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Mannose-binding lectin ( MBL)-deficiency is associated with an increased susceptibility to pneumococcal infections and other forms of disease. Pneumococcal vaccination is recommended in MBL-deficient patients with recurrent respiratory tract infections ( RRTI). The response to pneumococcal vaccination in MBL-deficient individuals has not yet been studied in detail. An impaired response to pneumococcal polysaccharides in MBL-deficient patients might explain the association between MBL deficiency and pneumococcal infections. This study investigates the antibody response to pneumococcal vaccination in MBL-deficient adult patients with RRTI. Furthermore, we investigated whether there was a difference in clinical presentation between MBL-deficient and -sufficient patients with RRTI. Eighteen MBL-deficient and 63 MBL-sufficient adult patients with RRTI were all vaccinated with the 23-valent pneumococcal polysaccharide vaccine and antibodies to 14 pneumococcal serotypes were measured on a Luminex platform. There were no differences observed in the response to pneumococcal vaccination between MBL-sufficient and -deficient patients. Forty-three MBL-sufficient patients could be classified as responders to pneumococcal vaccination and 20 as low responders, compared to 15 responders and three low responders in the MBL-deficient patients. We found no clear difference in clinical, radiological, lung function and medication parameters between MBL-sufficient and -deficient patients. In conclusion, our study suggests that MBL-deficient adults with RRTI have a response to a pneumococcal capsular polysaccharide vaccine comparable with MBL-sufficient patients. Moreover, we did not find a clear clinical role of MBL deficiency in adults with RRTI. As MBL deficiency is associated with an increased susceptibility to pneumococcal infections, pneumococcal vaccination might be protective in MBL-deficient patients with RRTI. [ABSTRACT FROM AUTHOR]

Summary Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease of unknown aetiology. Interleukin (IL)-1β plays an important role in inflammation and has been associated with fibrotic remodelling. We investigated the balance between IL-1β and IL-1 receptor antagonist (IL-1Ra) in bronchoalveolar lavage fluid (BALF) and serum as well as the influence of genetic variability in the IL1B and IL1RN gene on disease susceptibility and cytokine levels. In 77 IPF patients and 349 healthy controls, single nucleotide polymorphisms (SNPs) in the IL1RN and IL1B genes were determined. Serum and BALF IL-1Ra and IL-1β levels were measured using a multiplex suspension bead array system and were correlated with genotypes. Both in serum and BALF a significantly decreased IL-1Ra/IL-1β ratio was found in IPF patients compared to healthy controls. In the IL1RN gene, one SNP was associated with both the susceptibility to IPF and reduced IL-1Ra/IL-1β ratios in BALF. Our results show that genetic variability in the IL1RN gene may play a role in the pathogenesis of IPF and that this role may be more important than thought until recently. The imbalance between IL-1Ra and IL-1β might contribute to a proinflammatory and pro-fibrotic environment in their lungs. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a systemic disorder characterized by the formation of non-caseating granulomas in variable organs. Toll-like receptor (TLR)-9 is important in the innate immune response against both Mycobacterium tuberculosis and Propionibacterium acnes, candidate causative agents in sarcoidosis. The aim of our study was to investigate possible genetic and functional differences in TLR-9 between patients and controls. TLR-9 single nucleotide polymorphisms were genotyped in 533 patients and divided into a study cohort and validation cohort and 185 healthy controls. Furthermore, part of the promotor as well as the entire coding region of the TLR-9 gene were sequenced in 20 patients in order to detect new mutations. No genetic differences were found between patients and controls. In order to test TLR-9 function, peripheral blood mononuclear cells (PBMCs) of 12 healthy controls and 12 sarcoidosis patients were stimulated with a TLR-9 agonist and the induction of interleukin (IL)-6, interferon (IFN)-γ and IL-23 was measured. Sarcoidosis patients produce significantly less IFN-γ upon stimulation with different stimuli. Regarding IL-23 production, a significant difference between patients and controls was found only after stimulation with the TLR-9 agonist. In conclusion, we did not find genetic differences in the TLR-9 gene between sarcoidosis patients and controls. Sarcoidosis patients produce less IFN-γ regardless of the stimulating agent, probably reflecting the anergic state often seen in their peripheral blood T lymphocytes. The differences in TLR-9-induced IL-23 production could indicate that functional defects in the TLR-9 pathway of sarcoidosis patients play a role in disease susceptibility or evolution. [ABSTRACT FROM AUTHOR]

