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Biomedical subjects

G Sønderstrup

Publications and source records attributed to G Sønderstrup.

11 recordsLinked to original sources
PubMed2000

Multiple cross-reactive self-ligands for Borrelia burgdorferi-specific HLA-DR4-restricted T cells.

T cell recognition of self antigens is a key event in the pathogenesis of autoimmune diseases. To date, the initial events that trigger autoreactive T cells are unknown. The "molecular mimicry" hypothesis predicts that during an infection T cells that recognize both a microbial antigen and a related self peptide become activated and cause autoimmune disease. We have systematically examined the recognition of self antigens by HLA-DR4-restricted T cells specific for peptides of the outer surface protein A (OspA) of Borrelia burgdorferi, the etiological agent of Lyme disease. We used the peptide spot synthesis technique for complete peptide substitution analyses of two immunodominant OspA epitopes. Each amino acid residue of the epitopes was substituted with all 20 naturally occurring amino acids and the altered peptides were tested for recognition by a panel of OspA-specific T cells. The binding motifs (supertopes) revealed by these analyses were used to screen public databases for matching human or murine peptides. Several hundred peptides were identified by this search and synthesized. Of these, 28 were recognized by OspA-specific T cells. Thus, T cell cross-reactivity is a common phenomenon and the existence of cross-reactive epitopes alone does not imply molecular mimicry-mediated pathology and autoimmunity.

Animals↗
PubMed1999

T cell responses to a human cartilage autoantigen in the context of rheumatoid arthritis-associated and nonassociated HLA-DR4 alleles.

OBJECTIVE: To analyze the CD4+ T cell responses to the human cartilage antigen glycoprotein-39 (HCgp-39) in the context of rheumatoid arthritis (RA)-associated (DRalphabeta1*0401) and nonassociated (DRalphabeta1*0402) HLA class II molecules. METHODS: Large numbers of HCgp-39-specific T cell hybridomas were generated following immunization of HLA-DR4/human CD4 transgenic, murine major histocompatibility complex class II deficient mice with native HCgp-39. Fine epitope mapping of DRalphabeta1*0401-and DRalphabeta1*0402-restricted T cell hybridomas was performed using overlapping synthetic peptides. Antigen-specific cytokine production by lymph node T cells was evaluated after immunization with native antigen. Proliferative T cell responses of healthy human subjects were compared with the T cell responses of patients with active RA using HCgp-39 epitopes defined in HLA-DR4 transgenic mice. RESULTS: CD4+ T cells from DRalphabeta1*0401 and DRalphabeta1*0402 transgenic mice identified completely different immunodominant peptide epitopes of HCgp-39, and this was not explained by known DR4-binding motifs or direct peptide-binding studies. DRalphabeta1*0401-restricted, antigen-specific T cells produced significantly more interferon-gamma and tumor necrosis factor a in response to HCgp-39 than did T cells from DRalphabeta1*0402 transgenic mice. Finally, HCgp-39 peptides defined in DRalphabeta1*0401 transgenic mice stimulated T cells from HLA-DR4 positive human subjects and RA patients, but not T cells from HLA-DR4 negative individuals. CONCLUSION: T cell epitopes of HCgp-39 that were defined in HLA-DR4 transgenic mice stimulated T cells from human subjects carrying RA-associated HLA-DR4 alleles. HLA-DR4 molecules may influence the disease process in RA both by presentation of selected peptide epitopes and by promoting the production of proinflammatory cytokines in synovial joints.

Adipokines↗
PubMed1999

HLA class II transgenic mice: models of the human CD4+ T-cell immune response.

This review examines the field of current HLA class II transgenic mouse models and the individual approaches applied in production of these mice. The majority of these mice have been created with the objective of obtaining a disease model with clinical features mimicking human autoimmune disease. The development process of a different type of HLA class II transgenic mice, which are designed to function as a substitute for a normal human immune system in studies of human autoantigens, is described. Several HLA-DR4 transgenic lines with normally expressed HLA-DR4 molecules have been produced. To obtain adequate positive selection of the HLA-DR4-restricted CD4+ T-cell repertoire in these mice it is essential both to introduce a human CD4 transgene, and to delete the murine major histocompatibility complex (MHC) class II molecules. These HLA-DR4 transgenic mice have been used to determine the immunogenic CD4+ T-cell epitopes of several human autoantigenic proteins.

Animals↗
PubMed1998

T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin.

