This is a competitive renewal application for grant AI-41236-A1. Our major goal is to obtain definitive proof that the CD4+CD25+Foxp3+ T regulatory cells (Treg) control self-tolerance. We have recently succeeded in establishing an excellent autoimmune disease model induced by Treg depletion alone. Diphtherial toxin treatment of B6AF1-DEREG mice (express DTR-foxp3 transgene in artificial chromosome) leads to transient Treg loss for 7 days. Six weeks later, the mice develop multi-organ autoimmune disease that targets the testis, ovary, stomach and lacrimal gland. The mice produce autoAb against the testis germ cell and Leydig cell Ag, ovarian theca cell Ag and the ZP3 (335) epitope, and gastric ATPase. They are healthy-looking, gain weight and survive normally. Our focus is on the gonadal diseases because they resemble the disease in >60% of autoimmune polyendocrine sydnrome type I (APS1) patients. APS1 is rare but of immense significance. The cause is a mutation of the autoimmune Responder (AIRE) gene, a known participant in central tolerance. We are acknowledged as leaders in gonadal autoimmunity research and the best candidate for this investigation. We discovered that Treg depletion leads to a Teff and Treg imbalance, governed by the intrinsic Treg strength. The net response determines disease outcome. B6AF1-DEREG mice show dominant Teff cell response and develop autoimmune disease. B6-DEREG mcie show a dominant Treg response and do not have autoimmunity. We also discovered that the Teff cells of B6AF1-DEREG mice with AO resist Treg suppression, and they express low levels Cbl-b. Cbl-b is an E3 ligase the controls the TCR response threshold.
In Aim 1, we will verify the T cell imbalance hypothesis and study the causal relation of Treg resistance to Cbl-b expression. Unexpectedly, the germ cell-specific response is Th2-dominant and autoAb is IgG1-dominant. AO is not associated with testis inflammation, but is associated with massive IgG1+ immune complex (IC) that targets germ cell Ag. Importantly, the cause of testis failure and infertility are Sertoli cell injury and blood-testis barrier (BTB) disruption. The Sertoli cells normally control BTB and sperm production.
In Aim 2, we will investigate eosinophil in promoting the IgG1 autoAb response, and define an Fc receptor-dependent mechanism for the Sertoli cell injury as a cause of AO. Also unexpected is the finding that B6-DEREG mice, after Treg depletion, spontaneously lose testis immune privilege and stop making sperm. Amazingly, this novel process is reversible with full recovery, and thus it can be controlled by Treg. The B6AF1-DEREG mice also develop a similar "early" innate cell injury in the testis.
In Aim 3, we will determine whether this unique, non-autoimmune innate cell- mediate injury will predispose the testis to autoAb-mediated AO. In summary, our exciting and highly novel project will provide definitive proof for Treg as a non-redundant tolerance mechanism. Our study will define many Treg functions relevant to many common human diseases such as: pemphigus vulgaris, IC disease (SLE), Sjogren's syndrome, APS1, gastritis, and male and female idiopathic infertility due to gonadal failure.

Public Health Relevance

Autoimmune diseases are a major cause of human suffering and premature human death. They are chronic diseases and require costly management. There is no cure and palliative treatment has serious side effects. Therefore, top priorities are the discovery of new mechanisms of autoimmune disease and the identification of effective therapeutic measures. We have developed a model of human Type I Autoimmune Polyendocrine Syndrome (APS1): A human disease of extreme immunological significance. Our focus will be on autoimmune disease of the gonads. These diseases are cause of idiopathic human infertility affecting 1 of 7 married couples desiring children. Infertility is not fatal but t prevents life. Autoimmune orchitis and epididymitis occur in vasectomized animals and humans. Over half a million men per year are vasectomized in the US. Despite the great need, gonadal immunology is a major under-represented area of research. We will accrue new knowledge applicable to other human diseases such as glomerulonephritis, pemphigus vulgaris and systemic lupus erythematosus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI041236-19A1
Application #
8439347
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
1993-09-01
Project End
2017-10-31
Budget Start
2012-11-15
Budget End
2013-10-31
Support Year
19
Fiscal Year
2013
Total Cost
$371,300
Indirect Cost
$136,300
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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