Immunological aspects on cystic fibrosis lung disease

Sammanfattning: In cystic fibrosis (CF) colonization of the airways with Pseudomonas aeruginosa is a major cause of deterioration and death. Host defence fails to clear the invading bacteria, which results in a chronic destructive inflammatory process. This thesis deals with factors in the interaction between bacteria and host defence that determine the extent of tissue damage caused by the bacteria. (I) Autoantibodies against bactericidal/permeability increasing protein (BPI-ANCA) were measured in 46 CF patients and were found in a prevalence of 72 %. We found a strong correlation between BPI-ANCA concentration and lung damage, especially in P. aeruginosa colonized patients. (II) Precence of BPI-ANCA was found to predict severe adverse outcome in the 46 adult patients after 5-7 years. BPI-ANCA was measured in 366 patients. The patients were followed prospectively and we found that the BPI-ANCA response occurred following colonization with P. aeruginosa. In all patients who were lung transplanted, the BPI-ANCA levels decreased. In patients who were colonized with P. aeruginosa and had no BPI-ANCA, median lung function was normal. (III) Binding of mannan-binding lectin (MBL) may activate complement. About 10% of the population are MBL-deficient. When investigating 114 CF patients we found no correlation between MBL pathway deficiencies and severe lung disease. The levels of MBL in serum were found to be higher in CF patients than in controls. (IV) Isolates of P.aeruginosa from CF patients were collected and their interactions with human cells were investigated. We found that isolates from patients with positive BPI-ANCA had white phenotypes and evoked mild inflammatory responses. Conclusions: We suggest that P. aeruginosa is a risk factor for severe lung damage in CF particularly if accompanied by a rise in BPI-ANCA in serum. The BPI-ANCA response was secondary to colonization with P. aeruginosa, BPI-ANCA associated strains of P. aeruginosa evoked a mild inflammatory response. We speculate that inadequate inflammation impairs host defence, and thus allows bacterial proliferation, which apparently is a disadvantage to the host. MBL-deficiency was not a risk factor for severe lung disease in the studied cohort.