Mukoviszidose ist eine Autoimmunkrankheit

Abstract

In cystic fibrosis (CF) dysfunction of CFTR leads to pathologic changes in several or-gans including lungs and intestine. Based on the notion that inflammation may precede in-fection in CF, the aim of this study was to investigate whether the CF defect would be rec-ognized by cells of the innate immune system. Uninfected CF mouse strains and the respec-tive wild type (WT) strains of different ages were used to locate and quantify NKT cells, macrophages and neutrophils and other immunocompetent cells in lung and intestine tis-sues. Furthermore the hypothesis was tested that ceramide accumulates in CFTR-/- cells. A significant increase in NKT cell numbers was observed in lung tissues of 12 week old CFTR-/- mice compared to WT mice. Mucin staining revealed that NKT cells accumulated around submucosal glands, known to express CFTR. NKT cell numbers further increased in 28 week old CFTR-/- mice around submucosal glands and in other parts of the lung includ-ing the alveolar septa, suggesting that the CF defect triggers a progressive innate immune response. Besides NKT cells, an accumulation of macrophages and neutrophils and other immunocompetent cells was observed around submucosal glands forming lymphocyte ag-gregates. In lung tissues of CFTR-/- mice, significantly increased concentrations of cera-mide compared to control tissues were expressed in the area of submucosal glands and in other parts of the lung, including epithelial cells. The results suggest that defective CFTR provokes a high expression of ceramide which may lead to recognition by NKT cells possi-bly via endogenous glycosphingolipds. Treatment of CFTR-/- mice with amitriptyline, a blocker of acid sphingomyelinase, normalized the expression of ceramide and inhibited the clustering of NKT cells and macrophages around submucosal glands. High NKT cell ex-pression was also observed in the lamina propria of jejunum, ileum and colon of CFTR-/- mice but not in control mice, further suggesting that the observed NKT cell recruitment in CFTR-/- mice is correlated to the basic CF defect. This data suggests that the basic defect in CF provokes an autoimmune response, characterized by ceramide over expression and early NKT cell accumulation around submucosal glands which thereafter is augmented and in-volved other effector cells of the innate immune system and immuocompetent cells of the adaptive immune system.

Mukoviszidose ist eine autosomal rezessiv vererbare Krankheit, die durch Störungen oder Fehler des CFTR-Proteins in Organen, wie Pankreas, Darm oder Lunge, Pathomechanismen auslöst und die Besiedlung und die Infektion mit Bakterien begünstigt. Fragenstellungen dieser Arbeit waren, ob einer Entzündung in der Lunge (Mukoviszidose) eine Infektion vorangegangen ist oder nicht; sowie die Erhöhung von Ceramide in CFTR Zellen.