Background: The immune system needs stringent regulation in order to effectively eliminate infecting agents and, at the same time, protect the body from immunemediated tissue destruction. T cells have a major role in this regulation by secreting cytokines. Interferon-y (IFN-y) and interleukin-4 (IL-4) exert antagonistic regulatory functions and are mutually inhibitory. Thus, immune responses are generally functionally dominated by IFN-y or IL-4, a balance which is believed to be decisive for the outcome. Besides providing protection against pathogens, the immune system also has impact on several other conditions, e. g. reproduction and inflammatory diseases. Much is known about the role of IFN-y and IL-4 in animal models of these conditions, but less data are available from studies in humans. Data on IL-4 secretion are particularly rare, since this cytokine is extremely hard to detect.
Material and methods: Antigen-specific secretion of IFN-y and IL-4 was detected with ELISPOT -technique in different human conditions, including Borrelia-infection, inflammatory diseases in the peripheral nerves (the Guillain-Barre syndrome [GBS] and polyneuropathy associated with monoclonal gammopathy [PNMGUS]) and normal pregnancy. A novel assay was developed for the detection of fetus-specific cytokine secretion during pregnancy. Finally, a therapeutical approach for selective redirection of inappropriate IFN-y secretion to IL-4 secretion was developed in an experimental model of GBS.
Results: Predominant Borrelia-specific secretion of IFN-y and low or absent IL-4- secretion was found, both in patients with clinical Borrelia-infection and resistant individuals. A compartmentalization of this secretion to the central nervous system was evident in patients with neuro-borreliosis. There were indications that the specific IL-4 secretion increased over the disease course, and of lower numbers of Borrelia-specific IL-4 secreting cells in patients that did not fully recover compared with those who did. This suggests that Borrelia-specific IL-4 secretion might be necessary to down-regulate the inflammatory responses generated by IFN-y. Patients with a chronic disease course appeared to have a larger proportion of spontaneously IL-4 secreting cells compared with resistant individuals. Thus, individuals who develop chronic borreliosis may have limited ability to mount strong IFN-y secretion, which may be needed initially in the infection for eradication of the Borrelia bacteria.
An increase in the secretion of IL-4 in response to paternal but not to unrelated anaantigen was found in the blood of pregnant women. This is an extraordinary finding, since allo-reactivity usually is predominated by IFN-y secretion. The secretion of IL-4 exclusively to paternal allo-antigen, suggests that this is primarily selective for the fehls. Thus, responses to antigens that are not present at the maternal-fetal interfaCe may well be IFN-y predominated, which is needed to combat common infections. Auto-reactive secretion of IFN-ywas found in PNMGUS, which is a chronic disease. Conversely, autoreactive secretion of IL-4, associated with recovery, was detected in the self-limiting disease GBS. This supports the hypothesis that auto-reactive IFN- )' secretion is involved in the pathogenesis of organ-specific inflammatory diseases, whereas IL-4 secretion is beneficial.
Transfer of syngenic disease-specific cells, which had been ex vivo deviated to predominant secretion of IL-4, significantly ameliorated the disease in the experimental model of GBS. This may become a feasible approach for therapeutic intervention of organ-specific inflammatory diseases.
Conclusions: The ELISPOT-technique successfully detected alterations in the spontaneous as well as the antigen-induced secretion of IFN-y and IL-4, which a1so in humans appears to have implications for health and disease.
Linköping: Linköpings universitet , 1999. , 137 p.
1999-12-03, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Papers, included in the Ph.D. thesis, are not registered and included in the posts from 1999 and backwards.