Mice thymectomized at three days of age (D3Tx) develop as adults a variety of organ specific autoimmune diseases. The D3Tx model depends exclusively on perturbation of the normal developing immune system, is T-cell-mediated, and is genetically controlled. After D3Tx, organ specific autoantigens expressed at physiologic levels, trigger an autoimmune response capable of eliciting disease. The T-cell repertoire of both neonatal and adult D3Tx-mice is enriched for self-reactive T cells. In the normal adult repertoire, CD4+CD5(low) T cells have the capacity to elicit autoimmune disease when adoptively transferred into nude recipients. Thus the ability to transfer disease is due, in part, to failure of the neonatal thymus to delete autoreactive cells before it is removed. In addition, D3Tx mice are deficient in cD4+CD5(high) regulatory T cells needed to control disease inducing T cells that mature in the adult thymus. These findings indicate that expansion of the autoreactive neonatal T-cell repertoire, frozen by D3Tx, results in disease. The fact that disease susceptibility is genetically controlled leads us to hypothesize that the gene(s) controlling the phenotypic expression of autoimmunity in this model may include those that govern the induction and maintenance of peripheral tolerance to organ specific autoantigens. Previously, we mapped Aod1, the major gene controlling the abrogation of tolerance in D3Tx-induced autoimmune oophoritis to chromosome 16. In this study, we propose to: l) develop reciprocal congenic and recombinant congenic lines carrying the susceptible and resistant Aod1 allele on identical genetic backgrounds; and 2) identify, clone, and characterize the Aod1 locus. It is anticipated that the findings of the studies proposed in this application will extend our understanding of the mechanisms underlying the induction and maintenance of peripheral tolerance to organ specific autoantigens which play a role in the pathogenesis of organ specific autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041747-04
Application #
6137226
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Kirshner, Susan
Project Start
1997-01-01
Project End
2001-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
4
Fiscal Year
2000
Total Cost
$234,421
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Type
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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
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
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

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