Immunopathogenic aspects of resolving and progressing appendicitis

• Background: Appendicitis is one of the most common diseases requiringemergency surgical intervention. There are several indications that the diagnosisappendicitis harbours two different entities, one progressing to gangrene and perforation(advanced) and one that resolves spontaneously (phlegmonous). An immunologically drivenpathogenesis in appendicitis has been suggested on the basis of an inverse relationshipbetween appendicitis and ulcerative colitis, a positive association with Crohn’s disease, anda decreased incidence during pregnancy, generating the hypothesis that theimmunopathogenesis in advanced appendicitis is characterized by a Th1 inflammatoryresponse. The aim of this thesis was to test this hypothesis and investigate the immuneresponse in advanced and phlegmonous appendicitis.Material and Methods: The immunologic response was investigated in appendicitis tissue and compared to the immunological response in peripheral blood, analysed by enzyme-linked immunospot assay (ELISPOT). The response pattern was also investigated in patients with an actual appendicitis in the peripheral plasma and peripheral serum before surgery, analysed with Luminex. The immunological response pattern was investigated in peripheral blood several months to years after an appendectomy using ELISPOT and enzyme-linked immunosorbent assay (ELISA).Results: The local immune response in the appendiceal tissue in appendicitis was similar to the response in peripheral blood. Patients with actual advanced appendicitis had increased levels of IL-6, CCL20, CCL2, TGF-β, IL-17, IFN-γ, IL-12p70, IL-10, IL-1ra, IL-4, MMP-8, MMP-9 and MPO compared with those with phlegmonous appendicitis. Sex, age or duration of symptoms could not explain the differences between the groups. Individuals with a history of advanced appendicitis had increased secretion of IFN-γ months to years after the appendectomy compared with individuals with a history of phlegmonous appendicitis.Conclusions: The local immune response in the appendiceal tissue is mirrored in the blood, which justifies the use of peripheral blood in studies on appendicitis. The immunological response pattern in peripheral blood suggests Th1/Th17- induced inflammation in advanced appendicitis that is present at an early stage. Individuals with a history of advanced appendicitis have stronger Th1 responses than individuals with a history of phlegmonous appendicitis. This may reflect constitutional differences between patients with different outcomes of appendicitis. The increased inflammatory response observed early in advanced appendicitis suggests a more violent inflammation and supports the hypothesis of different immune pathogeneses, where excessive induction of Th1/Th17 immunity and/or deficiencies in down-regulatory feedback mechanisms may explain the excessive inflammation in advanced appendicitis, where the inflammation eventuates in gangrene and perforation.

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