6 research outputs found
Vitamin D insufficiency in cystic fibrosis : prevalence, consequences and intervention
Cystic fibrosis (CF) is the most common life-shortening autosomal recessive disease in
Caucasians. The major cause of morbidity and mortality is lung disease, characterized
by a vicious circle of infection and inflammation. Management of CF requires a
multifaceted approach, where intensive chest physiotherapy is combined with
aggressive antibiotic treatment, and tight nutritional follow-up. Vitamin D insufficiency
has high prevalence among CF patients worldwide. Vitamin D is crucial for
maintaining healthy skeleton. Recently, extraskeletal functions of vitamin D have been
described. These include immunomodulatory and glucose-lowering properties. Due to
lack of relevant studies, vitamin D supplementation in CF is recommended only as one
of the means of maintaining bone health. The aim of this thesis was to increase our
current understanding of the impact of vitamin D supplementation in CF patients, and
provide data needed for designing an efficient vitamin D supplementation policy.
First of all, we showed that a majority of Scandinavian CF patients had a suboptimal
serum 25-hydroxyvitamin D (s25OHD) level (Paper I), and that the vitamin D doses
needed to increase it were high. Cholecalciferol was more efficient at increasing
s25OHD than ergocalciferol, and s25OHD monitoring was needed (Paper III).
Secondly, we propose that vitamin D induces a broad spectrum of immunomodulatory
actions in CF. In the well-defined Scandinavian CF population (n=898),
s25OHD was associated negatively with serum total IgG, and positively with lung
function (FEV1) in a robust multiple linear regression (MLR) model (Paper I). In line
with that, three months long ergocalciferol supplementation in Stockholm CF patients
decreased serum total IgG and IgM, whereas cholecalciferol decreased expression of
the costimulatory molecule CD40 on dendritic cells. Patients receiving any form of
vitamin D decreased T cell activation and IL-8 levels at the end of the supplementation.
On the other hand, certain mechanisms of innate immunity were enhanced, such as
MCP-1 and sTREM-1. Soluble CD14 increased only in patients reaching 92 < s25OHD
< 97 nmol/L, which suggests bell-shaped relationship between s25OHD and soluble
CD14. Notably, increase in s25OHD levels was associated with positive changes in
lung function and in respiratory quality of life scores (Paper III).
Moreover, we demonstrated that s25OHD < 30 nmol/L, s25OHD < 50 nmol/L, and
vitamin D insufficiency degree are independent determinants of HbA1c values in
Scandinavian CF patients in a MLR model. This indicates that vitamin D may have
glucose-lowering properties in CF. In addition, s25OHD < 30 nmol/L and vitamin D
insufficiency degree determined the risk of CF-related diabetes (Paper II).
In Paper IV we aimed to assess the ability of CF bronchial epithelial (CFBE) cells
to convert the inactive 25OHD to the active 1,25(OH)2D, which is an important
mechanism ensuring adequate local concentrations of the biologically active
1,25(OH)2D in vivo. Upon addition of 25OHD (100 nmol/L), the amplitude of the
increase in 1,25(OH)2D was smaller for the CFBE cells than the non-CF human
bronchial epithelial cells (12.0 vs. 33.2 pmol/L). These results indicate that cells
harbouring mutations in cftr may have impaired ability to activate vitamin D.
