Priming and effector dependence on insulin B:9-23 peptide in NOD islet autoimmunity

Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center (UCHSC), Aurora, CO 80045-6511, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 08/2007; 117(7):1835-43. DOI: 10.1172/JCI31368
Source: PubMed

ABSTRACT NOD mice with knockout of both native insulin genes and a mutated proinsulin transgene, alanine at position B16 in preproinsulin (B16:A-dKO mice), do not develop diabetes. Transplantation of NOD islets, but not bone marrow, expressing native insulin sequences (tyrosine at position B16) into B16:A-dKO mice rapidly restored development of insulin autoantibodies (IAAs) and insulitis, despite the recipients' pancreatic islets lacking native insulin sequences. Splenocytes from B16:A-dKO mice that received native insulin-positive islets induced diabetes when transferred into wild-type NOD/SCID or B16:A-dKO NOD/SCID mice. Splenocytes from mice immunized with native insulin B chain amino acids 9-23 (insulin B:9-23) peptide in CFA induced rapid diabetes upon transfer only in recipients expressing the native insulin B:9-23 sequence in their pancreata. Additionally, CD4(+) T cells from B16:A-dKO mice immunized with native insulin B:9-23 peptide promoted IAAs in NOD/SCID mice. These results indicate that the provision of native insulin B:9-23 sequences is sufficient to prime anti-insulin autoimmunity and that subsequent transfer of diabetes following peptide immunization requires native insulin B:9-23 expression in islets. Our findings demonstrate dependence on B16 alanine versus tyrosine of insulin B:9-23 for both the initial priming and the effector phase of NOD anti-islet autoimmunity.

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Available from: Jean M Jasinski, Dec 27, 2013
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    • "Studies on the insulin peptides that contribute to type 1 diabetes in NOD mice lead to related conclusions . Insulin has long been thought to be the source of autoantigenic peptides that are required for induction of type 1 diabetes , in mice at least ( Levisetti et al . , 2007 Mohan et al . , 2007 ; Nakayama et al . , 2007 ; Jarchum and DiLorenzo , 2009 ) . Although the por - tion of insulin that contains the culprit peptide has long been known , the precise insulin peptide that drives disease was for many years unknown . It turns out that the crucial product is unexpected , a peptide that binds poorly rather than well to IA g7 ( Stadinski et al . , 2010b"
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    ABSTRACT: T cell recognition of foreign peptide antigen and tolerance to self peptides is key to the proper function of the immune system. Usually, in the thymus T cells that recognize self MHC + self peptides are deleted and those with the potential to recognize self MHC + foreign peptides are selected to mature. However there are exceptions to these rules. Autoimmunity and allergy are two of the most common immune diseases that can be related to recognition of self. Many genes work together to lead to autoimmunity. Of those, particular MHC alleles are the most strongly associated, reflecting the key importance of MHC presentation of self peptides in autoimmunity. T cells specific for combinations of self MHC and self peptides may escape thymus deletion, and thus be able to drive autoimmunity, for several reasons: the relevant self peptide may be presented at low abundance in the thymus but at high level in particular peripheral tissues; the relevant self peptide may bind to MHC in an unusual register, not present in the thymus but apparent elsewhere; finally the relevant self peptide may be post translationally modified in a tissue specific fashion. In some types of allergy, the peptide + MHC combination may also be fully derived from self. However the combination in question may be modified by the presence of other ligands, such as small drug molecules or metal ions. Thus these types of allergies may act like the post translationally modified peptides involved some types of autoimmunity.
    Protein & Cell 01/2013; 4(1):8-16. DOI:10.1007/s13238-012-2077-7 · 3.25 Impact Factor
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    • "Under certain conditions this can lead to a pathological attack on self-tissues. Several CD8+-T-cell-mediated autoimmune diseases have been identified, such as Type I diabetes [6–9], multiple sclerosis [10, 11], nephritis [12, 13], and psoriasis vulgaris [14]. To prevent the development of such diseases, secondary lymphoid organs generally serve as the site for elimination of CD8+ T cells recognizing self-Ag with high affinity, a process that has been referred to as cross-tolerance [15–17]. "
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    ABSTRACT: Antigens (Ag) from cancer or virus-infected cells must be internalized by dendritic cells (DCs) to be presented to CD8(+) T cells, which eventually differentiate into Ag-specific cytotoxic T lymphocytes (CTLs) that destroy cancer cells and infected cells. This pathway is termed cross-presentation and is also implicated as an essential step in triggering autoimmune diseases such as Type I diabetes. Internalized Ag locates within endosomes, followed by translocation through a putative pore structure spanning endosomal membranes into the cytosol, where it is degraded by the proteasome to generate antigen peptides. During translocation, Ag is believed to be unfolded since the pore size is too narrow to accept native Ag structure. Here, we show that paraformaldehyde-fixed, structurally inflexible Ag is less efficient in cross-presentation because of diminished translocation into the cytosol, supporting the "unfolded Ag" theory. We also show that HSP70 inhibitors block both endogenous and cross-presentation. ImageStream analysis revealed that the inhibition in cross-presentation is not due to blocking of Ag translocation because a HSP70 inhibitor rather facilitates the translocation, which is in marked contrast to the effect of an HSP90 inhibitor that blocks Ag translocation. Our results indicate that Ag translocation to the cytosol in cross-presentation is differentially regulated by HSP70 and HSP90.
    09/2012; 2012(4):745962. DOI:10.1155/2012/745962
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    • "For presentation via the classical MHC class I pathway proteins can be catabolized in the proteosome to be loaded onto MHC class I molecules in the endoplasmic reticulum (ER). To further examine the intracellular trafficking routes used by B cells to present autoantigen, NOD B cells were pulsed with insulin, a prominent islet autoantigen (33), and subsequently treated with inhibitors that would compromise the classical routes of antigen transport (34,35). Proliferation of self-reactive CD8+ T cells was determined as a measure of antigen presentation. "
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    ABSTRACT: For autoimmune conditions like type 1 diabetes to progress, self-reactive CD8(+) T cells would need to interact with peptide-antigen cross-presented on the surface of antigen-presenting cells in a major histocompatibility complex (MHC) class I-restricted fashion. However, the mechanisms by which autoantigen is cross-presented remain to be identified. In this study, we show cross-presentation of islet-derived autoantigens by B cells. B cells engage self-reactive CD8(+) T cells in the pancreatic lymph node, driving their proliferative expansion and differentiation into granzyme B(+)interferon-γ(+)lysosomal-associated membrane protein 1(+) effector cells. B-cell cross-presentation of insulin required proteolytic cleavage and endosomal localization and was sensitive to inhibitors of protein trafficking. Absent B-cell MHC class I, or B-cell receptor restriction to an irrelevant specificity, blunted the expansion of self-reactive CD8(+) T cells, suggesting B-cell antigen capture and presentation are critical in vivo events for CD8 activation. Indeed, the singular loss of B-cell MHC class I subverted the conversion to clinical diabetes in NOD mice, despite the presence of a pool of activated, and B cell-dependent, interleukin-21-expressing Vβ4(+)CD4(+) T cells. Thus, B cells govern the transition from clinically silent insulitis to frank diabetes by cross-presenting autoantigen to self-reactive CD8(+) T cells.
    Diabetes 07/2012; 61(11):2893-905. DOI:10.2337/db12-0006 · 8.10 Impact Factor
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