Cytokine Imbalance after Measles Virus Infection Has No Correlation with Immune Suppression |
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| Authors: | Mary Carsillo Kay Klapproth Stefan Niewiesk |
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| Affiliation: | Department of Veterinary Biosciences,1. Department for Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio,2. Institut fuer Virologie und Immunbiologie, University of Wuerzburg, Wuerzburg, Germany3. |
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| Abstract: | Measles virus infection leads to immune suppression. A potential mechanism is the reduction of interleukin 12 (IL-12) secretion during acute measles, resulting in a TH2 response. Studies in humans have reported conflicting results, detecting either a TH2 or a TH1 response. We have investigated the correlation between a TH2 response and immune suppression in specific-pathogen-free inbred cotton rats which were infected with measles vaccine and wild-type viruses. After infection of bone marrow-derived macrophages with wild-type virus, IL-12 secretion was reduced in contrast to the level for vaccine virus infection. In bronchoalveolar lavage cells, IL-12 secretion was suppressed after infection with both wild-type and vaccine virus on days 2, 4, and 6 and was detectable on days 8 and 10. After stimulation of mediastinal lymph node and spleen cells with UV-inactivated measles virus at various time points after infection, gamma interferon but no IL-4 was found. After stimulation with phorbol myristate acetate-ionomycin, high gamma interferon and low IL-4 levels were detected. To investigate whether the secretion of IL-4 contributes to immune suppression, a recombinant vaccine virus was created which secretes cotton rat IL-4. After infection with this recombinant virus, IL-4 secretion was enhanced. However, neither inhibition of concanavalin A-stimulated spleen cells nor keyhole limpet hemocyanin-specific proliferation of spleen cells was altered after infection with the recombinant virus in comparison to the levels with the parental virus. Our data indicate that measles virus infection leads to a decrease in IL-12 secretion and an increase in IL-4 secretion, but this does not seem to correlate with immune suppression.Acute measles is caused by infection with measles virus (MV) and is associated with high morbidity and mortality. The main reason for these is thought to be immune suppression due to MV infection. Studies addressing the mechanism of immune suppression have found evidence for a number of possible mechanisms. These include unidentified soluble mediators (10, 39, 40), interference with the type I interferon (IFN) system (for a review, see reference 9), apoptosis (8), impaired lymphoproliferation (23, 35), interleukin 12 (IL-12) downregulation (1, 18), and impaired dendritic cell (DC) function (36). Some of the mechanisms may operate in conjunction with each other; e.g., it is possible that the downregulation of IL-12 might lead to the development of a T-helper 2 (TH2) response that results in impaired lymphoproliferation. The evidence for this line of argument is that human macrophages, after stimulation through Toll-like receptor 4 (TLR-4), secrete less IL-12 when infected with MV (18). In MV-infected humans, the percentage of IL-12-expressing macrophages is reduced (1), and in Rhesus macaques, lowered serum levels of IL-12 have been found during MV infection (31). In macaques, this correlates with an increase of eosinophils in peripheral blood, indicative of increased secretion of IL-5 (31).In serum or supernatants of peripheral blood lymphocytes (PBLs) stimulated with phorbol myristate acetate (PMA)-ionomycin from patients with acute measles, an upregulation of IFN-γ and IL-2 (12) (or IL-2-receptor 37]) was found before and during the rash, whereas after the rash, a reduction in IL-2 and an increase in IL-4 (12) or IL-10 (22) levels were observed. In contrast, other studies found normal levels of IFN-γ and IL-2 secreted by stimulated PBLs (42) and increased levels of IFN-γ after the rash secreted by PMA-ionomycin-stimulated CD8 T cells (22).Results from the analysis of cytokines secreted by lymphocytes from MV vaccinees were also conflicting. In one study, an upregulation of IL-4 and downregulation of IFN-γ were found in the supernatants of phytohemagglutinin-stimulated cells (41). In another study, increased IL-12 and IFN-γ levels were detected after stimulation with MV antigen (11). In a third study, no differences in the expression levels of IL-4, IL-5, or IL-12 were found between vaccinated and unvaccinated individuals by ex vivo hybridization for cytokine mRNA in PBLs (21). However, when PBLs from vaccinees were stimulated with MV and analyzed on a per-cell basis by limiting dilution, it was found that nearly all T cells expressed IFN-γ, either alone or in combination with IL-4 (16). In a similar cohort of vaccinees, it could demonstrated by a IL-4-receptor-blocking enzyme-linked immunosorbent assay (ELISA) that PBLs from about half of the individuals secreted IL-4 (7) (IFN-γ secretion was not addressed). This might be explained by a recent report suggesting that the secretion of IFN-γ and IL-4 after MV stimulation is linked to the haplotype of human major histocompatibility complex class I (MHC-I) molecules (HLA) (28).Based on these data, no clear correlation can be drawn between reduced levels of IL-12, the secretion of TH2-type cytokines, and the inhibition of lymphocyte proliferation. Furthermore, at least three variables seem to confound the analysis: (i) the use of samples from patients with acute measles (wild-type virus) versus vaccinees (vaccine virus), (ii) the method of stimulation of cells and cytokine detection, and (iii) the individual genetic makeups of the study participants.In this report, we have used inbred cotton rats to compare the abilities of wild-type and vaccine MVs to inhibit IL-12 secretion, and we have compared the secretion of TH1 and -2 cytokines after stimulation with MV antigen versus that with PMA-ionomycin. In addition, we tested a recombinant MV expressing cotton rat IL-4 for its ability to suppress the immune system. |
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