Joyce Eskdale

Interferon‐λ1 (interleukin‐29) preferentially down‐regulates interleukin‐13 over other T helper type 2 cytokine responses in vitro

Interferon (IFN)‐λ1 [interleukin (IL)‐29] is a member of the interferon lambda family (also known as type III interferons), whose members are distantly related to both the type I interferons and members of the IL‐10 family. While IFN‐λ1 has significant antiviral activity, it is also becoming apparent that it has important immunoregulatory properties, especially with regard to the T helper type 2 (Th2) response. Previously, we have shown that IFN‐λ1 is capable of down‐regulating IL‐13 production in an IFN‐γ‐independent manner and that this is mediated in part via monocyte‐derived dendritic cells. Here, we have extended our knowledge of IFN‐λ1 regulation of the human in vitro Th2 response by examining the regulation of three major Th2 cytokines, IL‐4, IL‐5 and IL‐13, by IFN‐λ1. Our results reveal that IFN‐λ1 preferentially inhibits IL‐13 production, compared with IL‐4 or IL‐5. Levels of IL‐13 mRNA, the amount of secreted IL‐13 protein and numbers of IL‐13‐positive CD3+ CD4+ cells were all significantly diminished by IFN‐λ1. IFN‐λ1 significantly decreased some aspects of IL‐4 and IL‐5 production, but its effects were not as consistent as those seen on IL‐13. IFN‐λ1 was also effective at decreasing IL‐13 secretion under conditions designed to support the generation of Th2 cells. Irrespective of whether Concanavalin‐A or T‐cell‐stimulatory microbeads were used, IFN‐λ1 markedly diminished IL‐13 secretion in cultures where IL‐4 had been added. Thus, IFN‐λ1 appears to be an inhibitor of human Th2 responses whose action is primarily directed towards IL‐13 but which may also affect Th2 responses generally and does not invoke a complementary elevation of IFN‐γ secretion.

Frequency of functional interleukin-10 promoter polymorphism is different between relapse-onset and primary progressive multiple sclerosis.

Interleukin-10 (IL-10) secretion affects the inducibility of experimental autoimmune encephalomyelitis and the outcome of multiple sclerosis (MS). Here, we report that a G to A polymorphism in the IL-10 promoter at position -2849 is significantly associated with low IL-10 production. The frequency of this polymorphism is lower among patients with primary progressive compared with patients with relapse-onset MS and control persons.

Regulation of IFN-λ1 Promoter Activity (IFN-λ1/IL-29) in Human Airway Epithelial Cells

The type III (λ) IFNs (IFN-λ1, IFN-λ2, and IFN-λ3) and their receptor are the most recently discovered IFN family. They are induced by viruses and mediate antiviral activity, but type III IFNs have an important, specific functional niche at the immune/epithelial interface, as well as in the regulation of Th2 cytokines. Their expression appears diminished in bronchial epithelial cells of rhinovirus-infected asthmatic individuals. We investigated the regulation of IFN-λ1 expression in human airway epithelial cells using reporter genes analysis, chromatin immunoprecipitation, small interfering RNA knockdown, and DNase footprinting. In this article, we define the c-REL/p65 NF-κB heterodimer and IRF-1 as key transcriptional activators and ZEB1, B lymphocyte-induced maturation protein 1, and the p50 NF-κB homodimer as key repressors of the IFN-λ1 gene. We further show that ZEB1 selectively regulates type III IFNs. To our knowledge, this study presents the first characterization of any type III IFN promoter in its native context and conformation in epithelial cells and can now be applied to understanding pathogenic dysregulation of IFN-λ1 in human disease.

Novel hairpin-shaped primer assay to study the association of the -44 single-nucleotide polymorphism of the DEFB1 gene with early-onset periodontal disease.

ABSTRACT A powerful, cost-effective new method for studying single-nucleotide polymorphisms (SNPs) is described. This method is based on the use of hairpin-shaped primers (HP), which give a sensitive and specific PCR amplification of each specific allele, without the use of costly fluorophore-labeled probes and any post-PCR manipulation. The amplification is monitored in real-time using SYBR Green I dye and takes only 2 h to yield results. The HP assay has a simple design and utilizes a conventional real-time PCR apparatus. The −44 C→G transversion in the DEFB1 gene (which encodes human β-defensin 1) has been previously associated with Candida carriage in oral epithelia. In this study, we analyzed the association between early-onset periodontal disease (EOP) and the −44 SNP. We used an HP assay to study the distribution of the −44 SNP in 264 human DNAs obtained from two cohorts of EOP patients and healthy controls from different ethnic backgrounds. The results indicate that the −44 SNP has a similar distribution between EOP and healthy patients, suggesting that it is not associated with the disease.

The lambda interferons: guardians of the immune-epithelial interface and the T-helper 2 response.

The type-III interferons (IFNs) are the most recently discovered IFNs in the human immune system and have important, but as yet poorly characterized, functions in innate and adaptive immunity that complement their antiviral functions. It is now becoming clear that these type-III IFNs have a functional niche where epithelial surfaces interact with the adaptive immune system, that their antiviral capability is not as highly developed as that of the type-I IFNs, and that they have their own profile of immunomodulatory functions; specifically, they are key modulators of the T-helper (Th)2 response.

Family association studies of markers on chromosome 2q and Type 1 diabetes in subjects from South India

Several Type 1 diabetes susceptibility loci have been located to chromosome 2q12–21. However, results have not always been consistent and this may reflect study design and the population analysed. We have used a family‐based design to look for an association between Type 1 diabetes and markers located to 2q12–21.

Human Interleukin-19: Structure, Function and Disease Associations

Interleukin(IL) -19 is a member of the recently described IL-10 family of cytokines. Based on the genomic localization of its gene, its structure, conserved amino acids, cellular sources and receptor, IL-19 forms a subfamily with IL- 20 and IL-24. The IL-19-encoding gene comprises seven exons and is located on chromosome 1. Secreted IL-19 is composed of 159 amino acids that form an α-helical structure. IL-19 is produced by activated monocytes, and to a lesser extent, by B cells. As known so far, IL-19 functions through a receptor complex composed of IL-20R1 and IL-20R2, which is also utilized by IL-20 and IL-24. High levels of both receptor chains are present in several stromal tissues including the skin, lungs, and tissues from the reproductive organs. However, no expression is found in any immune cell population. Nonetheless, all effects of IL-19 described so far concern immune cells. Such conflicting data may be due to the existence of an additional (so far undiscovered) receptor complex for IL-19, or to the ability of the known IL-19 receptor to mediate its effects when present on the cell surface at a very low density. IL-19 has been shown to enhance the production of Th2 cytokines in T cells. Furthermore, it induced IL-10 expression in monocytes. Apart from the implied role for IL-19 in atopic and allergic responses and disorders, it also seems to be involved in the pathogenesis of the Th1-type skin disease psoriasis. IL-19 therefore represents an exciting new cytokine with immunoregulatory functions.