PubMed Health⌕ Search

Biomedical subjects

R R de Vries

Publications and source records attributed to R R de Vries.

At least 19 recordsLinked to original sources
PubMed1992

T-cell receptor beta-chain gene usage in the T-cell recognition of Mycobacterium leprae antigens in one tuberculoid leprosy patient.

The beta chain of the T-cell antigen receptor present on 20 T-cell clones isolated from a tuberculoid leprosy patient was studied by gene rearrangement and PCR analysis. These T-cell clones all responded to Mycobacterium leprae-encoded protein antigens, and 8 of them specifically recognized peptides of the mycobacterial 65-kDa heat shock polypeptide (65hsp). All T-cell clones studied were HLA-DR-restricted (DR2 or -3). In the DR3-restricted group, 7 of 10 used a beta-chain variable region V beta 5 gene family member, whereas in the DR2-restricted group, 2 of 10 T-cell clones used a V beta 5 gene segment and 5 used the V beta 18 gene segment. The deduced amino acid sequences of the beta chain from 8 T-cell clones have revealed that 3 of 4 DR3-restricted T-cell clones expressed the V beta 5.1 gene segment whereas the fourth DR3-restricted T-cell clone employed a V beta 5 family member not previously described. The V beta 5.1-positive T-cell clones all recognized the same 65hsp peptide from residues 2 to 12. The N-D-N segment (where D is diversity) of the junctional region of these T-cell clones was very similar, despite different beta-chain joining gene segments. Of the 4 DR2-restricted T-cell clones investigated, 3 used the V beta 18 gene segment and recognized the 65hsp peptide from residues 418 to 427. In conclusion, within this panel of M. leprae-reactive T-cell clones, the DR3-restricted T-cell clones mainly used a V beta 5 gene segment, whereas the DR2-restricted clones employed preferentially the V beta 18 gene segment.

Amino Acid Sequence↗
PubMed1992

T-cell receptor beta-chain gene rearrangements of T-cell populations expanded from multiple sites of synovial tissue obtained from a patient with rheumatoid arthritis.

In this study T-cell receptor (TcR) beta-chain gene rearrangements of T-cell lines prepared from multiple sites (n = 92) of synovial tissue derived from both knees of a patient with rheumatoid arthritis were analysed. In the majority of T-cell lines, dominant TcR beta-chain gene rearrangements were detected, involving C beta 1 as well as C beta 2. The dominant rearrangement patterns of T-cell lines from different tissue fragments showed significant variability, but some of the DNA restriction fragments were shared by T-cell lines from multiple sites in both knees. The latter observation suggests that identical T-cell clones may be present at different sites in the synovial tissue and in different joints. However, since many T-cell lines yielded different rearrangement patterns, these data also indicate considerable heterogeneity of T cells in the joints. Apart from theoretical implications, this TcR heterogeneity of T cells within an individual patient also has practical consequences for studies on synovial T cells obtained by biopsy.

Aged↗
PubMed1991

A systematic molecular analysis of the T cell-stimulating antigens from Mycobacterium leprae with T cell clones of leprosy patients. Identification of a novel M. leprae HSP 70 fragment by M. leprae-specific T cells.

