Autoimmunity is caused by conspiring effects of genetic predisposition and environmental factors such as injury, infection and microbiome constitution. While multiple genetic loci affect susceptibility, in most cases each in isolation has only a small effect, suggesting that disease develops only when multiple risk-conferring alleles that function in concert are inherited by a single individual. We hypothesize that such a situation exists in autoreactive B cells where multiple SLE risk alleles encode molecules that appear to function in signaling pathways that function normally to limit/terminate antigen receptor signaling. In this application we propose to test this hypothesis, analyzing the functional interplay of this set of genes/protein and their risk conferring alleles. Future development and implementation of ?precision? medical approaches for treatment of autoimmunity will require an understanding of the mechanisms by which genetic variations conspire to increase disease risk, and research proposed here represents a critical first step to enable these efforts. A number of autoimmunity risk alleles encode molecules previously proposed to function as intermediaries in signaling pathways involved in regulation of B cell activation. As such they may be important in keeping autoreactive B cells from becoming activated and contributing to autoimmunity. In this application we request support to define the functions and functional interactions of proteins encoded by six genes, variants of which confer increased risk of autoimmunity. Previous reports indicate that B cell-targeted deletion of genes encoding SHIP-1, PTEN, SHP-1 or LYN, expression of PTPN22 (PEP-R619W), or increased expression of CSK, promote the development of autoimmunity. However the mechanism by which this occurs is unknown. We hypothesize that these proteins function as intermediaries in a bifurcating pathway in which final effectors are the inositol lipid phosphatases SHIP-1 and the tyrosine phosphatase SHP-1. Further, we suggest that both terminal effectors are required for maintenance of antigen unresponsiveness of anergic B cells. The studies will employ reductionist genetic models in which risk allele mimetic changes in expression/function of the proteins can be induced acutely in anergic B cells, and subsequent cell activation, proliferation, differentiation and autoantibody production monitored.
Aim 1 will test the hypothesis that PTPN22, CSK and LYN act in linear pathways upstream of SHIP-1 and SHP-1, and that genetic variations that confer risk compromise anergy by undermining their regulatory function.
Aim 2 will define the downstream consequences of acute introduction of risk allele mimetic conditions in terms of development of autoimmune disease, and will test candidate therapeutic kinase inhibitors.
Aim 3 will translate findings, examining the role of SHIP-1 and SHP-1 phosphatases in maintenance anergy of human B cells. Proposed studies will provide important new insight regarding the in vivo lifestyle of autoreactive B cells whose anergy is compromised by autoimmunity risk alleles.

Public Health Relevance

In this application we propose to define the mechanisms by which certain genes that increase risk of autoimmunity work together to activate autoreactive B cells, leading to autoimmunity. The overarching goal of the studies is to better understand how genetic factors contribute to autoimmunity, and to define new therapeutic targets that can be targeted for personalized or precision approaches to therapy for those patients who carry specific risk alleles.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI124487-03
Application #
9429034
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Peyman, John A
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Ruiz-Moreno, Juan Sebastian; Hamann, Lutz; Jin, Lei et al. (2017) The cGAS/STING pathway detects Streptococcus pneumoniae but appears dispensable for anti-pneumococcal defense in mice and humans. Infect Immun :
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Getahun, Andrew; Beavers, Nicole A; Larson, Sandy R et al. (2016) Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells. J Exp Med 213:751-69
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: