Perceived stress is associated with impaired T-cell response to HPV16 in women with cervical dysplasia.

BACKGROUND: Infection with high-risk subtypes of human papillomavirus (HPV) is a central factor in the development of cervical neoplasia. Cell-mediated immunity against HPV16 plays an important role in the resolution of HPV infection and in controlling cervical disease progression. Research suggests that stress is associated with cervical disease progression, but few studies have examined the biological mechanisms that may be driving this association. PURPOSE: This study examines whether stress is associated with immune response to HPV16 among women with cervical dysplasia. METHODS: Seventy-four women presenting for colposcopy completed measures of health behaviors, stressful life events and perceived stress. A blood sample was obtained to evaluate proliferative T-cell response to HPV16, and a cervical sample was obtained during gynecologic exam for HPV-typing. RESULTS: More than 55% tested positive for one or more HPV subtypes. Women who did not show proliferative responses to HPV (i.e. non-responders) were more likely to be HPV(+) compared to women who had a response (i.e. responders). Consistent with study hypotheses, logistic regression revealed that higher levels of perceived stress were associated with a non-response to HPV16, controlling for relevant covariates. Stressful life events were not associated with T-cell response to HPV. CONCLUSIONS: Higher levels of perceived stress are associated with impaired HPV-specific immune response in women with cervical dysplasia, suggesting a potential mechanism by which stress may influence cervical disease progression.

The effects of avoidance on cytotoxic/suppressor T cells in women with cervical lesions.

The purpose of this study was to examine the relationship between avoidant and intrusive ideation about cancer risk and immune responses among women with mild cervical dysplasia. Participants were 54 women undergoing diagnostic follow-up (i.e. colposcopy) for an abnormal Pap smear test result. Baseline assessments, collected prior to the colposcopy appointment, included demographic and medical history, levels of depression, and the intrusion and avoidance subscales of the Revised Impact of Events Scale. In addition, a sample of blood was obtained at baseline and 6-month follow-up for immune assessments. Hierarchical regression analyses revealed that higher levels of cognitive and behavioral avoidance at baseline predicted a significantly lower percentage of circulating cytotoxic/suppressor T cells (CD3(+)/CD8(+)) at 6-month follow-up, after controlling for baseline levels of cytotoxic/suppressor T cells and potential confounding variables (e.g. age, smoking status). Baseline intrusive ideation was unrelated to changes in percentage of cytotoxic/suppressor T cells. Avoidant ideation, but not intrusive ideation or depression, appears to be associated with alterations in immunologic measures in women with cervical lesions. The findings suggest that it may be important to evaluate the impact of cognitive and behavioral avoidance on progression of precancerous cervical lesions.

Increased proliferation within T lymphocyte subsets of HIV-infected adolescents.

Proliferation within T lymphocyte subsets of HIV-infected adolescents was quantified by detection of Ki-67, a nuclear antigen found in cells in late G(1), S, or G(2) phases of the cell cycle. Median percentages and absolute counts of Ki-67(+) cells for all subsets tested (CD4 naive and memory, CD8 naive and memory) were significantly higher for HIV-infected adolescents compared to uninfected controls. CD8 naive cells of HIV-infected adolescents had the greatest increase in rate of proliferation and number of proliferating cells compared to uninfected controls. In HIV-infected adolescents, the percentage and absolute number of proliferating CD4 naive cells were considerably lower than corresponding values for the other subsets. CD4 percent correlated inversely with Ki-67 expression in CD4 memory, CD8 naive, and CD8 memory cells, while Ki-67 expression in CD4 and CD8 memory cells correlated directly with average CD38 molecules/CD8 cell and absolute number of CD8/CD38/HLA-DR cells, consistent with T cell activation. These results indicate that in adolescents, HIV infection is associated with increased proliferation within CD4 and CD8 naive and memory subsets. Proliferation within the CD8 naive subset was higher than that observed previously for HIV-infected adults, suggesting that adolescents have a greater ability to regenerate and/or expand CD8 naive cells. CD4 naive cells of HIV-infected adolescents had a low rate of proliferation, and the total number of CD4 naive cells was low, suggesting that regeneration and/or peripheral expansion are limited and may contribute to the reduced size of this subset. The Ki-67 assay provided new and useful information on in vivo lymphocyte proliferation in HIV-infected adolescents.

A role for PKC-delta and PI 3-kinase in TNF-alpha-mediated antiapoptotic signaling in the human neutrophil.

The proinflammatory cytokine tumor necrosis factor (TNF)-alpha has been implicated in the attenuation of neutrophil spontaneous apoptosis during sepsis. Antiapoptotic signaling is principally mediated through the p60TNF receptor (p60TNFR). In neutrophils, TNF-alpha is an incomplete secretagogue and requires input from a ligated integrin(s) for neutrophil activation. In adherent neutrophils, TNF-alpha triggers association of both protein kinase C (PKC)-delta and phosphatidylinositol (PI) 3-kinase with the p60TNFR. In this study, a role for PKC-delta and PI 3-kinase in TNF-alpha-mediated antiapoptotic signaling was examined. TNF-alpha inhibited spontaneous apoptosis in fibronectin-adherent neutrophils, and this antiapoptotic signaling was blocked by the PKC-delta inhibitor rottlerin, but not by an inhibitor of Ca(2+)-dependent PKC isotypes, Go-6976. Inhibition of PI 3-kinase by LY-294002 also inhibited TNF-alpha-mediated antiapoptotic signaling. Cycloheximide blocked TNF-alpha-mediated antiapoptotic signaling, suggesting protein synthesis is required. Inhibition of either PKC-delta or PI 3-kinase attenuated TNF-alpha-mediated activation of the antiapoptotic transcription factor NFkappaB. Thus both PKC-delta and PI 3-kinase have essential roles in TNF-alpha-mediated antiapoptotic signaling in adherent neutrophils.