Both protective immunity and immunopathology induced by mycobacteria are dependent on Ag-specific, CD4+ MHC class II-restricted T lymphocytes. The identification of Ag recognized by T cells is fundamental to the understanding of protective and pathologic immunity as well as to the design of effective immunoprophylaxis and immunotherapy strategies. Although some T cell clones are known to respond to recombinant mycobacterial heat shock proteins (hsp) like hsp3 65, the specificity of most T cells has remained unknown. We therefore have undertaken a specificity analysis of 48 well defined Mycobacterium leprae- and/or Mycobacterium tuberculosis-reactive (Th-1-like) T cell clones. Most clones (n = 44) were derived from different leprosy patients, and the remainder from one healthy control. Their HLA restriction molecules were DR2, DR3, DR4, DR5, DR7, DQ, or DP. T cell clones were stimulated with large numbers (n = 20 to 40) of mycobacterial SDS-PAGE-separated fractions bound to nitrocellulose. Each clone recognized a single fraction or peak with a particular Mr range. Some of the clones (n = 7) recognized the fraction that contained the hsp 65 as confirmed with the recombinant Ag. Most clones (n = 41), however, responded to Ag other than the hsp 65. Nine clones responded to a 67- to 80-kDa fraction. Five of them responded also to an ATP-purified, 70-kDa M. leprae protein, but only one of these five (that was HLA-DR2 restricted and cross-reactive with M. tuberculosis) recognized the recombinant C-terminal half (amino acids 278-621) of the M. leprae hsp 70 molecule and also recognized the recombinant M. tuberculosis hsp 70. We therefore have used the 5' part of the M. leprae hsp 70 gene that we have cloned recently. This fragment (that encodes amino acids 6-279) was indeed recognized by the other four M. leprae-specific T cells that were all HLA-DR3 restricted and did not cross-react with the highly homologous (95%) M. tuberculosis hsp 70. These results suggest that this novel fragment is a relevant T cell-stimulating Ag for leprosy patients. A panel of other recombinant Ag, including hsp 18 was tested. The majority of T cell clones appeared to recognize antigenic fractions distinct from hsp. In conclusion, T cells of leprosy patients see a large variety of different Ag including non-hsp, and one newly recognized moiety is the N-terminal M. leprae hsp 70 fragment.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1991

Selection of a human T helper type 1-like T cell subset by mycobacteria.

Mycobacteria elicit a cellular immune response in their hosts. This response usually leads to protective immunity, but may sometimes be accompanied by immunopathology due to delayed type hypersensitivity (DTH). A striking example in man is tuberculoid leprosy, which is characterized by high cellular immunity to Mycobacterium leprae and immunopathology due to DTH. Skin lesions of patients suffering from this disease have the characteristics of DTH reactions in which macrophages and CD4+ T lymphocytes predominate. In animal models, it has been shown that DTH responses are associated with the presence of a particular subset of CD4+ T cells (T helper type 1 [Th1]) that secrete only certain cytokines, such as interleukin 2 (IL-2), interferon gamma (IFN-gamma), and lymphotoxin, but no IL-4 or IL-5. We studied the cytokine release of activated M. leprae-reactive CD4+ T cell clones derived from tuberculoid leprosy patients. These T cell clones, which were reactive with mycobacterial heat shock proteins, exhibited a Th1-like cytokine secretion pattern with very high levels of IFN-gamma. Half of these clones secreted low levels of IL-4 and IL-5, but the ratio of IFN-gamma to IL-4 and IL-5 was much higher than that of T cell clones reactive with nonmycobacterial antigens. A Th1-like cytokine secretion pattern was also observed for T cell clones and polyclonal T cell lines from control individuals that recognized both heat shock and other mycobacterial antigens. The levels of IFN-gamma secreted by these clones were, however, significantly less than those of patient-derived T cell clones. This Th1-like pattern was not found with T cell clones from the same patients and healthy individuals generated in the same manner, but reactive with nonmycobacterial antigens. Our data thus indicate that mycobacteria selectively induce human T cells with a Th1-like cytokine secretion profile.

Amino Acid Sequence↗
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

Heat shock proteins in immunopathology.

In recent years, studies have suggested that autoimmunity and/or immunopathology may sometimes result from the immune response to heat shock proteins of autologous cells and microorganisms. Focusing on the T-cell mediated responses, we review the latest literature on this issue with regard to three hypothetical concepts of immunopathology in which heat shock proteins might play a role.

Autoimmune Diseases↗
PubMed1991

Heart conduction disturbance: an HLA-B27 associated disease.

In recent studies from Sweden an increased prevalence of HLA-B27 associated diseases and of HLA-B27 was found in an unselected group of men with permanently implanted pacemakers and with a heart block. Furthermore, a significantly increased prevalence of HLA-B27 was found in men with a pacemaker who had no clinical or radiological signs of HLA-B27 associated disease. To obtain more insight into the association between HLA-B27 and heart block, and the possible role of HLA-B27 in causing this block, a study was made of 35 patients with a pacemaker and heart block of unknown cause, selected from a total group of 350 men with pacemakers who were still alive at the time of the study. One of these 35 men had ankylosing spondylitis and two patients had an asymptomatic sacroiliitis, but all three were HLA-B27 negative. HLA-B27 was present in five (14%) patients, which is a significantly higher prevalence than in healthy controls (17/292, 6%). This percentage is equal to the percentage of HLA-B27 positivity found in the Swedish study on unselected men with an implanted pacemaker, in whom the presence of an HLA-B27 associated disease had been excluded. It suggests that factors other than HLA-B27 are important in the pathogenesis of heart block in most patients.

