indicated that NOD pancreaticβcells may bind small amounts of autoantibody. Because of the possible importance of an early humoral response to the initiation of insulitis and subsequent disease, we have investigated a number of aspects of this phenomenon to determine the nature and specificity of the early autoantibodies as well as the time at which autoantibody binds toβcells. Results of this study demonstrate that NOD/Uf mice are sensitized to islet-cell associated antigens, including GAD, prior to the first appearance of insulitis; that a small percentage of theβcells of NOD/Uf mice have autoantibody bound to their surface prior to insulitis; that sera collected from preinsulitis NOD/Uf mice contain autoantibodies which will bind toβcells of both IDD-prone and IDD-resistant mice; and that the autoantibodies which bind pancreaticβcells are predominantly IgM with lesser amounts of IgG and IgA. These findings suggest that, in the natural course of IDD, insulitis may develop in response to an initial autoantibody-mediated injury ofβcells.

ISSN:0891-6934    

DOI:10.3109/08916939309043887

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

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 encephalo-myelitis (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.

ISSN:0891-6934    

DOI:10.3109/08916939309043888

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

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-1βtreated and control conditions), suggesting that a subset of islet cells contain nitric oxide synthase. Theβ-cell appears to be the endocrine cell type which contains constitutive nitric oxide synthase as demonstrated by immunohistochemical co-localization of constitutive nitric oxide synthase and insulin. IL-1βis believed to stimulate the expression of cytokine inducible nitric oxide synthase because the synthetic glucocorticoid, dexamethasone, prevents IL-1βinduced inhibition of glucose stimulated insulin secretion and cGMP accumulation by islets. Both dexamethasone, and the nitric oxide synthase inhibitors NMMA and aminoguanidine also prevent IL-1βinduced islet degeneration. These results indicate that nitric oxide produced by the inducible isoform of nitric oxide synthase mediates cytokine induced islet dysfunction and destruction, and that theβ-cell is the islet endocrine cellular source of constitutive nitric oxide synthase.

ISSN:0891-6934    

DOI:10.3109/08916939309043889

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

T cell tolerance to self antigens is at least partly a reflection of clonal deletion of immature T cells in the thymus. Although it is well accepted that intrathymic tolerance is primarily a reflection of T cell contact with bone-marrow (BM)-derived antigen-presented cells (APC), evidence is presented that thymic epithelial cells (TEC) can contribute to tolerance induction. Studies with thymocytes from BM chimeras suggest that selective contact with antigen on TEC induces clonal deletion of a subset of high-affinity T cells; these cells are primarily responsible for in vivo effector functions such as allograft rejection and induction of lethal graft-versus-host disease. Intrathymic contact with TEC fails to delete the typical low-affinity T cells which mediate cytotoxic responses in vitro when cultured with lymphokines. Deletion of these low-affinity T cells appears to require contact with BM-derived APC. Despite the evidence that self tolerance involves clonal deletion in the thymus, it is often stated that backup mechanisms for tolerance induction must exist in the post-thymic environment, but this has yet to be proved. The competing argument is that normal self/nonself discrimination is solely a reflection of intrathymic tolerance: the failure of T cells to react against tissue-specific antigens is not a reflection of post-thymic tolerance but simply that T cells and tissue-specific antigens are kept segregated.

ISSN:0891-6934    

DOI:10.3109/08916939309043890

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

To better understand the structural basis for rheumatoid factor [RF] activity and the origin of auto-antibodies in human autoimmune diseases, we isolated the RF producing B cells from the peripheral blood and from the synovial fluid of a patient suffering from rheumatoid arthritis [RA]. We previously demonstrated that a significant fraction of these RF were derived from three VkIII genes known to encode most of the monoclonal RF light chain variable regions. To get more insight into the actual repertoire of RF-Vkgenes during RA, we analyzed the nucleotide sequences of RF light chain variable regions of other Vkfamilies. Using two sets of polymerase chain reactions in order to amplify the cDNA derived from RF producing cells from the same patient KRA, we isolated only three different rearranged Vk-Jkcomplexes: slkv5, slkv7 and bkv42, all derived from VkI germ-line genes not previously known to be associated with RF activity; this suggests that the repertoire of VL genes coding for RF during RA is more diverse than the one involved in the generation of paraprotein RF during monoclonal lymphoid proliferations, although there remains a possible bias in favor of the VkIII family. Moreover, each of these genes is somatically mutated with a pattern suggesting a selective pressure of the antigen. Particularly interesting is the additional proline residue at the Vk-Jkjunction of bkv42, an unorthodox feature that we found previously in more than 50% of RF VkIII-Jkgene complexes. Finally, the homogeneity of some non conservative mutations suggests the existence of a restricted set of pathogenic epitopes driving the production of RF during RA.

ISSN:0891-6934    

DOI:10.3109/08916939309043891

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor