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  • 1
    Electronic Resource
    Electronic Resource
    Inhibition of insulin-specific autoreactive T-cells by sulphatide which is variably expressed in beta cells (1999)
    Springer
    Diabetologia 42 (1999), S. 1212-1218 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Type I diabetes mellitus ; insulin ; autoreactive T-cells ; sulphatide ; beta cells.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Sulphatide and insulin are present in the secretory granules and at the surface of beta cells in islets of Langerhans. Insulin autoantibodies and T-cell reactivity against insulin exist during the development of Type I (insulin-dependent) diabetes during which active beta cells may be more vulnerable than passive. Our aims were to examine the presence of sulphatide in active and passive beta cells and to clarify whether sulphatide influences the direct autoimmunity against insulin. Methods. We incubated rat islets in 2.8, 11.0 or 20.0 mmol/l glucose for 24 h and did an electron microscopic evaluation after labelling with a specific anti-sulphatide monoclonal antibody. The reactivity of an insulin-specific T-cell clone isolated from a patient with Type I diabetes, was examined using insulin or insulin B-chain (B11–27) peptide incubated together with sulphatide. Results. We detected lower amounts of sulphatide per insulin secretory granule in active compared with passive beta cells (p = 0.003). The presence of sulphatide in vitro at doses of 43–8.3 μmol/l resulted in greatly reduced proliferation (median 3.4 % of control value, p = 0.0004) of the insulin-specific T-cell clone. No inhibition was found using the precursor of sulphatide, galactosylceramide, or GM1. Sulphatide did not reduce non-aspecific proliferation (induced by phorbol myristate acetate plus anti-CD3) or specific proliferation induced by insulin peptide. Conclusion/interpretation. These results imply that sulphatide possibly affect processing of the insulin molecule. Sulphatide which has been reported to interfere with phagosome-lysosome fusion, conceivably interacts with insulin. We hypothesize a (patho)physiological role of sulphatide, variably expressed in beta cells, by reducing the antigenicity of insulin. [Diabetologia (1999) 42: 1212–1218]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051294
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  • 2
    Electronic Resource
    Electronic Resource
    Autoreactive and immunoregulatory T-cell subsets in insulindependent diabetes mellitus (1999)
    Springer
    Diabetologia 42 (1999), S. 443-449 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Autoreacitivity ; autoimmune disease ; regulation ; suppression ; T-cell subset ; CD45.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is a T-cell mediated autoimmune disease. Several subsets of T-cells, in particular CD4+ and in vivo activate CD45RA+RO+ T-cells, have been shown to be increased at disease onset. The functional implications of these relative increases in CD4 T-cells were investigated. Methods. Subsets of T-cells were sorted on the basis of their activation status (CD45RA+ naïve cells, CD45RA+RO+ recently activated cells and CD45RO+ memory cells) and stimulated with autoantigens or recall antigen in vitro. Results. Proliferative responses to tetanus toxoid were primarily or exclusively observed in resting memory T-cells (CD45RO+). Autoimmune T-cell responses were, however, primarily measured in activated T-cells (CD45RA+RO+) in newly diagnosed Type I diabetic patients, whereas those with longer disease duration reacted to autoantigens with memory T-cells (CD45RO+) (p 〈 0.004). Interestingly, in non-diabetic control subjects not responding to autoantigens in the regular assay, considerable autoreactive T-cell responses were detectable after sorting in the CD45RO+ or CD45RA+RO+ lymphocyte subsets. Remixing these subsets showed that these autoimmune responses in activated cells could be down-modulated by CD45RA+ lymphocytes, whereas resting memory cells appeared unaffected by the suppressive CD45RA subset. Conclusion/interpretation. These results show that autoimmune T-cell responses can be linked to particular subsets which differ depending on clinical status. Furthermore, the CD45RA T-cell subset harbours lymphocytes potentially capable of suppressing autoimmune T-cell responses. The changes in responsiveness to exogenous insulin may help to unravel the mechanism by which isohormonal therapy could prevent the onset of Type I diabetes. [Diabetologia (1999) 42: 443–449]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051177
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  • 3
    Electronic Resource
    Electronic Resource
    Autoantibodies to the islet antigen ICA 69 occur in IDDM and in rheumatoid arthritis (1995)
    Springer
    Diabetologia 38 (1995), S. 351-355 
    Details
    ISSN: 1432-0428
    Keywords: Key words ICA 69 ; insulin-dependent diabetes mellitus; rheumatoid arthritis.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Islet cell antigen (ICA) 69 is a newly-recognized islet cell antigen to which autoantibodies have been observed in prediabetic relatives of patients with insulin-dependent-diabetes mellitus (IDDM). Here we extend the earlier analysis of ICA 69 antibodies to patients with recent-onset IDDM and to patients with other immune-mediated diseases. ICA 69 antibodies were determined by Western blot using an affinity purified recombinant fusion protein of ICA 69 and maltose binding protein. ICA 69 antibody quantities were determined as titres using a titration curve of a standard serum as reference. Mean logarithmic ICA 69 antibody titres were 3.4 (± 1.4) in 99 patients with acute IDDM compared to 2.8 (± 0.9) in 49 healthy blood donors (p 〈 0.001). A higher mean ICA 69 antibody titre of 4.1 (± 0.8) was observed in 16 patients with rheumatoid arthritis in comparison to acute IDDM (p 〈 0.01) and healthy control subjects (p 〈 0.001). The percentage of sera with ICA 69 antibody titres above the 2 SD level of normal subjects was 21 % in IDDM, 31 % in rheumatoid arthritis and 6 % in healthy blood donors. None of the patients with autoimmune thyroid disease (n = 20), inflammatory bowel disease (n = 9) or multiple sclerosis (n = 7) had elevated ICA 69 antibodies. In IDDM, presence of ICA 69 antibodies persisted and the titre remained the same over 18 months of follow-up. The relationship of ICA 69 antibodies to islet cell antibodies (ICA) or insulin autoantibodies (IAA) was tested. The production of ICA 69 antibodies was not associated in diabetic patients with the presence of any of the two other autoantibodies. In conclusion, this study describes ICA 69 antibodies in acute IDDM and finds them to be independent of other islet autoantibodies. In addition ICA 69 is a target of humoural autoimmunity not only in IDDM but also in rheumatoid arthritis. [Diabetologia (1995) 38: 351–355]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400641
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  • 4
    Electronic Resource
    Electronic Resource
    Altered immune response to insulin in newly diagnosed compared to insulin-treated diabetic patients and healthy control subjects (1997)
    Springer
    Diabetologia 40 (1997), S. 564-572 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin ; autoantibodies ; autoreactivity ; T-lymphocytes ; insulin-dependent diabetes mellitus.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin-dependent diabetes mellitus (IDDM) is the result of a T-cell mediated autoimmune beta-cell destruction,which is accompanied by autoantibodies. We analysed the cellular and humoral immune response to insulin and insulin peptides in patients with recent-onset IDDM, IDDM patients treated with insulin, non-diabetic first degree relatives and unrelated control subjects. There were no differences in T-cell reactivity to whole insulin or insulin peptides in general between age-matched groups of IDDM patients, relatives or healthy control subjects. In contrast to investigations in NOD mice, no immunodominant or disease-specific insulin peptide could be identified. Surprisingly, a positive correlation of T-cell responses to insulin with age was noted (p 〈 0.005). This resulted in an inverse relation of insulin autoantibodies (IAA) and insulin reactive T-cells (p 〈 0.001) together with the well-described negative correlation of IAA with age. Interestingly, insulin-treated patients differed from age-matched recent-onset IDDM patients: first, simultaneous immune recognition of insulin with T-cells and IAA was only seen in patients treated for 6 months with insulin; second, insulin-treated patients rarely responded to whole insulin; third, they displayed less determinant spreading, and finally, recognition of multiple insulin peptides was not accompanied by crossreactivity to whole insulin. These distinct observations in insulin-treated IDDM patients, together with the inverse correlation between humoral and cellular responses to insulin, may result from activation or modulation of different T-cell subsets, and may be of relevance to insulin therapy trials, in which selective activation of non-destructive T-cell subsets may be a key to successful intervention. [Diabetologia (1997) 40: 564–572]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050716
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  • 5
    Electronic Resource
    Electronic Resource
    Molecular mimicry in diabetes mellitus: the homologous domain in coxsackie B virus protein 2C and islet autoantigen GAD65 is highly conserved in the coxsackie B-like enteroviruses and binds to the diabetes associated HLA-DR3 molecule (1998)
    Springer
    Diabetologia 41 (1998), S. 40-46 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Coxsackie B virus ; peptide binding ; HLA-DR ; molecular mimicry ; IDDM.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It has been proposed that molecular mimicry between protein 2C (p2C) of coxsackie virus B4 and the autoantigen glutamic acid decarboxylase (GAD65) plays a role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). In this study we show that the amino acid sequence of p2C which shares homology with a sequence in GAD65 (PEVKEK), is highly conserved in coxsackie virus B4 isolates as well as in different viruses of the subgroup of coxsackie B-like enteroviruses. These are the most prevalent enteroviruses and therefore exposure to the mimicry motif will be a frequent event throughout life. Presentation of the homologous peptides by HLA molecules is essential for T-cell reactivity. Therefore, we tested whether the PEVKEK motif can bind to the IDDM-associated HLA-DR1, -DR3 and -DR4 molecules. Synthetic peptides with sequences derived from p2C and GAD65 did bind to HLA-DR3 but not to HLA-DR1 or -DR4. Replacement of amino acids within the motif showed that the PEVKEK motif binds specifically to HLA-DR3. Moreover, both p2C and GAD65 peptides bind in the same position within the peptide binding groove of the DR3 molecule which is an essential requirement for T-cell cross-reactivity. The results support molecular mimicry between p2C of coxsackie B-like enteroviruses and GAD65. However, this molecular mimicry may be limited to the HLA-DR3 positive subpopulation of IDDM patients. [Diabetologia (1998) 41: 40–46]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050864
