Beta-defensin 38

Background: Spontaneous preterm birth (sPTB) is a major contributor to infant mortality and its etiology remains poorly understood. Host immunity and maternal stress may play a role in the pathogenesis of sPTB but mechanisms are poorly delineated. Antimicrobial proteins in the cervicovaginal space, such as beta defensins, modulate immune responses to bacteria and have been shown to modulate the risk of sPTB from non-optimal microbiota. While stress is known to induce immunological changes, no study has examined the interplay between maternal stress and the immune response in association with sPTB. Objectives: Our objectives were to determine whether psychosocial stress was associated with a mediator of the immune system in the cervicovaginal space, beta defensin-2, and to examine the combined impact of high stress and low cervicovaginal beta defensin-2 levels on the odds of sPTB. Study design: From the Motherhood & Microbiome cohort study (n=2000), we performed a secondary, nested case-control study, frequency matched by race/ethnicity, of 519 pregnant women (110 sPTB and 409 term). Stress and cervicovaginal beta defensin-2 levels were measured at 16-20 weeks of gestation. Stress was dichotomized at a score of 30 on Cohen's Perceived Stress Scale (PSS-14). We measured cervicovaginal beta defensin-2 levels with ELISA and dichotomized at the median. We modeled associations of high stress and low cervicovaginal beta defensin-2 levels using multivariable logistic regression. We also compared the proportion of women with high stress and low cervicovaginal beta defensin-2 levels among women with spontaneous preterm and term births using Chi-Square tests. We modeled adjusted associations of stress and cervicovaginal beta defensin-2 levels with odds of sPTB using logistic regression. Results: The majority of the study population was non-Hispanic black (72.8%), insured by Medicaid (51.1%), and had a PSS-14 score < 30 (80.2%). High stress was associated with reduced adjusted odds of low beta defensin-2 levels (aOR 0.63, 95% CI: 0.38 -0.99). In a model adjusted for race and smoking, both high stress (aOR 1.72, 95% CI: 1.03-2.90) and low beta defensin-2 (aOR 1.58, 95% CI: 1.004-2.49) were associated with increased odds of sPTB. We then built a model of the four possible combinations of low and high stress and low and high beta defensin-2 levels with the odds of sPTB. Women with either high stress (aOR 1.37, 95% CI: 0.68 - 2.78) or low beta defensin-2 (aOR 1.40, 95% CI: 0.83-2.34), had slightly elevated but not significantly increased odds of sPTB compared to women with neither exposure. However, women with both high stress and low beta defensin-2 had significantly elevated odds of sPTB compared to women with neither exposure (aOR 3.16, 95 % CI: 1.46 - 6.84). Conclusion: High perceived stress and low cervicovaginal beta defensin-2 levels are associated with higher odds of sPTB, and when present concurrently, they result in the highest odds of sPTB in a largely non-Hispanic black cohort. Our findings warrant further work to examine social determinants of health and the host cervicovaginal immune responses that may modulate the pathogenesis of sPTB.

Background: Chronic obstructive pulmonary disease (COPD) and asthma have heterogeneous inflammation with inhaled corticosteroids (ICS) as a mainstay of treatment. There is increased prevalence of non-typeable Haemophilus influenzae (NTHi) persistence in airways of patients with neutrophilic airway inflammation, potentially due to suppressed host defence after corticosteroid treatment. Antimicrobial peptides (AMPs) have antimicrobial activity against pathogens and immunomodulatory effects. We investigated whether AMPs associate with NTHi presence in COPD and asthma, and whether ICS alter this. Methods: Secretory leukocyte protease inhibitor (SLPI), osteopontin, elafin and beta defensin-1 were measured in sputum supernatants from healthy donors (n=9), asthmatics (n=21) and patients with COPD (n=14). Elafin and beta defensin-1 were measured in a primary human bronchial epithelial cells (HBECs) from healthy and COPD donors infected with NTHi and pre-treated with fluticasone propionate (FP) and budesonide (BUD). Internalised NTHi was quantified by qPCR. Results: Sputum SLPI was negatively correlated with FEV1 (p<0.001, r=-0.610), FEV1% predicted (p<0.001, r=-0.583) and FEV1/FVC (p=0.001, r=-0.528). Sputum beta defensin-1 was negatively associated with FEV1 (p<0.001***r=-0.594). SLPI and beta defensin-1 levels in sputum were higher in the healthy controls and COPD group compared to the asthma group (p=0.001 and p=0.014) and (p<0.001 and p=0.007, respectively). ICS use was associated with higher sputum osteopontin compared to those with no ICS use. NTHi infection of COPD HBECs produced higher levels of beta defensin-1 compared to healthy donors (mean (SD) release: 45.1pg/mL (7.3) vs 21.2pg/mL (7.3) respectively, p=0.014). Elafin release from HBECs from COPD donors did not change following NTHi infection; however, elafin from healthy donors was significantly reduced (%mean reduction: 23.7%, 95% confidence intervals (CI) of reduction: 5.3-38.4%, p<0.01). Conclusion: Sputum SLPI and beta defensin-1 may be markers to identify those patients with declining lung function. ICS use was associated with higher sputum osteopontin compared to those with no ICS use.