Periostin as a biomarker of airway inflammation

No abstract available

Response

No abstract available

Interleukin-33 promoting Th1 lymphocyte differentiation dependents on IL-12

No abstract available.The pro-Th2 cytokine IL-33 is now emerging as an important Th1 cytokine-IFN-γ inducer in murine CD4+ T cells that is essential for protective cell-mediated immunity against viral infection in mice. However, whether IL-33 can promote human Th1 cell differentiation and how IL-33 polarizes Th1 cells is less understood. We assessed the ability of IL-33 to induce Th1 cell differentiation and IFN-γ production in vitro and in vivo. We report here that IL-33 alone had no ability in Th1 cell polarization. However it potentiated IL-12-mediated Th1 cell differentiation and IFN-γ production in TCR-stimulated murine and human CD4+ T cells in vitro and in vivo. IL-33 promoted Th1 cell development via MyD88 and synergized with IL-12 to enhance St2 and IL-12R expression in CD4+ T cells. These data therefore provide a novel mechanism for Th1 cell differentiation and optimal induction of a Type 1 response. Thus, IL-33 is capable of inducing IL-12-dependent Th1 cell differentiation in human and mouse CD4+ T cells

Immunological studies in extrinsic allergic alveolitis

Summary available: pp. xiv-xvii

MicroRNA-155 regulates monocyte chemokine and chemokine receptor expression in Rheumatoid Arthritis

Objectives: To test the hypothesis that miR-155 regulates monocyte migratory potential via modulation of chemokine and chemokine receptor expression in rheumatoid arthritis (RA); and thereby is associated with disease activity. Methods: miR-155 copy-number in monocytes from peripheral blood (PB) of healthy (n=22), RA (n=24), and RA synovial fluid (SF; n=11) were assessed by real time- PCR using synthetic miR-155 as quantitative standard. To evaluate the functional impact of miR-155, human monocytes were transfected with control or miR-155 mimic and the effect on transcript levels, and production of chemokines was evaluated by TLDA and multiplex assays. A comparative study evaluated constitutive chemokine receptor expression in miR-155-/- and wild-type murine (CD115+Ly6C+Ly6G-) monocytes. Results: Compared with healthy monocytes, miR-155 copy-number was higher in RA PB and SF monocytes (PB p<0.01, and SF p<0.0001). MiR-155 copy-number in RA PB monocytes were higher in ACPA positive compared with ACPA negative patients (p=0.033) and correlated (95% C.I.) with DAS28 (ESR), R=0.728 (0.460, 0.874), with tender, R=0.631 (0.306, 0.824) and swollen, R=0.503 (0.125, 0.753) joint counts. Enforced-expression of miR-155 in RA monocytes stimulated the production of CCL3, CCL4, CCL5, CCL8; up-regulated CCR7 expression and down-regulated CCR2. Conversely, miR155-/- monocytes showed down-regulated CCR7 and upregulated CCR2 expression. Conclusions: Given the observed correlations with disease activity, these data provide strong evidence that miR-155 can contribute to RA pathogenesis by regulating chemokine production and pro-inflammatory chemokine receptor expression, thereby promoting inflammatory cell recruitment and retention in the RA synovium

MicroRNA-155—at the critical interface of innate and adaptive immunity in arthritis

MicroRNAs (miRNAs) are small non-coding RNAs that fine-tune the cell response to a changing environment by modulating the cell transcriptome. MiR-155 is a multifunctional miRNA enriched in cells of the immune system and is indispensable for the immune response. However, when deregulated, miR-155 contributes to the development of chronic inflammation, autoimmunity, cancer and fibrosis. Herein, we review the evidence for the pathogenic role of miR-155 in driving aberrant activation of the immune system in Rheumatoid Arthritis, and its potential as a disease biomarker and therapeutic target

IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice

Background<p></p> The initiation and regulation of pulmonary fibrosis are not well understood. IL-33, an important cytokine for respiratory diseases, is overexpressed in the lungs of patients with idiopathic pulmonary fibrosis.<p></p> Objectives<p></p> We aimed to determine the effects and mechanism of IL-33 on the development and severity of pulmonary fibrosis in murine bleomycin-induced fibrosis.<p></p> Methods<p></p> Lung fibrosis was induced by bleomycin in wild-type or Il33r (St2)−/− C57BL/6 mice treated with the recombinant mature form of IL-33 or anti–IL-33 antibody or transferred with type 2 innate lymphoid cells (ILC2s). The development and severity of fibrosis was evaluated based on lung histology, collagen levels, and lavage cytology. Cytokine and chemokine levels were quantified by using quantitative PCR, ELISA, and cytometry.<p></p> Results<p></p> IL-33 is constitutively expressed in lung epithelial cells but is induced in macrophages by bleomycin. Bleomycin enhanced the production of the mature but reduced full-length form of IL-33 in lung tissue. ST2 deficiency, anti–IL-33 antibody treatment, or alveolar macrophage depletion attenuated and exogenous IL-33 or adoptive transfer of ILC2s enhanced bleomycin-induced lung inflammation and fibrosis. These pathologic changes were accompanied, respectively, by reduced or increased IL-33, IL-13, TGF-β1, and inflammatory chemokine production in the lung. Furthermore, IL-33 polarized M2 macrophages to produce IL-13 and TGF-β1 and induced the expansion of ILC2s to produce IL-13 in vitro and in vivo.<p></p> Conclusions<p></p> IL-33 is a novel profibrogenic cytokine that signals through ST2 to promote the initiation and progression of pulmonary fibrosis by recruiting and directing inflammatory cell function and enhancing profibrogenic cytokine production in an ST2- and macrophage-dependent manner

