Characterizing the pregnancy immune phenotype: results of the viral immunity and pregnancy (VIP) study.

PURPOSE: The increased risk of morbidity and mortality from certain microbial infections and the demonstrated improvements in the clinical course of some autoimmune diseases support the existence of pregnancy-related alterations in immune status. Elucidating the changes in innate and adaptive immunity during gestation may improve pregnancy outcomes and facilitate the development of targeted therapies for autoimmune diseases. METHOD: The Viral Immunity and Pregnancy (VIP) study evaluated over 50 subjects longitudinally at three time points during pregnancy and at two time points post-delivery. Leukocyte enumeration was performed; functional responses of NK cells and CD4 T cells were analyzed, and soluble factors such as cytokines, defensins, and steroid hormones were measured in maternal blood. RESULTS: In comparison to the post-partum period, the latter part of pregnancy was characterized by significant increases in blood phagocytes and pDCs and decreases in the number and activity of NK and T cells. Alterations were found in antimicrobial proteins and serum cytokines. CONCLUSIONS: These data show that pregnancy is not a period of immunosuppression but an alteration in immune priorities characterized by a strengthening of innate immune barriers and a concomitant reduction in adaptive/inflammatory immunity in the later stages of pregnancy.

Apoptotic cells inhibit LPS-induced cytokine and chemokine production and IFN responses in macrophages.

Apoptosis is a critical process in tissue homeostasis and results in immediate removal of the dying cell by professional phagocytes such as macrophages and dendritic cells. Phagocytosis of apoptotic cells actively suppresses production of proinflammatory growth factors and cytokines. Impaired phagocytosis of apoptotic cells has been implicated in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study we found that, in addition to suppressing lipopolysaccharide (LPS)-induced production of TNF-alpha and IL-6, phagocytosis of apoptotic cells by macrophages suppressed production of the chemokine CXCL10 that is activated by LPS-induced autocrine-acting type I IFNs. Inhibition of cytokine and chemokine production was not universally affected because LPS-induced production of IL-10 and IL-8 was not significantly affected. Apoptotic cells had minimal effects on LPS-induced activation of NF-kappaB and MAPKs, but induced expression of SOCS proteins and substantially suppressed induction of CXCL10 expression by IFN-alpha. In addition to suppressing LPS responses, apoptotic cells inhibited macrophage responses to another major macrophage activator IFN-gamma by attenuating IFN-gamma-induced STAT1 activation and downstream gene expression. These results identify suppressive effects of apoptotic cells on signal transduction, and extend our understanding of the anti-inflammatory effects of apoptotic cells to include suppression of Jak-STAT signaling.

Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells.

Exposure of adult humans to manganese (Mn) has long been known to cause neurotoxicity. Recent evidence also suggests that exposure of children to Mn is associated with developmental neurotoxicity. Astrocytes are critical for the proper functioning of the nervous system, and they play active roles in neurogenesis, synaptogenesis and synaptic neurotransmission. In this report, to help elucidate the molecular events underlying Mn neurotoxicity, we systematically identified the molecular targets of Mn in primary human astrocytes at a genome-wide level, by using microarray gene expression profiling and computational data analysis algorithms. We found that Mn altered the expression of diverse genes ranging from those encoding cytokines and transporters to signal transducers and transcriptional regulators. Particularly, 28 genes encoding proinflammatory chemokines, cytokines and related functions were up-regulated, whereas 15 genes encoding functions involved in DNA replication and repair and cell cycle checkpoint control were down-regulated. Consistent with the increased expression of proinflammatory factors, analysis of common regulators revealed that 16 targets known to be positively affected by the interferon-gamma signaling pathway were up-regulated by Mn(2+). In addition, 68 genes were found to be similarly up- or down-regulated by both Mn(2+) and hypoxia. These results from genomic analysis are further supported by data from real-time RT-PCR, Western blotting, flow cytometric and toxicological analyses. Together, these analyses show that Mn(2+) selectively affects cell cycle progression, the expression of hypoxia-responsive genes, and the expression of proinflammatory factors in primary human astrocytes. These results provide important insights into the molecular mechanisms underlying Mn neurotoxicity.

Immunogenicity of trivalent inactivated influenza vaccination received during pregnancy or postpartum.