Approximately one-half of Caucasians with newly diagnosed insulin-dependent diabetes mellitus (IDDM) have autoantibodies to insulin, and the majority of those express the HLA-DR4 genotype [Ziegler, R., Alper, C. A., Awdeh, Z. L., Castano, L., Brink, S. J., Soeldner, J. S., Jackson, R. A. & Eisenbarth, G. S. (1991) Diabetes 40, 709-714]. However, it has been difficult to demonstrate T cell proliferative responses to human insulin in IDDM patients [Durinovic-Bello, I., Hummel, M. & Ziegler, A. G. (1996) Diabetes 45, 795-800]. We have immunized transgenic mice expressing the susceptible HLA-DR (alpha1*0101,beta1*0401) (hereafter called DRB1*0401) and human CD4 molecules on a murine major histocompatibility complex class II null background, with human preproinsulin (PPI), proinsulin (PI), and insulin and derived large panels of T cell hybridomas to determine the immunogenic epitopes of these proteins. These results show that the prohormones PI or PPI carry the major immunogenic T cell epitope in the DRB1*0401 transgenic mice. The PPI/PI immunodominant epitope LALEGSLQK was localized at the C-peptide/A-chain junction. This T cell epitope PPI/PI LALEGSLQK is unusual because, normally, it is proteolytically destroyed during the maturation of the insulin molecule. Additionally, this T cell epitope is both processed and presented by human DRB1*0401-positive Epstein-Barr virus transformed B cells, and it can also stimulate T cells from the peripheral blood of HLA-DR4-positive patients with type 1 diabetes. These findings may partly explain why susceptibility to type 1 diabetes is associated with HLA-DR4-positive individuals and why T cell responses to the mature insulin protein are rarely detected in IDDM patients.

Amino Acid Sequence↗
PubMed1998

Autoreactivity versus autoaggression: a different perspective on human autoantigens.

Antigen-specific B and T cell responses against myelin basic protein, as well as responses against beta-islet-cells or joint tissue, are commonly found both in patients with autoimmune disease and in normal control subjects with disease-associated HLA-DR/DQ alleles. Thus, autoreactive immune responses are not disease-specific; however, the presence of certain autoantibodies may have prognostic value and may aid in disease management.

Animals↗
PubMed1998

Identification of autoantigen epitopes in MHC class II transgenic mice.

MHC class II molecules function by selective binding of antigenic peptides, thereby both shaping the T-cell receptor (TCR) repertoire in the thymus and influencing presentation of immunogenic peptides to CD4+ T cells in the periphery. The strong association between a number of human autoimmune diseases (type 1 diabetes, rheumatoid arthritis, and multiple sclerosis) and certain HLA-DR/DQ alleles suggests that it may be possible to alter pathological autoimmune responses by deliberate introduction of autoantigenic peptides in a "tolerogenic" manner. Since there are likely to be differences in epitope selection and epitope spreading in different patients over time, this approach requires identification of all the immunogenic CD4+ T-cell epitopes (dominant, subdominant, or cryptic) of an autoantigen which elicit T-cell responses restricted to the HLA-DR/DQ alleles predisposing to these autoimmune diseases. This paper describes a new approach for the identification of immunogenic peptide epitopes of human autoantigenic proteins using HLA-DR and DQ transgenic mice. These mice are engineered to select a full TCR repertoire which can identify immunogenic peptide epitopes similar or identical to human subjects of the same HLA-DR/DQ genotype. This experimental system also allows comparison of autoantigenic immune responses restricted to disease-susceptible and disease-resistant HLA-DR/DQ alleles.

Amino Acid Sequence↗
PubMedDate not supplied

Citrullination of self-proteins and autoimmunity.

Citrullination (deimination is an enzymatic, posttranslational conversion of arginine residues to citrulline residues) of joint-associated self-proteins may be a possible mechanism in the induction of autoimmune CD4 T-cell responses in rheumatoid arthritis. We have studied the immune response to normal or deiminated human fibrinogen (hFBG) in mouse strains expressing major histocompatibility complex (MHC) class II antigens similar to either RA-susceptible or non-susceptible HLA-DR4 alleles. Upon immunization with deiminated hFBG, all mouse strains analysed produced high amounts of anti-FBG antibodies, while relatively low levels of anti-citrulline antibodies and little or no anti-FBG antibodies crossreactive with mouse FBG (mFBG) were obtained. Mice immunized with normal hFBG also produced high amounts of anti-hFBG antibodies. However, whereas mice with MHC class II molecules similar to RA-non-susceptible HLA-DR4 alleles produced low levels of anti-hFBG antibodies with crossreactivity to mFBG, mouse strains with RA-susceptible HLA-DR4-equivalent MHC class II molecules contained high levels of such crossreactive anti-mFBG antibodies. Similar results were obtained with HLA-DR4*0401, human CD4-double-transgenic mice. However, none of the more than 600 mice investigated developed arthritis. These data indicate that the quality and/or quantity of anti-FBG autoantibodies or of anti-citrulline antibodies, produced in the studied mouse strains, are insufficient to induce arthritis.

Animals↗