Idiopathic pulmonary fibrosis is a chronic and usually progressive lung disorder of unknown etiology. A growing body of evidence suggests that, in contrast to other interstitial lung diseases, IPF is a distinct entity in which inflammation is a secondary and non-relevant pathogenic partner. Evidence includes the presence of similar mild/moderate inflammation either in early or late disease, and the lack of response to potent anti-inflammatory therapy. Additionally, it is clear from experimental models and some human diseases that it is possible to have fibrosis without inflammation. An evolving hypothesis proposes that IPF may result from epithelial micro-injuries and abnormal wound healing.

/pdf/idiopathic-pulmonary-fibrosis-an-epithelial-fibroblastic-pad0k3nehl.pdf

Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder

BACKGROUND There has been much interest recently in the effects of various cytokine gene expression polymorphisms on graft outcome. However, the results of these investigations reveal the outcomes to be organ-specific and center-specific. We sought to confirm and add to some of the earlier findings by studying the impact of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6) polymorphisms and the interleukin-4 (IL-4) receptor alpha-chain variant on posttransplant renal allograft outcome. METHOD TNF-alpha, IL-6, IFN-gamma, and IL-10 gene promoter region polymorphisms were assayed genotypically by PCR-SSP on 120 patients transplanted at the Albany Medical Center. These patients were also typed for the IL-4 receptor alpha-chain variant Q576R. RESULTS Producers of high levels of the proinflammatory cytokine TNF-alpha were found to be at increased risk for acute rejection episodes if the allograft was mismatched for the molecular products of the class II region of the human major histocompatibility complex (HLA-DR). Expression level polymorphisms of the IL-6, IFN-gamma, and IL-10 genes were not associated with acute rejection episodes, nor was the IL-4 receptor alpha-chain variant Q576R. CONCLUSIONS These data would suggest that the production of high levels of the cytokine TNF-alpha is especially detrimental to graft survival when the recipient's T-helper lymphocytes are being activated by mismatched donor HLA-class II antigens. Typing all potential kidney recipients for TNF-alpha, and providing well-matched organs for high producers of this cytokines, may be expected to increase rejection-free graft survival in these patients.

TNF-alpha, IL-6, IFN-gamma, and IL-10 gene expression polymorphisms and the IL-4 receptor alpha-chain variant Q576R: effects on renal allograft outcome.

Background
Allergic bronchopulmonary aspergillosis occurs in 7–10% of cystic fibrosis (CF) and 1–2% of asthmatic patients. HLA-DR restriction and increased sensitivity to IL-4 stimulation have been proposed as risk factors in these populations.

/pdf/il-4-alpha-chain-receptor-il-4ra-polymorphisms-in-allergic-1ie86kon0b.pdf

IL-4 alpha chain receptor (IL-4Rα) polymorphisms in allergic bronchopulmonary sspergillosis

The genetic basis of atopic diseases is represented by a complex network of interacting genes or common genetic variants rather than a few disease-causing mutations. The individual risk of developing asthma or other atopic diseases is defined by the concert of interaction of these hereditary factors and environmental stimuli. The first decade of asthma genetics has been spent identifying those genetic regions through linkage analysis, which are likely to harbour asthma genes. At the same time, several candidate genes for asthma and atopy have been identified and their variants characterized, some of them even to a level of functional understanding. Rather than adding new candidate regions and genes to the pool of knowledge, the interest in the past year has moved to a more sophisticated statistical evaluation of the given linkage and association data and a more precise definition of so-called 'intermediate phenotypes'. Some of the results are quite surprising and have helped us to understand the underlying pathophysiology. For example, the distinct clinical traits of asthma, such as atopic sensitization or inflammation of the bronchial epithelium, seem to be defined by distinct subsets of predisposing genes. At the same time, the very same subsets of genes might underlie further clinical diseases with similar clinical features. Polymorphisms within IL-4R alpha, which had been shown to be associated with asthma and atopy, have also been shown to be associated with kidney allograft rejection, systemic lupus erythematosus and Crohn's disease. There might thus just be a few asthma and atopy genes. Finally, asthma and atopy genetics has now reached a point of practical application. The genetics of susceptibility to environmental stimuli, pharmacogenetic data, and the advent of new pharmaceutical targets will greatly influence the whole field of asthma and atopy.

Genes for atopy and asthma.

Relevance of IL10, TGFbeta1, TNFalpha, and IL4Ralpha gene polymorphisms in kidney transplantation: a collaborative transplant study report.

The involvement of the interleukin-4 (IL-4) pathway in B-lymphocyte activation and induction of a T helper 2 (Th2) cell response prompted us to investigate the influence of a recently described gain-of function mutation in the IL-4 receptor alpha-chain gene (IL-4R alpha; CD 124) on renal allograft survival. We developed a genotyping assay for the IL-4R alpha variant Q576R and investigated 203 renal transplant patients, all of whom underwent transplantation surgery at a single institution. The overall frequency of the IL-4R alpha variant Q576R in this group was 38.9% (79/203). The Kaplan-Meier method was used to estimate the graft survival of 156 patients with complete follow-up time of 24 months. Significantly higher graft survival rates (P=0.012, log-rank test) were found in patients with the wild-type IL-4 receptor (2-year graft survival 78.8%) as compared to patients with the IL-4R alpha variant Q576R (2-year graft survival 60.6%). Multifactorial cox regression analysis showed that this effect was independent of HLA matching, sex of donor and recipient, age of recipient, year of transplantation and preformed antibodies (P=0.017). These results indicate a strong association of the IL-4R alpha variant Q576R with kidney allograft loss. Genotyping of kidney allograft recipients for the IL-4R alpha variant may offer a simple method to identify high-risk patients in the post-transplantation period.

The IL-4 receptor alpha-chain variant Q576R is strongly associated with decreased kidney allograft survival.

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The IL-4 receptor alpha-chain variant Q576R is strongly associated with decreased kidney allograft survival.