OBJECTIVE: To estimate the effects of gestational age and other maternal factors on immunologic responses to influenza vaccination. METHODS: Antepartum and postpartum women receiving influenza vaccination as part of routine clinical care were enrolled through four consecutive vaccination seasons (starting October 2006 through January 2010). Immunologic responses to trivalent inactivated influenza vaccine and monovalent H1N1 were assessed as well as factors influencing vaccine responsiveness. Serum samples were obtained at baseline and 4-8 weeks postvaccination. RESULTS: Two hundred thirty-nine participants were included in the current analysis. Seroconversion rates to trivalent inactivated influenza vaccine strains were lowest in the first trimester (54.8%) and immediately postpartum (54.8%) and were highest in the late third trimester (69.6%) and late postpartum (69.4%); these differences were not statistically significant (P=.23). In a multivariable model, higher baseline antibody levels (P<.001) and prior year flu vaccination (P=.03) were both significantly associated with reduced odds of seroconversion. Overall, results were consistent when comparing trivalent inactivated influenza vaccine and monovalent pandemic H1N1 responses. Although there was overall no significant association between gestational age at vaccination (P=.23) or prepregnancy body mass index (P=.16), we observed somewhat lower rates of seroconversion for women vaccinated in the first trimester and for obese women. CONCLUSION: Adequate immunologic responses to inactivated influenza vaccines were demonstrated during pregnancy and the postpartum period. No diminution of immunogenicity was observed in the third trimester, a time of increased clinical vulnerability to influenza.

The epidemiology of hospitalized postpartum depression in New York State, 1995-2004.

PURPOSE: The purpose of this study is to describe the patterns of hospitalization for depression in the year after delivery in relation to social, demographic, and behavioral characteristics. METHODS: Data on births were linked to hospitalizations for depression over the subsequent year to describe the frequency and patterns of hospitalized postpartum depression among 2,355,886 deliveries in New York State from 1995 to 2004. We identified "definite postpartum depression" based on International Classification of Diseases (ICD) codes indicative of "mental disorders specific to pregnancy," and "possible postpartum depression" by ICD codes for hospitalization with any depressive disorders. RESULTS: In New York State, we identified 1363 women (5.8 per 10,000) who were hospitalized with definite postpartum depression, and 6041 women (25.6 per 10,000) with possible postpartum depression, with lower risks in the New York City area. Postpartum depression was more common in later years and among mothers who were older, Black, smokers, lacking private insurance, and with multiple gestations, and was rarer among Asians. For possible postpartum depression, socioeconomic gradients were enhanced. CONCLUSIONS: Risk of hospitalized postpartum depression is strongly associated with socioeconomic deprivation and varies markedly by ethnicity, with direct implications for screening and health services, also providing suggestions for etiologic studies.

Peripheral blood cytokine profiling during pregnancy and post-partum periods.

PROBLEM: Pregnancy requires that the maternal immune system adapt to prevent rejection of the fetal semi-allograft. This immunologic adaptation may contribute to pregnancy-related alterations in disease susceptibility and severity of infections from viral pathogens such as influenza virus. METHOD OF STUDY: As part of a larger study investigating the maternal systemic immune response during pregnancy, peripheral blood was collected three times during pregnancy and twice post-partum to measure serum levels of 23 cytokines, chemokines, and growth factors. This longitudinal study design allowed each woman's post-partum blood draw to serve as her own comparison, thus controlling for interpersonal variability in expression levels. RESULTS: When compared to the post-partum samples, significant pregnancy-related changes in IFNγ, TNFα, VEGF, GCSF, Eotaxin, and MCP-1 expression were observed. These changes have significant immunologic effects in vivo and in culture. CONCLUSION: Pregnancy-associated changes to steady state serum cytokines may have important immunologic consequence.

Comparison of the incidence of de novo solid malignancies after heart transplantation to that in the general population.

An increased incidence of lymphomas and skin cancers has been shown in heart transplant recipients compared with the general population. However, the incidence of de novo solid tumors in heart transplant recipients has not been compared with the general population. Accordingly, 851 consecutive adult heart transplant recipients at a single large center were followed up from January 1, 1994, to May 31, 2007, to determine the incidence and type of de novo solid-tumor malignancies. The observed incidence of each cancer type was compared with the expected incidence from the Surveillance Epidemiology End Result database, matching for age, gender, and race. Observed counts divided by expected counts yielded a standardized incidence ratio (SIR), which was tested for significance. Of 851 patients, 73 (8.6%) developed de novo solid-tumor malignancies. Sixty men (83.3%) and 12 women (16.7%) aged 58 +/- 8 years at transplantation were given a diagnosis of cancer at age 62 +/- 8 years. Cancers were divided into 22 categories, and the 3 most frequent cancers were prostate (22), lung (8), and breast (6). SIRs were increased for cervical cancer (SIR 14.3, 95% confidence interval 1.7 to 51.5) and thyroid cancer (SIR 7.7, 95% confidence interval 1.6 to 22.5). Logistic regression showed that age and retransplantation were significant risk factors for cancer. In conclusion, heart transplant recipients did not have a significantly increased frequency of many common malignancies despite long-term immunosuppression.