Article

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: 13.77). 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.

Download full-text

Full-text

Available from: Jean M Jasinski, Dec 27, 2013
0 Followers
 · 
127 Views
  • Source
    • "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"
    [Show abstract] [Hide abstract]
    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 · 2.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Successful and rapid synthesis of thin defect free hydroxy sodalite (H-SOD) membranes with a thickness of 2m on α-Al2O3 supports was achieved using direct hydrothermal synthesis. The membranes were characterized by X-ray diffraction (XRD) , scanning electron microscopy (SEM) and single gas permeation measurements. Single component pervaporation experiments were carried out to investigate water flux through H-SOD membranes at different temperatures and pressures. The membranes were used for pervaporative separation of water from water-isopropanol (IPA) mixtures. The effects of IPA feed concentration and temperature were studied on the permeation flux and the separation factor of water with respect to IPA. The membrane was impermeable to N2 and He permeance was as low as 10-11 mols-1m-2Pa-1, which validates absence of defects. Pervaporation fluxes of water up to 2.25 kgm-2h-1 at 423 K were obtained. In pervaporation of water from water/IPA mixtures, the membranes showed absolute selectivity towards water regardless of temperature or feed concentration. Increasing temperature seemed to have little effect on flux values; but increasing the water content in feed led to a dramatic increase in flux through the membrane.
    Studies in surface science and catalysis 01/2007; 170:1028-1035. DOI:10.1016/S0167-2991(07)80956-6
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although multiple islet autoantigens are recognized by T lymphocytes and autoantibodies before the development of type 1A (immune-mediated diabetes), there is increasing evidence that autoimmunity to insulin may be central to disease pathogenesis. Evidence is strongest for the NOD mouse model where blocking immune responses to insulin prevents diabetes, and insulin peptides can be utilized to induce diabetes. In man insulin gene polymorphisms are associated with disease risk, and autoantibodies and T cells reacting with multiple insulin/proinsulin epitopes are present. It is not currently clear why insulin autoimmunity is so prominent and frequent, and though insulin can be used to immunologically prevent diabetes of NOD mice, insulin-based preventive immunoregulation of diabetes in man is not yet possible.
    Current Opinion in Immunology 03/2008; 20(1):111-8. DOI:10.1016/j.coi.2007.11.005 · 7.87 Impact Factor
Show more