Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6,809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA

Genetic deficiency in alpha-1-proteinase inhibitor associated with emphysema.

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Small animal models of emphysema

The present chapter takes a different approach in an attempt to selectively and critically review small animal models of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke exposure. Because cigarette smoke has been identified as the most important risk factor for the development of COPD10, these models may provide the basis for the understanding of the complex pathogenetic cellular and molecular mechanisms involved in the development of the disease. In addition pharmacological studies of cigarette smoke-induced models of COPD are also considered here since the results could be of interest for future potential therapeutical approaches in man

The dual role of neutrophil elastase in lung destruction and repair

The purpose of this review was to modify the prevailing view that neutrophil elastase (NE) is mainly a matrix-degrading enzyme. Recent observations indicate that the role of NE in inflammation is more complex than the simple degradation of extra-cellular matrix components. Several lines of evidence suggest that NE aims specifically at a variety of regulatory functions in local inflammatory processes. This enzyme can modulate many biological functions by promoting chemokine and cytokine activation and degradation, cytokine receptor shedding, proteolysis of cytokine binding proteins and the activation of different specific cell surface receptors. However, the current knowledge of regulatory mechanisms by which NE potentially regulates inflammatory processes is primarily derived from in vitro studies. The extent of these NE-dependent pathways and their relevance under various pathophysiological conditions remains poorly understood and a matter for further investigation. Recent studies suggest that NE not only plays a key role in lung destruction (emphysema) but can also modulate proliferative changes (fibrosis) in inflammatory processes. Thus, NE could be considered to have potential multiple roles in the pathogenesis of both emphysema and lung fibrosis

Pallid mice with genetic emphysema. Neutrophil elastase burden and elastin loss occur without alteration in the bronchoalveolar lavage cell population

According to a current hypothesis, pulmonary emphysema results from damage to the elastic fiber network caused by an imbalance within the lower respiratory tract between elastase(s) and protease inhibitors. This hypothesis is based largely on studies of persons with genetic deficiency of serum alpha 1-proteinase inhibitor. We recently reported a spontaneously occurring emphysema in the pallid mouse with an inherited deficiency of serum alpha 1-proteinase inhibitor. This animal reproduces important features of the human condition. We describe here the changes in alveolar elastolytic burden and in the bronchoalveolar lavage (BAL) cell population, which precede and accompany the development of emphysema in pallid mice. A possible correlation between the levels of lung elastase burden and the loss of lung elastin content was investigated in the period of development of emphysema in pallid mice. Changes in alveolar cells were investigated for specimens from BAL fluids and lung tissue by cytologic, histologic, and immunogold-electron microscopic methods. An immunogold-positive reaction for elastase was observed on elastin within the alveolar walls of pallid mice from 2 months onward. The average of gold particle density progressively increased with age, reaching high values at 12 and 16 months of age, the age at which parenchymal destruction was previously reported to occur. Lung elastin content had normal values at 2, 4, and 8 months of age. However, it was significantly lower at 12 and 16 months of age. The immunogold values of elastase burden correlated inversely with the decrease in lung elastin content. Total and differential cell counts from BAL fluids of pallid mice did not differ significantly at any time in life and were similar to age-matched controls. However, in pallid mice from 8 months of life onward, pulmonary macrophages contained characteristic intracytoplasmic crystalloid inclusions, which were electrondense and bounded by a single membrane. Using electron microscopy and an immunogold-labeling technique with anti-mouse I-III collagen IgG, these inclusions were identified as collagen-derived products. The data reported in this paper suggest that emphysematous lesions in pallid mice are associated with a progressive increase of elastase in alveolar intestitium and with loss of lung elastin. Surprisingly, the number of neutrophils in BAL fluids does not increase with the increase of lung elastolytic burden. However, intracytoplasmic crystalloid inclusions related to collagen degradation were observed in pulmonary macrophages of pallid mice at the time of septal disruption. The presence of similar structures in alveolar macrophages from mice or other animal species may be indicative of connective tissue breakdown or remodeling of tissue collagen

A scanning electron microscopic investigation of genetic emphysema in tight-skin, pallid, and beige mice, three different C57 Bl/6J mutants

Three mutants of the C57 BL/6J strain, i.e., the tight-skin (Tsk), pallid (pa), and beige (bg) mice have been reported to develop spontaneous emphysema. However, the pathogenic mechanisms of this lesion may be different in the three mutants. Differences and similarities of these models were investigated by means of scanning electron microscopy. A light microscopic investigation provided the background for the SEM study. C57 BL/6J (control), pa, Tsk, and bg mice were killed when they were 1, 12, and 24 months old. At light microscopic investigation the lungs of the controls appeared normal at all ages. Those of the pa mice had normal appearance at 1 month, showed a few areas of air space enlargement with destruction of alveolar septa at 12 months, and had a generalized enlargement of the air spaces associated with distortion of alveolar septa at 24 months. The Tsk mice had a generalized panlobular emphysema at all ages. The lungs of the bg mice showed at all ages a generalized enlargement of the air spaces not accompanied by changes of the alveolar septa. At scanning electron microscopy the lung parenchyma of control mice was essentially normal at all ages. Both alveolar ducts and alveoli increased in size (the latter also in depth) with age. The number of interalveolar pores (Np) increased by 54% between 1 and 12 months of age and by 49% between 12 and 24 months. The parenchyma of pa mice did not differ significantly from that of the controls at 1 month. At 12 months the alveoli appeared to be larger. At 24 months in some fields alveolar ducts were enlarged, the alveoli were also enlarged and very shallow. Np was not different from controls at 1 month but greater at 12 (+ 49%) and 24 (+ 26%) months. The parenchyma of Tsk mice of all ages appeared distorted with enlargement of alveolar ducts and sacs and with alveoli with a large number of pores. These changes increased with age. Np was larger than the controls at all ages (+ 59% at 1 month, + 119% at 12 months, and + 80% at 24 months). The parenchyma of the bg mice of all ages appeared disorganized with large alveoli of different shapes. There was a deterioration with age. No difference in Np was seen at any age between bg and control mice. Parenchymal changes characterized by distortion and enlargement of alveolar ducts and sacs were observed, even if with different onset and extent, in all mutants. However, an increase in Np, which is considered to represent the early development of emphysema, was found only in Tsk and pa mice. In Tsk mice, high Np values were observed at all ages, whereas in pa mice Np was increased only late in life when the pulmonary lesion develops. These differences indicate different pathogenetic mechanisms for these three mutants