Adult neonatal thymectomized (NTx) mice develop, depending upon the day of thymectomy, a spectrum of autoimmune phenomenon ranging from autoantibodies (DOTX and D3Tx) and wasting disease (DOTx) to organ-specific autoimmune diseases (D3Tx) such as autoimmune ovarian dysgenesis (AOD) and autoimmune gastritis (AG). The uniquely distinguishing feature of NTx-induced autoimmunity is it dependency upon the disruption of neonatal thympoiesis and establishment and maintenance of a peripheral CD4+CD25+ T suppressor cell repertoire required for the prevention of autoimmune disease, importantly, D3Tx does not lead to autoimmune disease in all strains of mice indicating that this process is genetically controlled. In this regard, we have identified linkage of D3Tx-induced AOD and its intermediate phenotypes, anti-ovarian autoantibody responsiveness, oophoritis, and atrophy, to five quantitative trait loci (QTL) designated Aodl-Aod5 and to H2 and Gasa2, a QTL controlling susceptibility to D3Tx-induced AG. The working hypothesis underlying our genetic studies on D3Tx-induced AOD is that one or more of the QTL controlling susceptibility to D3Tx-induced autoimmunity plays a role in the genesis and/or functionality of CD4 +CD25+ suppressor T cells mediating peripheral tolerance to self antigens. Toward this end, we have established, or are in the process of establishing, panels of interval specific bi-directional recombinant congenic lines encompassing each of the AOD QTL. To date, we have shown that Aod1 is comprised of two linked QTL (Aodla and Aod1 b)with opposing allelic effects on susceptibility to autoimmune oophoritis; and that stefin A1 (Stfal) and A2 (Stfa2), inhibitors of cathepsin S, a cysteine protease required for autoantigen presentation and the development of autoimmune disease following D3Tx, are candidates for Aod1b. In this application we will: 1) complete the congenic mapping for each of the AOD QTL at a resolution of 1 cM or less and 2) directly assess the IL2 structural polymorphism as a candidate for a shared autoimmune disease QTL underlying Aod2, Idd3, and eae3.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041747-10
Application #
7334750
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
1997-01-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
10
Fiscal Year
2008
Total Cost
$277,004
Indirect Cost
Name
University of Vermont & St Agric College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Krementsov, Dimitry N; Case, Laure K; Dienz, Oliver et al. (2017) Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection. Proc Natl Acad Sci U S A 114:3491-3496
Reynolds, Jacob D; Case, Laure K; Krementsov, Dimitry N et al. (2017) Modeling month-season of birth as a risk factor in mouse models of chronic disease: from multiple sclerosis to autoimmune encephalomyelitis. FASEB J 31:2709-2719
Krementsov, Dimitry N; Noubade, Rajkumar; Dragon, Julie A et al. (2014) Sex-specific control of central nervous system autoimmunity by p38 mitogen-activated protein kinase signaling in myeloid cells. Ann Neurol 75:50-66
Wall, Emma H; Case, Laure K; Hewitt, Sylvia C et al. (2014) Genetic control of ductal morphology, estrogen-induced ductal growth, and gene expression in female mouse mammary gland. Endocrinology 155:3025-35
Saligrama, Naresha; Case, Laure K; Krementsov, Dimitry N et al. (2014) Histamine H? receptor signaling × environment interactions determine susceptibility to experimental allergic encephalomyelitis. FASEB J 28:1898-909
Bramwell, Kenneth K C; Ma, Ying; Weis, John H et al. (2014) Lysosomal ?-glucuronidase regulates Lyme and rheumatoid arthritis severity. J Clin Invest 124:311-20
Krementsov, Dimitry N; Katchy, Anne; Case, Laure K et al. (2013) Studies in experimental autoimmune encephalomyelitis do not support developmental bisphenol a exposure as an environmental factor in increasing multiple sclerosis risk. Toxicol Sci 135:91-102
Krementsov, Dimitry N; Wall, Emma H; Martin, Rebecca A et al. (2013) Histamine H(3) receptor integrates peripheral inflammatory signals in the neurogenic control of immune responses and autoimmune disease susceptibility. PLoS One 8:e62743
Saligrama, Naresha; Case, Laure K; del Rio, Roxana et al. (2013) Systemic lack of canonical histamine receptor signaling results in increased resistance to autoimmune encephalomyelitis. J Immunol 191:614-22
Wall, Emma H; Hewitt, Sylvia C; Liu, Liwen et al. (2013) Genetic control of estrogen-regulated transcriptional and cellular responses in mouse uterus. FASEB J 27:1874-86

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