Identity and activation of the natural interferon-α producing cellsVallin, Helena;
This thesis focuses on the identity and activation of the human natural interferon-a (IFN-a) producing cells (NIPC), infrequent but highly efficient producers of IFN-a/p among peripheral blood mononuclear cells (PBMC) upon exposure to most types of virus. The capacity of NIPC to become activated by bacteria and immuno-stimulatory DNA (isDNA) is studied, as is the involvement of NIPC and IFN-a in the autoimmune disease systemic lupus erythematosus (SLE). It was found that also the bacteria E. coli and Staphylococcus aureus Cowan I (SAC) induced IFN-a production in PBMC, and that at least SAC activated NIPC. This effect of SAC appeared to require bacterial surface proteins, such as protein A, on intact bacteria. The SAC also inhibited the IFN-a production induced by herpes simplex virus (HSV) in NIPC. The phenotype of HSV-induced NIPC determined by flow cytometry (FCM) resembled that of immature dendritic cells (DC), as did the morphology and antigen presenting ability of NIPC purified by fluorescence-activated cell sorting. The number of functional NIPC was greatly reduced at the blood level in SLE patients. The NIPC was partially reconstituted by exposure in vitro to the costimulatory cytokines IFNa2b, IFN-y and GM-CSF. An ongoing production of IFN-a is commonly found in SLE patients. Interestingly, several SLE sera were found to induce IFN-a production in normal PBMC in vitro, indicating presence of a circulating IFN-a inducing factor (IIF) in the disease. The low levels of NIPC in SLE could therefore be due to their depletion by activation, as well as deficient costimulatory cytokines. The IIF was frequently found in SLE serum, especially in serum from patients with active disease and measurable serum IFN-a levels. The activity of IIF on normal PBMC was markedly increased by IFN-a 2b and GM-CSF. The SLE-IIF was shown by means of FCM to specifically trigger NIPC. The SLE-IIF had a molecular weight of 300-1000 kD and appeared to consist of immunoglobulin G (IgG) and DNA, possibly as small immune complexes. Further analysis of SLE-IIF revealed that the essential IgG component was anti-dsDNA antibodies, and that the DNA could well be isDNA with unmethylated CpG motifs. The SLE-IIF may be a pathogenic factor in SLE by causing production of IFN-a, which then promotes development of autoimmunity. The combination of anti-DNA antibodies and the isDNA containing plasmid pcDNA3 was shown to mimic the SLE-IIF with respect to specificity for NIPC. They were also both influenced in a similar manner by cytokines, being stimulated by IFNa, IFN-p and GM-CSF, but strongly inhibited by IL-10. The results of the present thesis have further clarified the composition and function of the normal IFN-a/p system and its role in the development of SLE.
type I interferon; dendritic cells; systemic lupus erythematosus; interferon inducer; immunostimulatory DNA; autoimmunity; herpes simplex virus; Sendai virus
Published inActa Universitatis Agriculturae Sueciae. Veterinaria 1999, number: 47
Publisher: Swedish University of Agricultural Sciences
UKÄ Subject classification
Immunology in the medical area
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