Insights into frequent asthma exacerbations from a primary care perspective and the implications of UK National Review of Asthma Deaths recommendations

The United Kingdom National Review of Asthma Deaths (NRAD) recommends that patients who require ≥3 courses of oral corticosteroids (OCS) for exacerbations in the past year or those on British Thoracic Society (BTS) Step 4/5 treatment must be referred to a specialist asthma service. The aim of the study was to identify the proportion of asthma patients in primary care that fulfil NRAD criteria for specialist referral and factors associated with frequent exacerbations. A total of 2639 adult asthma patients from 10 primary care practices in Glasgow, UK were retrospectively studied between 2014 and 2015. Frequent exacerbators and short-acting β2-agonist (SABA) over-users were identified if they received ≥2 confirmed OCS courses for asthma and ≥13 SABA inhalers in the past year, respectively. Community dispensing data were used to assess treatment adherence defined as taking ≥75% of prescribed inhaled corticosteroid (ICS) dose. The study population included 185 (7%) frequent exacerbators, 137 (5%) SABA over-users, and 319 (12%) patients on BTS Step 4/5 treatment. Among frequent exacerbators, 41% required BTS Step 4/5 treatment, 46% had suboptimal ICS adherence, 42% had not attended an asthma review in the past year and 42% had no previous input from a specialist asthma service. Older age, female gender, BTS Step 4/5, SABA over-use and co-existing COPD diagnosis increased the risk of frequent exacerbations independently. Fourteen per 100 asthma patients would fulfil the NRAD criteria for specialist referral. Better collaboration between primary and secondary care asthma services is needed to improve chronic asthma care

Natural immunity to Ascaris lumbricoides associated with immunoglobulin E antibody to ABA-1 allergen and inflammation indicators in children, Infect. Immun. 67

Children putatively immune to the large roundworm Ascaris lumbricoides were identified in an area of Nigeria where infection is hyperendemic. Immunity was associated with higher levels of serum ferritin, C-reactive protein, and eosinophil cationic protein, indicating ongoing acute phase or inflammatory processes. In contrast, children who were susceptible to the infection had little serological evidence of inflammation despite their high parasite burdens. Immunoglobulin G (IgG) antibody activity in all subclasses was present in high titer in most children but appeared to have no protective function. Despite exceptionally high total IgE levels, there was no evidence that atopic responses to local common allergens was associated with natural immunity to Ascaris. Among those individuals who produced IgG antibody to recombinant ABA-1 allergen of Ascaris, the naturally immune group had significantly more IgE antibody to the allergen than did those susceptible to the infection. IgE antibody responses in conjunction with innate inflammatory processes therefore appear to associate with natural immunity to ascariasis. Helminth parasites are renowned for inducing elevated levels of serum immunoglobulin E (IgE) (20, 33), but the protective role of the antibody component of this response remains debatable The large roundworm of humans, Ascaris lumbricoides, inhabits the intestine, but juvenile-stage worms undergo a tissuemigratory phase involving the liver and lungs before returning to the intestine, where they mature to large adult worms. The pulmonary phase can cause potentially lethal hypersensitivity responses in infected individuals, particularly children, and worm material is notorious for the allergic reactions that it provokes in laboratory workers (33). A. lumbricoides infects a quarter of humanity and people can remain infected for much of their lives, although at the population level, intensity of infection decreases with age after a peak within the first decade of life in high-intensity areas We have examined a range of serum factors in African children living in an area highly endemic for A. lumbricoides, using the number of worms developing to maturity as a measure of immunity status. Quantifying worm burden is superior to using the number of eggs released, because egg production is a poor indicator of the number of adult worms present (15, 18) and may miss low-level infections. The children were examined for infection on two separate occasions, and those either consistently infected or putatively immune were identified. Neither the mechanisms by which immunity to A. lumbricoides operates nor the site within the body at which it is manifest is known. Therefore, in addition to measuring of antibody in the different isotypes, we examined a range of serological markers for inflammatory responses to provide an indication of the pathological processes which might accompany immune killing of the parasites. We find that natural immunity to Ascaris is associated with IgE antibody to a major allergen of the parasite and a serum protein profile consistent with ongoing inflammatory processes. MATERIALS AND METHODS Study population. The study site was in an area of Nigeria (Ile-Ife) in which more than 80% of the school children (5 to 15 years old) were infected with intestinal nematodes, particularly A. lumbricoides (for full details, see reference 18). A group of children were treated for their intestinal nematode infections, and their worm burdens were collected and counted over a 48-h period after anthelminthic treatment (phase 1). The anthelminthic used was Ketrax (levamisole; ICI Pharmaceuticals, Macclesfield, United Kingdom), and children were given the appropriate dosage according to the manufacturer's instructions. The exercise was repeated 6 months later (phase 2), at which time blood samples were collected from 92 of the children. The children were classified as follows: category 1, those with no worms on either of the two occasions (putatively immune); category 2, those with consistently light infections (1 to 24 worms in phase 1 and 1 to 8 worms in phase 2); or category 3, those who were consistently heavily infected or susceptible, i.e., had more than the population mean plus 1 standard deviation worm burden on both occasions. The means Ϯ standard deviations of the worm burdens in phases 1 and 2 were 11.02 Ϯ 13.7 and 3.5 Ϯ 5.6, respectively. Category 3 comprised children with worm counts of Ն25 after the first treatment and Ն9 after the second treatment. There were 22, 47, and 23 children in categories 1, 2, and 3, respectively. None of the children showed overt signs o