Publications

Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. Here, we identify a highly conserved noncoding DNA element that is essential for Aire expression. This element shows enrichment of enhancer-associated histone marks in mTECs and also has characteristics of being an NF-κB-responsive element. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance.

BACKGROUND AND AIMS

Tenofovir (TDF)-associated renal dysfunction has been described in various studies of human immunodeficiency virus-infected patients. Our goal is to examine the incidence and magnitude of decrease in renal function in chronic hepatitis B patients treated with TDF.

METHODS

We performed a case-cohort study of 103 patients on TDF 300 mg and 103 patients unexposed to TDF (Entecavir) at 4 centers, who were matched for age±10 years, sex, and baseline estimated glomerular filtration rate (eGFR) group. Calculation and evaluation of eGFR were performed with both the Cockcroft-Gault formula and the Modification of Diet in Renal Disease formula.

RESULTS

The exposed and unexposed populations were well matched with a similar mean age (44±10 y), proportion of male patients (63.1%), and baseline eGFR groups (86.4% unimpaired). There was no significant difference in the proportion of patients reclassified to a more severe renal classification (RMSRC) or in the proportion of patients with decrease in eGFR of ≥20% in those exposed to TDF versus control. The incidence density for RMSRC was 7.4 cases per 100 patient-years in the exposed group compared with 11.5 cases per 100 patient-years in the unexposed group (95% CI, 0.31-1.34). The relative risk of exposed to unexposed was 0.64 (95% CI, 0.31-1.34). On Cox proportional hazard analysis following adjustment for sex, age, baseline diagnosis hypertension, diabetes, impaired baseline renal function, and cirrhosis, TDF was not a predictor for RMSRC or decrease in eGFR≥20%.

CONCLUSIONS

TDF treatment was not an independent predictor for significant deterioration of renal function. Renal function of chronic hepatitis B patients on antiviral therapy should be monitored, especially in those who are older and/or with mildly impaired renal function.