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  • 6
    Electronic Resource
    Electronic Resource
    Autoantibodies to the islet antigen ICA 69 occur in IDDM and in rheumatoid arthritis (1995)
    Springer
    Diabetologia 38 (1995), S. 351-355 
    Details
    ISSN: 1432-0428
    Keywords: ICA 69 ; insulin-dependent diabetes mellitus ; rheumatoid arthritis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Islet cell antigen (ICA) 69 is a newly-recognized islet cell antigen to which autoantibodies have been observed in prediabetic relatives of patients with insulin-dependent-diabetes mellitus (IDDM). Here we extend the earlier analysis of ICA 69 antibodies to patients with recent-onset IDDM and to patients with other immune-mediated diseases. ICA 69 antibodies were determined by Western blot using an affinity purified recombinant fusion protein of ICA 69 and maltose binding protein. ICA 69 antibody quantities were determined as titres using a titration curve of a standard serum as reference. Mean logarithmic ICA 69 antibody titres were 3.4 (±1.4) in 99 patients with acute IDDM compared to 2.8 (±0.9) in 49 healthy blood donors (p〈0.001). A higher mean ICA 69 antibody titre of 4.1 (±0.8) was observed in 16 patients with rheumatoid arthritis in comparison to acute IDDM (p〈0.01) and healthy control subjects (p〈0.001). The percentage of sera with ICA 69 antibody titres above the 2 SD level of normal subjects was 21% in IDDM, 31% in rheumatoid arthritis and 6% in healthy blood donors. None of the patients with autoimmune thyroid disease (n=20), inflammatory bowel disease (n=9) or multiple sclerosis (n=7) had elevated ICA 69 antibodies. In IDDM, presence of ICA 69 antibodies persisted and the titre remained the same over 18 months of follow-up. The relationship of ICA 69 antibodies to islet cell antibodies (ICA) or insulin autoantibodies (IAA) was tested. The production of ICA 69 antibodies was not associated in diabetic patients with the presence of any of the two other autoantibodies. In conclusion, this study describes ICA 69 antibodies in acute IDDM and finds them to be independent of other islet autoantibodies. In addition ICA 69 is a target of humoural autoimmunity not only in IDDM but also in rheumatoid arthritis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400641
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    Paper (German National Licenses)
    Fulltext
  • 7
    Electronic Resource
    Electronic Resource
    T-cell reactivity to GAD65 peptide sequences shared with coxsackie virus protein in recent-onset IDDM, post-onset IDDM patients and control subjects (1997)
    Springer
    Diabetologia 40 (1997), S. 332-338 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Autoreactivity ; autoimmunity ; human T-cells ; GAD65 ; GAD autoantibodies ; insulin-dependent diabetes ; molecular mimicry.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary GAD65 is one of the major autoantigens associated with insulin-dependent diabetes mellitus (IDDM). The two peptides p17 and p18 of GAD65 that share sequence similarity with coxsackie virus (amino acid sequence identity: PEVKEK) appeared to be the major determinants of GAD65 recognized preferably by T cells from new-onset IDDM patients and their first degree relatives. In contrast, in our study unrelated control subjects frequently recognized the two GAD peptides (55 %, 16/29), similar to first degree relatives (41 %, 12/29) and IDDM patients post-onset (68 %, 15/22). However, recent-onset IDDM patients, responded less frequently (25 %, 4/16) compared with IDDM patients post-onset (p 〈 0.03) or unrelated control subjects (borderline significant) confirming previous observations in humans and NOD mice that T-cell reactivity to GADp17/p18 at diabetes onset is decreased. Moreover, this study demonstrated a positive correlation of T-cell proliferation to GAD p17 (amino acid 247–266) and p18 (amino acid 260–279) with simultaneous responses to both peptides in 13 % of all subjects tested (n = 97) (p 〈 0.001). T-cell proliferation to GAD p17 was higher than to p18 in recent-onset diabetic patients, first degree relatives and unrelated control subjects (p 〈 0.02, p 〈 0.004, p 〈 0.002, respectively). However, in post-onset IDDM patients, the two peptides were recognized equally well. Our results show that T-cell reactivity to GAD65 peptides homologous with coxsackie protein is very frequently observed, but not primarily associated with IDDM. The temporary decline of T-cell proliferation is not associated with the beta-cell destruction process, but with clinical manifestation. The positive correlation of reactivity to the two peptides in the viral motif implicates that PEVKEK is an immunogenic epitope. [Diabetologia (1997) 40: 332–338]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050683
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  • 8
    Electronic Resource
    Electronic Resource
    Failure and Success in Abolition of Virus-Specific CTL-Response Defects by Dendritic Cells (1988)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 532 (1988), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1988.tb36359.x
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