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B O Roep

Publications and source records attributed to B O Roep.

81 records · Page 5Linked to original sources
PubMed1992

Relative contribution of HLA-DQA and -DQB alleles to predisposition to insulin-dependent diabetes mellitus.

The presence of DQA and DQB alleles conferring protection or susceptibility was assessed in a panel of 39 insulin-dependent diabetes mellitus patients and 39 healthy control subjects from the central highland of Ethiopia. The results were grouped into three entities: a combination of alleles conferring susceptibility, a group conferring protection, and a group without any apparent HLA-DQ or -DR predisposition to insulin-dependent (type 1) diabetes mellitus (IDDM). Statistical analysis revealed that the relative risk of the first group is 64.1. If a similar approach is applied to the data on a study in caucasoid IDDM patients and controls of Kahlil and colleagues, the pattern is fully consistent with the data presented here, with an extraordinarily high relative risk (RR 258.2). It will be of interest to study whether this subdivision is reflected or supported by clinical or etiologic differences of the disease. The predictive value of susceptibility phenotypes appears to be more accurate by the proposed subdivision. Furthermore, in combination with islet-cell antibody analysis, assessment of genotype will permit more accurate identification of prediabetic individuals to be entered in clinical trials.

Alleles↗
PubMed1992

Beta-cell antigen-specific lysis of macrophages by CD4 T-cell clones from newly diagnosed IDDM patient. A putative mechanism of T-cell-mediated autoimmune islet cell destruction.

Immunophenotyping of the early lesion in the pancreatic islets of Langerhans demonstrates a predominance of CD4+ lymphocytes, which may be preceded by an increase in islet macrophages. This observation implies that both types of cells may be involved in autoimmune-mediated beta-cell destruction leading to IDDM. In an attempt to attribute a role to beta-cell antigen-specific CD4-expressing T-cell clones recently isolated from a newly diagnosed IDDM patient, we investigated whether such CD4 T-cells may be pathogenic in an in vitro cytotoxicity assay with HLA-DR-matched antigen-presenting macrophages as target. We report herein that, indeed, beta-cell antigen-specific CD4+ T-cells are capable of lysing macrophages in an antigen-specific fashion. This cytotoxicity is HLA-DR restricted, T-cell receptor complex mediated, and CD4 dependent. These observations imply that both helper T-cells and macrophages may be involved in the disease process via interaction between T-cells and macrophages pulsed with beta-cell antigen.

Animals↗
PubMed1991

T-cell reactivity to 38 kD insulin-secretory-granule protein in patients with recent-onset type 1 diabetes.

Type 1 diabetes seems to be an autoimmune disease in which T cells have a substantial role. A possible target antigen was suggested by the proliferation of CD4 T cells from a newly diagnosed patient in response to a 38 kD polypeptide of the insulin-secretory-granule membrane. To see whether this reactivity is widespread at disease onset, we have generated T-cell lines in vitro from peripheral blood mononuclear cells of nineteen children of caucasoid origin with newly diagnosed type 1 diabetes and sixteen healthy controls matched for age and HLA antigens. The procedure involved two cycles of incubation with a rat beta-cell tumour subcellular fraction enriched in secretory granules and plasma membrane components, followed by a proliferation assay. Fourteen (74% [95% confidence interval 49-91%]) of the patients' cell lines showed a positive proliferative response on subsequent exposure to the islet-cell antigen preparation compared with only two (13% [2-38%]) of the controls (p = 3 x 10(-4); difference 61% [44-87%]). Two subjects who had high titres of islet-cell autoantibodies (ICA) without clinical diabetes produced responsive T-cell lines. Reactivity towards the 38 kD fraction of insulin-secretory-granule membranes was found only in patients (eight of ten responders tested; 95% CI 44-98%) and one ICA-positive non-diabetic subject. Detection of an ongoing autoimmune T-cell response might be useful diagnostically and could lead to prevention of diabetes through specific immunotherapy.

Adolescent↗
PubMed1991

Expression of HLA-DQ antigens in the small-intestinal mucosa of patients with coeliac disease.

Studies at the DNA and product level of B-cell lines of coeliac patients have shown a strong association between coeliac disease and the HLA-DQ alpha 2.3 and HLA-DQ beta 2.7 alleles. The monoclonal antisera SFR20-DQ alpha 5 and XIII-358.4, which specifically react with HLA-DQ alpha 2.3 and with HLA-DQ beta 2.3 and -DQ beta 2.7, respectively, have been used to detect the expression of these specificities in the small-intestinal mucosa of 7 coeliac patients and 11 non-coeliac persons. An immunoperoxidase technique on frozen tissue sections of jejunal biopsy specimens was used. Positive specimens showed immunoperoxidase staining of lymphocytes and histiocytes in the lamina propria. The epithelial cells showed no immunoperoxidase staining. Positive results at the intestinal level correlated with the HLA typing of the patients and controls. The distribution found for the HLA-DQ alleles in the intestinal mucosa makes the role of a HLA-DQ alpha/beta dimer as gliadin receptor at the epithelial cell less probable, but it is compatible with the hypothesis that these DQ molecules are involved in the regulation of the intestinal immune response to gluten.