Female↗
PubMed1991

Genetic control of immunopathology induced by Mycobacterium leprae.

The pathogenesis of leprosy is almost totally attributable to the immune response of the host towards Mycobacterium leprae, a virtually non-toxic intra-cellular parasite. At one end of the leprosy spectrum are tuberculoid leprosy patients, who develop immunity but also delayed-type hypersensitivity towards M. leprae; at the other end are lepromatous leprosy patients, who lack helper T cell activity and therefore do not develop immunity, but who can nevertheless produce antibodies that may cause immunopathology due to immune complexes. A range of immunopathology is seen between these poles.

Antigens, Bacterial↗
PubMed1990

High antigen reactivity in mononuclear cells from sites of chronic inflammation.

Antigen-specific in-vitro responses of mononuclear cells from synovial fluid and peripheral blood of patients with rheumatoid arthritis were compared with those of mononuclear cells from pleural exudate and peripheral blood of non-rheumatoid-arthritis patients with chronic pleuritis not caused by tuberculosis. The antigens tested were an acetone-precipitable fraction of Mycobacterium tuberculosis (AP-Mt), an Escherichia coli lysate containing the 65 kD heat-shock protein of M bovis BCG (65 kD/E coli), the M bovis heat-shock protein alone (65 kD), and E coli alone. The mean proliferative responses to AP-Mt were higher in synovial-fluid than in peripheral-blood mononuclear cells in rheumatoid arthritis patients (mean [SEM] stimulation index 10.5 [3.1] vs 2.6 [0.9]) and in pleural-exudate than in peripheral-blood mononuclear cells in the pleuritic patients (7.5 [1.7] vs 3.5 [2.0]). The same pattern was seen for the other three antigens. Only 1 of 26 synovial-fluid mononuclear cell samples from rheumatoid arthritis patients showed a positive response (stimulation index 3 or more) to 65 kD compared with 5 of 22 pleural-exudate mononuclear cell samples, so 65 kD seems not to be the major antigen recognised by synovial-fluid T cells in rheumatoid arthritis. Enhanced reactivity against mycobacterial and other bacterial antigens is not restricted to mononuclear cells from chronically inflamed joints but seems to be a common feature of chronic inflammation.

Antigens, Bacterial↗
PubMed1990

Mycobacterium leprae-specific T cells from a tuberculoid leprosy patient suppress HLA-DR3-restricted T cell responses to an immunodominant epitope on 65-kDa hsp of mycobacteria.

The polar tuberculoid type (TT) of leprosy, characterized by high T cell reactivity to Mycobacterium leprae, is associated with HLA-DR3. Surprisingly, DR3-restricted low T cell responsiveness to M. leprae was found in HLA-DR3-positive TT leprosy patients. This low responsiveness was specifically induced by M. leprae but not by M. tuberculosis and was seen only in patients and not in healthy controls. We studied this patient-specific, M. leprae-induced, DR3-restricted low T cell responsiveness in depth in one representative HLA-DR3-positive TT leprosy patient by using T cell clones. From this patient two types of T cell clones were obtained: one type was cross-reactive with M. tuberculosis and recognized an immunodominant epitope (amino acids 3 to 13) on the 65-kDa heat shock protein (hsp) the other type was M. leprae specific and reacted to a protein other than the 65-kDa one. To examine whether these M. leprae-specific T cell clones were responsible for the DR3-restricted low responsiveness to M. leprae, we tested them for the ability to suppress the proliferation of the DR3-restricted, 65-kDa, hsp-reactive clones. The DR3-restricted, M. leprae-specific T cells completely suppressed the proliferative responses of DR3-restricted, cross-reactive T cell clones to the 65-kDa hsp from the same patient as well as from other individuals. Also, DR3-restricted responses to an irrelevant Ag were suppressed by the M. leprae-specific T cell clones. However, no suppression of non-DR3-restricted T cell responses was seen. Although the mechanism must still be elucidated, this M. leprae-induced, DR3-restricted immunosuppression may at least partly explain the observed DR3-associated low T cell responsiveness in TT leprosy patients.

