The BB (BioBreeding) rat is one of the best models of spontaneous autoimmune diabetes and is used to study non-MHC loci contributing to Type 1 diabetes. Type 1 diabetes in the diabetes-prone BB (BBDP) rat is polygenic, dependent upon mutations at several loci.Iddm1, on chromosome 4, is responsible for a lymphopenia (lyp) phenotype and is essential to diabetes. In this study, we report the positional cloning of theIddm1/lyp locus. We show that lymphopenia is due to a frameshift deletion in a novel member (Ian5) of the Immune-Associated Nucleotide (IAN)-related gene family, resulting in truncation of a significant portion of the protein. This mutation was absent in 37 other inbred rat strains that are nonlymphopenic and nondiabetic. The IAN gene family, lying within a tight cluster on rat chromosome 4, mouse chromosome 6, and human chromosome 7, is poorly characterized. Some members of the family have been shown to be expressed in mature T cells and switched on during thymic T-cell development, suggesting thatIan5 may be a key factor in T-cell development. The lymphopenia mutation may thus be useful not only to elucidate Type 1 diabetes, but also in the function of the Ian gene family as a whole.[Sequence data reported in this paper has been deposited in GenBank and assigned the following accession nos:AF517674, AF517675, AF517676, and AF517677. Supplemental material is available online at http://depts.washington.edu/rhwlab/ and http:www.genome.org. ] The following individuals and institutions kindly provided reagents, samples, or unpublished information as indicated in the paper: K. Matsumoto and the Sir Frederick Banting Research Centre.
Studies of the stability of HLA-DQ have revealed a correlation between SDS stability of MHC class II αβ dimers and insulin-dependent diabetes mellitus (IDDM) susceptibility. The MHC class II αβ dimer encoded by HLA-DQA1*0102/DQB1*0602 (DQ0602), which is a dominant protective allele in IDDM, exhibits the greatest SDS stability among HLA-DQ molecules in EBV-transformed B-lymphoblastoid cells and PBLs. DQ0602 is also uniquely SDS stable in the HLA-DM-deficient cell line, BLS-1. We addressed the molecular mechanism of the stability of DQ0602 in BLS-1. A panel of mutants based on the polymorphic differences between HLA-DQA1*0102/DQB1*0602 and HLA-DQA1*0102/DQB1*0604 were generated and expressed in BLS-1. An Asp at β57 was found to be critical for SDS stability, whereas Tyr at β30, Gly at β70, and Ala at β86 played secondary roles. Furthermore, the level of class II-associated invariant chain peptide bound to HLA-DQ did not correlate with SDS stability, suggesting that class II-associated invariant chain peptide does not play a direct role in the unique SDS stability of DQ0602. These results support a role for DQB1 codon 57 in HLA-DQ αβ dimer stability and IDDM susceptibility.
Expansion of human regulatory T cells (Tregs) for clinical applications offers great promise for the treatment of undesirable immune responses in autoimmunity, transplantation, allergy, and antidrug antibody responses, including inhibitor responses in hemophilia A patients. However, polyclonal Tregs are nonspecific and therefore could potentially cause global immunosuppression. To avoid this undesirable outcome, the generation of antigen-specific Tregs would be advantageous. Herein, we report the production and properties of engineered antigen-specific Tregs, created by transduction of a recombinant T-cell receptor obtained from a hemophilia A subject's T-cell clone, into expanded human FoxP3(+) Tregs. Such engineered factor VIII (FVIII)-specific Tregs efficiently suppressed the proliferation and cytokine production of FVIII-specific T-effector cells. Moreover, studies with an HLA-transgenic, FVIII-deficient mouse model demonstrated that antibody production from FVIII-primed spleen cells in vitro were profoundly inhibited in the presence of these FVIII-specific Tregs, suggesting potential utility to treat anti-FVIII inhibitory antibody formation in hemophilia A patients.
To cite this article: James EA, Kwok WW, Ettinger RA, Thompson AR, Pratt KP. T-cell responses over time in a mild hemophilia A inhibitor subject: epitope identification and transient immunogenicity of the corresponding self-peptide. J Thromb Haemost 2007; 5: 2399-407.Summary. Background: Antibodies that neutralize factor (F) VIII activity, clinically referred to as ÔinhibitorsÕ, complicate the treatment of hemophilia A patients; current tolerance and bypass strategies are extremely costly and sometimes ineffective. The development of inhibitors requires T-cell help. Objectives:We characterized T-cell responses of a subject with mild hemophilia A with missense genotype A2201P for one year following his initial inhibitor response, with the goals of defining the primary epitope(s) and its (their) MHC Class II restriction. We investigated the possible involvement of regulatory T cells in modulating immune responses. Patients/methods: The subject developed high-titer FVIII-neutralizing antibodies (250 BU mL ) that declined over time to 8 BU ml )1. His clotting activity was initially impaired (3%) but returned to baseline (8-10%) within four weeks. MHC Class II tetramers were used to analyze his CD4 T cells, which were stimulated with peptides spanning the C2 domain. Responses of total and CD25-depleted CD4 cells to sequences containing A2201 (native), P2201 (hemophilic), and other predicted T-cell epitopes were evaluated. Results and conclusions: An HLA-DRA-DRB1*0101 restricted T-cell epitope containing the wild-type A2201 sequence was identified. Interestingly, peptides containing A2201 were recognized by CD4 T cells at all time points, whereas a P2201 peptide was recognized only near the initial peak response. The responsiveness of CD25-depleted CD4 cells to an A2201 peptide was enhanced 11 and 19 weeks following inhibitor detection, suggesting the possible involvement of CD4+CD25+ regulatory T cells in modulating immune responses. Patient-derived T-cell clones proliferated in response to C2 protein and to peptides containing A2201 but not P2201.
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