Autoimmunity affects nearly ten million Americans and, for unknown reasons, is increasing in frequency. Available evidence indicates that autoimmune diseases arise due to a combination of genetically determined susceptibility and innate immune stimulation, which conspire to stimulate adaptive immunity to self. Underpinning autoimmunity is the breakdown of immune tolerance to self in T cell and/or B cell compartments. While a great deal is known about the mechanisms that maintain B cell tolerance, we understand little about the mechanisms that cause it to fail in autoimmunity. In this application we propose to study mechanisms operative in loss of B cell tolerance to insulin in murine and human Type 1 Diabetes, a disease known to require B cells that are thought to function by antigen presentation to CD4 T cells. Our approach will build upon our previous work defining signaling pathways operative in maintaining antigen unresponsiveness of anergic B cells. We will analyze by flow cytometry changes in the status of insulin-specific B cells isolated using a novel magnetic bead-based approach from normal, prediabetic and diabetic mice and patients. In some cases immunoglobulin heavy chain transgenesis will be used to generate a diverse antigen receptor repertoire that is nonetheless enriched in insulin-specific cells.
Aim 1 will explore how peripheral insulin-specific B cells are silenced in normal mice and whether this silencing is breached in diabetic mice.
In Aim 2 we will study the role of antigen receptor affinit for insulin in determining mode of silencing, fate and diabetogenic potential. This will involve a retrotransgenic approach to generate a repertoire with defined antigen receptor affinity for insulin.
In Aim 3 we will extend studies to the human, comparing insulin-specific B cells in prediabetic and diabetic individuals to non-diabetic first- degree relatives. Finally, in Aim 4 we will assess the therapeutic efficacy in T1D of a novel B cell desensitizing therapy, comparing this therapy to anti-CD20, which depletes B cells. The experiments will address the overarching hypothesis that in Type 1 Diabetes the silence of high affinity insulin-specific B cells is broken and these cells promote disease by presentation of autoantigen to CD4 T cells.

Public Health Relevance

Type 1 Diabetes (T1D) is an autoimmune disease in which insulin-producing cells in the pancreas are attacked by the immune system. While T lymphocytes are responsible for actual organ damage, insulin-specific B cells are required for development of the disease. This application proposes analysis of the role of these B cells in TID, and will test the therapeutic effectiveness of a novel B cell-targeted therapy in this disease

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK096492-03
Application #
8690052
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Spain, Lisa M
Project Start
2012-08-20
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Smith, Mia J; Hinman, Rochelle M; Getahun, Andrew et al. (2018) Silencing of high-affinity insulin-reactive B lymphocytes by anergy and impact of the NOD genetic background in mice. Diabetologia 61:2621-2632
Smith, Mia J; Rihanek, Marynette; Wasserfall, Clive et al. (2018) Loss of B-Cell Anergy in Type 1 Diabetes Is Associated With High-Risk HLA and Non-HLA Disease Susceptibility Alleles. Diabetes 67:697-703
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Smith, Mia J; Simmons, Kimber M; Cambier, John C (2017) B cells in type 1 diabetes mellitus and diabetic kidney disease. Nat Rev Nephrol 13:712-720
Franks, S Elizabeth; Getahun, Andrew; Hogarth, P Mark et al. (2016) Targeting B cells in treatment of autoimmunity. Curr Opin Immunol 43:39-45
Seay, Howard R; Yusko, Erik; Rothweiler, Stephanie J et al. (2016) Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes. JCI Insight 1:e88242
Packard, Thomas A; Smith, Mia J; Conrad, Francis J et al. (2016) B Cell Receptor Affinity for Insulin Dictates Autoantigen Acquisition and B Cell Functionality in Autoimmune Diabetes. J Clin Med 5:

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