Publications

Signaling through the T cell antigen receptor (TCR) is important for the homeostasis of naïve and memory CD4(+) T cells. The significance of TCR signaling in regulatory T (Treg) cells has not been systematically addressed. Using an Ox40-cre allele that is prominently expressed in Treg cells, and a conditional null allele of the gene encoding p56(Lck), we have examined the importance of TCR signaling in Treg cells. Inactivation of p56(Lck) resulted in abnormal Treg homeostasis characterized by impaired turnover, preferential redistribution to the lymph nodes, loss of suppressive function, and striking changes in gene expression. Abnormal Treg cell homeostasis and function did not reflect the involvement of p56(Lck) in CD4 function because these effects were not observed when CD4 expression was inactivated by Ox40-cre.The results make clear multiple aspects of Treg cell homeostasis and phenotype that are dependent on a sustained capacity to signal through the TCR.

The role of polarity signaling in cancer metastasis is ill defined. Using two three-dimensional culture models of mammary epithelial cells and an orthotopic mouse model of breast cancer, we reveal that Par6 signaling, which is regulated directly by TGFbeta, plays a role in breast cancer metastasis. Interference with Par6 signaling blocked TGFbeta-dependent loss of polarity in acini-like structures formed by non-transformed mammary cells grown in three-dimensional structures and suppressed the protrusive morphology of mesenchymal-like invasive mammary tumor cells without rescuing E-cadherin expression. Moreover, blockade of Par6 signaling in an in vivo orthotopic model of metastatic breast cancer induced the formation of ZO-1-positive epithelium-like structures in the primary tumor and suppressed metastasis to the lungs. Analysis of the pathway in tissue microarrays of human breast tumors further revealed that Par6 activation correlated with markers of the basal carcinoma subtype in BRCA1-associated tumors. These studies thus reveal a key role for polarity signaling and the control of morphologic transformation in breast cancer metastasis.

The human genome, human endogenous retroviruses (HERV), of which HERV-K113 and HERV-K115 are the only known full-length proviruses that are insertionally polymorphic. Although a handful of previously published papers have documented their prevalence in the global population; to date, there has been no report on their prevalence in the United States population. Here, we studied the geographic distribution of K113 and K115 among 156 HIV-1+ subjects from the United States, including African Americans, Hispanics, and Caucasians. In the individuals studied, we found higher insertion frequencies of K113 (21%) and K115 (35%) in African Americans compared with Caucasians (K113 9% and K115 6%) within the United States. We also report the presence of three single nucleotide polymorphism sites in the K113 5' long terminal repeats (LTRs) and four in the K115 5' LTR that together constituted four haplotypes for K113 and five haplotypes for K115. HERV insertion times can be estimated from the sequence differences between the 5' and 3' LTR of each insertion, but this dating method cannot be used with HERV-K115. We developed a method to estimate insertion times by applying coalescent inference to 5' LTR sequences within our study population and validated this approach using an independent estimate derived from the genetic distance between K113 5' and 3' LTR sequences. Using our method, we estimated the insertion dates of K113 and K115 to be a minimum of 800,000 and 1.1 million years ago, respectively. Both these insertion dates predate the emergence of anatomically modern Homo sapiens.

BACKGROUND

Professional use of hypochlorite (bleach) has been associated with respiratory symptoms. Bleach is capable of inactivating allergens, and there are indications that its domestic use may reduce the risk of allergies in children.

OBJECTIVE

To study the associations between household use of bleach and atopic sensitization, allergic diseases, and respiratory health status in adults.

METHODS

We identified 3626 participants of the European Community Respiratory Health Survey II in 10 countries who did the cleaning in their homes and for whom data on specific serum IgE to 4 environmental allergens were available. Frequency of bleach use and information on respiratory symptoms were obtained in face-to-face interviews. House dust mite and cat allergens in mattress dust were measured in a subsample. Associations between the frequency of bleach use and health outcomes were evaluated by using multivariable mixed logistic regression analyses.

RESULTS

The use of bleach was associated with less atopic sensitization (odds ratio [OR], 0.75; 95% CI, 0.63-0.89). This association was apparent for specific IgE to both indoor (cat) and outdoor (grass) allergens, and was consistent in various subgroups, including those without any history of respiratory problems (OR, 0.85). Dose-response relationships (P < .05) were apparent for the frequency of bleach use and sensitization rates. Lower respiratory tract symptoms, but not allergic symptoms, were more prevalent among those using bleach 4 or more days per week (OR, 1.24-1.49). The use of bleach was not associated with indoor allergen concentrations.

CONCLUSION

People who clean their homes with hypochlorite bleach are less likely to be atopic but more likely to have respiratory symptoms.