Adult↗
PubMed1990

T-cell clones from a type-1 diabetes patient respond to insulin secretory granule proteins.

T LYMPHOCYTES reactive to pancreatic beta-cells are thought to have a central role in the autoimmune process leading to type 1 (insulin-dependent) diabetes, but the molecular targets of these T cells have not yet been defined. As identification of such antigens may enable measures to be developed to prevent the disease, we have characterized an antigen that is recognized by insulinoma membrane-reactive T-cell clones established from a newly diagnosed type-1 diabetes patient. Subcellular fractionation studies using rat insulinoma indicate that the antigenic determinant recognized by one of these clones is an integral membrane component of the insulin secretory granule. After a 5,000-fold purification, we have defined the antigen as a monomer of relative molecular mass 38,000. As granular membrane proteins are transiently exposed on the cell surface during exocytosis, their accessibility to components of the immune system may be a function of the secretory activity of beta-cells.

Animals↗
PubMed1989

Human T cell clones with specificity for insulinoma cell antigens.

Several lines of evidence suggest that islet-specific T cells are important in the pathogenesis of the insulitis resulting in insulin-dependent diabetes mellitus (IDDM). Therefore, we decided to analyze islet-specific T cell reactivity in the peripheral blood of IDDM patients. With the use of insulinoma membranes as antigen, T cell lines were generated from peripheral blood mononuclear cells of patients with recent onset of the disease. In a proliferation assay such T cell lines responded to insulinoma membranes and, though to a lesser extent, also to fibroblast membranes, the control antigen used. One of the T cell lines was cloned. Eight clones were isolated that respond to insulinoma antigens. Five of these eight clones appeared to be specific for insulinoma membranes, i.e. they demonstrated proliferation in response to insulinoma but not fibroblast membranes. These insulinoma-specific proliferative responses are HLA-DR restricted.

Adenoma, Islet Cell↗
PubMed1988

Failure or success in the restoration of virus-specific cytotoxic T lymphocyte response defects by dendritic cells.

C57BL/6 (B6, H-2b) mice are CTL responders to both Sendai virus and Moloney leukemia virus. In the former response the H-2Kb class I MHC molecule is used as CTL restriction element, in the latter response the H-2Db molecule. B6 dendritic cells (DC) are superior in the presentation of Sendai virus Ag to CTL in comparison with B6 normal spleen cells. Con A blasts have even less capacity to present viral Ag than NSC, and LPS blasts show an intermediate capacity to present viral Ag. H-2Kb mutant bm1 mice do not generate a CTL response to Sendai virus, but respond to Moloney leukemia virus, as demonstrated by undetectable CTL precursors to Sendai virus and a normal CTL precursor frequency to Moloney virus. Compared to B6 mice, other H-2Kb mutant mice show decreased Sendai virus-specific CTL precursor frequencies in a hierarchy reflecting the response in bulk culture. The Sendai virus-specific CTL response defect of bm1 mice was not restored by highly potent Sendai virus-infected DC as APC for in vivo priming and/or in vitro restimulation. In mirror image to H-2Kb mutant bm1 mice, H-2Db mutant bm14 mice do not generate a CTL response to Moloney virus, but respond normally to Sendai virus. This specific CTL response defect was restored by syngeneic Moloney virus-infected DC for in vitro restimulation. This response was Kb restricted indicating that the Dbm14 molecule remained largely defective and that a dormant Kb repertoire was aroused after optimal Ag presentation by DC. In conclusion, DC very effectively present viral Ag to CTL. However, their capacity to restore MHC class I determined specific CTL response defects probably requires at least some ability of a particular MHC class I/virus combination to associate and thus form an immunogenic complex.

Animals↗
PubMed1988

An HLA-DQ alpha allele identified at DNA and protein level is strongly associated with celiac disease.

An HLA-DQ alpha cDNA probe showed upon hybridization a highly significant discrepancy between the RFLP of celiac disease patients and healthy controls. The 4.0-kb Bgl II restriction fragment was present in 97% of celiac disease patients (n = 30), compared to 56% in a healthy control population (n = 72) (RR = 14.9; p less than 0.0005). At the product level all celiac disease patients tested to date have one DQ alpha chain in common, designated HLA-DQ alpha 2.3, which is associated with the 4.0-kb Bgl II fragment. This HLA-DQ alpha allele identified at the DNA level and product level seems to be a better marker for genetic susceptibility to develop celiac disease than those available to date.

Alleles↗