Bacterial Proteins↗
PubMed1990

Major histocompatibility complex class II-restricted antigen presentation across a species barrier: conservation of restriction determinants in evolution.

The existence of at least three alleles of the HLA-DRB3 gene within the human population is evident. These alleles express DRw52 determinants and react with monoclonal antibody (mAb) 7.3.19.1. The polymorphic epitope recognized by 7.3.19.1 is not only present on human cells but is also expressed on chimpanzee (Pan troglodytes) class II-positive cells. The 7.3.19.1 determinant already existed before speciation of man and chimpanzee, and is at least 5,000,000 yr old. Two-dimensional gel electrophoresis demonstrated that the various HLA- and Patr-DRw52 molecules that are reactive with 7.3.19.1 exhibit isoelectric point differences due to primary amino acid heterogeneity, as was confirmed by sequencing data. Sequence comparison allowed us to map the binding site of mAb 7.3.19.1 to the alpha helix of the major histocompatibility complex (MHC) class II DRB1 domain surrounding the antigen-binding cleft. Despite MHC sequence variation, chimpanzee antigen-presenting cells can present antigen (purified protein derivative) to human T cell lines and vice versa. Only the HLA- and Patr-DRw52 molecules were shown to function as restriction elements for antigen presentation across this species barrier. It is concluded that these particular restriction determinants probably have been conserved in evolution. The HLA- and Patr-DRw52 molecules represent alleles displaying polymorphism that has been selected for in evolution. Such "biomutants" may thus be more useful to study the biological significance of MHC molecules than MHC variants that have been generated by in vitro mutagenesis experiments.

Amino Acid Sequence↗
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↗
PubMed1990

Molecular mapping of interactions between a Mycobacterium leprae-specific T cell epitope, the restricting HLA-DR2 molecule, and two specific T cell receptors.

A systematic series of 89 single residue substitution analogs of the Mycobacterium leprae 65-kDa protein-derived peptide LQAAPALDKL were tested for stimulation of two HLA-DR2 restricted 65 kDa-reactive T cell clones from a tuberculoid leprosy patient. Some analogs with substitutions outside a "core" region showed enhanced stimulation of the T cell clones. This core region of seven or eight residues was essential for recognition, whereas substitution of amino acids outside this region did not affect T cell recognition although these residues could not be omitted. Thus these core residues interact directly with the presenting HLA-DR2 molecule and/or the TCR. Except for analogs of position 419 for clone 2B6, the majority of the nonstimulatory substitution analogs did not inhibit the presentation of LQAAPALDKL and thus probably failed to bind to the HLA-DR2 molecule. Unless all of the core residues are physically involved in binding to DR2, substitution at a position not directly involved in binding appears to have an influence on other residues that do bind to the DR2 molecule. Active peptide analogs with two or more internal prolines suggest that not all analogs need be helical for activity with clone 2F10.

Amino Acid Sequence↗
PubMed1990

Reduction of the risk of rheumatoid arthritis among women who take oral contraceptives.

Discrepant results among investigations of the association between oral contraceptive use and rheumatoid arthritis (RA) have been ascribed to shortcomings in the study methods. In the present study, we obtained detailed information on oral contraceptive use in 135 young women with confirmed definite or classic RA of recent onset and in 378 controls with soft tissue rheumatism or osteoarthritis. All patients had at least 2 years of followup to confirm the consistency of the diagnosis. Oral contraceptive use at any time before disease onset was reported by 70% of the RA patients and 85% of the controls; the latter figure corresponded to general population data for The Netherlands. This yielded a relative risk for RA of 0.39 among those who had ever used oral contraceptives and 0.58 for those using oral contraceptives at the time of symptom onset. The preventive effect of oral contraceptive use on the risk of RA was found to be independent of the dose, duration of use, or presence of HLA-DR4. The strongest protection was seen in women with a family history of RA and in women ages 31-40 at symptom onset. The conflicting results in the literature are discussed, and a possible biologic mechanism for this phenomenon is suggested.

Adult↗