The intracellular pathogens Propionibacterium acnes and Mycobacterium tuberculosis have been leading suspects as the cause of sarcoidosis, a systemic disorder characterized by the formation of non-caseating granulomas. Toll-like receptor (TLR) 2 is important in the innate immune response against both pathogens, and is therefore of interest in sarcoidosis research. In the present study, three single nucleotide polymorphisms and one dinucleotide repeat polymorphism in the TLR-2 gene were genotyped in 419 sarcoidosis patients, divided into a study cohort and a validation cohort, and 196 healthy controls. In the study cohort we found a significant increase in prevalence of the AA-genotype at promotor location −16934 in patients with chronic disease compared to patients with acute/self-remitting sarcoidosis (34·5% versus 15·9%, respectively, P = 0·006, Pc = 0·019). These results could not be confirmed in our validation cohort, implicating a possible role for TLR-2 genetics in only a small percentage of sarcoidosis patients. Furthermore, linkage was found between the promotor polymorphism −16934 A/T and the number of GT repeats in intron 1 ( P < 0·0001). After in vitro stimulation of peripheral blood mononuclear cells (PMBCs) with different TLR-2 agonists, a correlation between induction of TNF-α ( P = 0·008), interleukin (IL)-12 ( P = 0·008) as well as IL-6 ( P = 0·02), and the number of GT repeats was observed. In conclusion, the data show that polymorphisms in TLR-2 might be important in a small group of sarcoidosis patients and that their functional consequences explain partly some of the variance in cytokine pattern observed in different clinical phenotypes of this disease. [ABSTRACT FROM AUTHOR]

Modification of intestinal microbiota early in life by administration of probiotic bacteria may be a potential approach to prevent allergic disease. To select probiotic bacteria for in vivo purposes, we investigated the capacity of probiotic bacteria to interact with neonatal dendritic cells (DC) and studied the ensuing T cell polarizing effect. Immature DC were generated from cord blood-derived monocytes and maturation was induced by maturation factors (MF), lipopolysaccharide (LPS) plus MF and Bifidobacterium bifidum, B. infantis, Lactobacillus salivarius, Lactococcus lactis alone or combined with MF. After 12 days of co-culture with DC and Staphylococcus aureus enterotoxin B (SEB) as antigenic stimulus, cytokine production by autologous T cells was determined by intracellular cytokine staining. Additionally, cells were stimulated with CD3 and CD28 monoclonal antibodies and cytokines were measured in supernatants by multiplex assay. The probiotic strains induced partial maturation of DC. Full maturation of DC was induced for all strains tested when MF was added. The percentage of interleukin (IL)-4 producing T cells was lower in T cell cultures stimulated with B. bifidum matured DC compared to MF and LPS matured DC, which coincided with a higher percentage of interferon (IFN)-γ-producing T cells. Furthermore, T cells stimulated by B. bifidum matured DC produced significantly more IL-10 compared to MF matured DC. Selected species of the Bifidobacterium genus prime in vitro cultured neonatal DC to polarize T cell responses and may therefore be candidates to use in primary prevention of allergic diseases. [ABSTRACT FROM AUTHOR]

SUMMARY Chemotherapy has, besides the beneficial effects, several adverse effects. Suppression of the immune system is one of the most important problems. Infections caused by encapsulated bacteria like Streptococcus pneumoniae are responsible for a major part of infectious problems during and after treatment. The splenic marginal zone is essential in the initiation of an immune response to encapsulated bacteria. In this study, we analysed the effects of three different cytostatic agents on humoral immune responses. We found a reduced, but detectable immune response capacity at two days after treatment although the marginal zone B cell population is severely reduced at this time point. Twenty-four days after cessation of treatment, the immune response capacity was largely restored although lymphoid compartments were still not completely restored at that time point. Apparently, the presence of only few marginal zone B cells is sufficient to evoke a rise in antibody titres and although antibody titre increases are low, even small rises are most likely clinically relevant. [ABSTRACT FROM AUTHOR]

The difference between newborn and adult mononuclear cells in the antigen dose required for optimal antibody production in vitro can be ascribed to differences in the antigen-presenting capacities of the respective monocytes (Van Tol et al ., 1984b). We have therefore studied the expression of cell surface determinants on human neonatal and adult monocytes by the use of monoclonal antibodies to membrane proteins including MHC antigens. No difference was observed in the expression of LeuM3 with regard to both the percentage of positive cells and the density of the respective determinant. In contrast, neonatal cells express the antigens OKM5, LFA1, OKM1 and LeuM5 at a lower density than adult cells do. The same holds for β2-microglobulin, but neonatal and adult monocytes express MHC class I α-chains at a similar density, whereas among the class II MHC antigens, HLA-DR is significantly more highly expressed on neonatal cells. This difference remains after treatment in vitro with γ-interferon (γ-IFN). Treatment with γ-IFN also resulted in a less dense expression of the LeuM3 antigen. Preincubation of monocytes with LeuM3 monoclonal antibody partially abrogates subsequent upregulation of class II MHC antigens by γ-IFN, a phenomenon observed with both neonatal and adult monocytes. These data indicate a functional involvement or LeuM3 with the cellular action of γ-IFN. Taken together, the cell surface phenotype of neonatal monocytes is that of a highly efficient antigen presenting cell. [ABSTRACT FROM AUTHOR]