In conclusion, this thesis contributes to the understanding of the multifunctional
importance of vitamin D in CF. It creates hypotheses about role of vitamin D in chronic
inflammation, diabetes and lung function, which need to be studied further
Coxsackievirus B infections are common in Cystic Fibrosis and experimental evidence supports protection by vaccination
Viral respiratory tract infections exacerbate airway disease and facilitate life-threatening bacterial colonization in cystic fibrosis (CF). Annual influenza vaccination is recommended and vaccines against other common respiratory viruses may further reduce pulmonary morbidity risk. Enteroviruses have been found in nasopharyngeal samples from CF patients experiencing pulmonary exacerbations. Using serology tests, we found that infections by a group of enteroviruses, Coxsackievirus Bs (CVBs), are prevalent in CF. We next showed that a CVB vaccine, currently undergoing clinical development, prevents infection and CVB-instigated lung damage in a murine model of CF. Finally, we demonstrate that individuals with CF have normal vaccine responses to a similar, commonly used enterovirus vaccine (inactivated poliovirus vaccine). Our study demonstrates that CVB infections are common in CF and provides experimental evidence indicating that CVB vaccines could be efficacious in the CF population. The role of CVB infections in contributing to pulmonary exacerbations in CF should be further studied.publishedVersionPeer reviewe
MAIT cell counts are associated with the risk of hospitalization in COPD
Background Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation associated with chronic inflammation in the airways. Mucosal-associated invariant T (MAIT) cells are unconventional, innate-like T cells highly abundant in mucosal tissues including the lung. We hypothesized that the characteristics of MAIT cells in circulation may be prospectively associated with COPD morbidity. Methods COPD subjects (n = 61) from the Tools for Identifying Exacerbations (TIE) study were recruited when in stable condition. At study entry, forced expiratory volume in 1 s (FEV1) was measured and peripheral blood mononuclear cells were cryopreserved for later analysis by flow cytometry. Patients were followed for 3 years to record clinically meaningful outcomes. Results Patients who required hospitalization at one or more occasions during the 3-year follow-up (n = 21) had lower MAIT cell counts in peripheral blood at study inclusion, compared with patients who did not get hospitalized (p = 0.036). In contrast, hospitalized and never hospitalized patients did not differ in CD8 or CD4 T cell counts (p = 0.482 and p = 0.221, respectively). Moreover, MAIT cells in hospitalized subjects showed a more activated phenotype with higher CD38 expression (p = 0.014), and there was a trend towards higher LAG-3 expression (p = 0.052). Conventional CD4 and CD8 T cells were similar between the groups. Next we performed multi-variable logistic regression analysis with hospitalizations as dependent variable, and FEV1, GOLD 2017 group, and quantity or activation of MAIT and conventional T cells as independent variables. MAIT cell count, CD38 expression on MAIT cells, and LAG-3 expression on both MAIT and CD8 T cells were all independently associated with the risk of hospitalization. Conclusions These findings suggest that MAIT cells might reflect a novel, FEV1-independent immunological dimension in the complexity of COPD. The potential implication of MAIT cells in COPD pathogenesis and MAIT cells’ prognostic potential deserve further investigation
Mucins 3A and 3B are expressed in the epithelium of human large airway
Abstract
Aberrant mucus secretion is a hallmark of chronic obstructive pulmonary disease (COPD). Expression of the membrane-tethered mucins 3A and 3B (MUC3A, MUC3B) in human lung is largely unknown. In this observational cross-sectional study, we recruited subjects 45–65 years old from the general population of Stockholm, Sweden, during the years 2007–2011. Bronchial mucosal biopsies, bronchial brushings, and bronchoalveolar lavage fluid (BALF) were retrieved from COPD patients (n = 38), healthy never-smokers (n = 40), and smokers with normal lung function (n = 40). Protein expression of MUC3A and MUC3B in bronchial mucosal biopsies was assessed by immunohistochemical staining. In a subgroup of subjects (n = 28), MUC3A and MUC3B mRNAs were quantified in bronchial brushings using microarray. Non-parametric tests were used to perform correlation and group comparison analyses. A value of p %lt; 0.05 was considered statistically significant. MUC3A and MUC3B immunohistochemical expression was localized to ciliated cells. MUC3B was also expressed in basal cells. MUC3A and MUC3B immunohistochemical expression was equal in all study groups but subjects with emphysema had higher MUC3A expression, compared to those without emphysema. Smokers had higher mRNA levels of MUC3A and MUC3B than non-smokers. MUC3A and MUC3B mRNA were higher in male subjects and correlated negatively with expiratory air flows. MUC3B mRNA correlated positively with total cell concentration and macrophage percentage, and negatively with CD4/CD8 T cell ratio in BALF. We concluded that MUC3A and MUC3B in large airways may be a marker of disease or may play a role in the pathophysiology of airway obstruction
A Link Between a Common Mutation in CFTR and Impaired Innate and Adaptive Viral Defense
textabstractAcute respiratory virus infections predispose the cystic fibrosis (CF) lung to chronic bacterial colonization, which contributes to high mortality. For reasons unknown, respiratory virus infections have a prolonged duration in CF. Here, we demonstrate that mice carrying the most frequent cystic fibrosis transmembrane conductance regulator (CFTR) mutation in humans, ΔF508, show increased morbidity and mortality following infection with a common human enterovirus. ΔF508 mice demonstrated impaired viral clearance, a slower type I interferon response and delayed production of virus-neutralizing antibodies. While the ΔF508 mice had a normal immune cell repertoire, unchanged serum immunoglobulin concentrations and an intact immune response to a T-cell-independent antigen, their response to a T-cell-dependent antigen was significantly delayed. Our studies reveal a novel function for CFTR in antiviral immunity and demonstrate that the ΔF508 mutation in cftr is coupled to an impaired adaptive immune response. This important insight could open up new approaches for patient care and treatment