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Identity and activation of the natural interferon-α producing cells

Vallin, Helena (1999). Identity and activation of the natural interferon-α producing cells. Diss. (sammanfattning/summary) Sveriges lantbruksuniv., Acta Universitatis Agriculturae Sueciae. Veterinaria, 1401-6257
ISBN 91-576-5415-8
[Doctoral thesis]

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Abstract

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.

Authors/Creators:Vallin, Helena
Title:Identity and activation of the natural interferon-α producing cells
Series Name/Journal:Acta Universitatis Agriculturae Sueciae. Veterinaria
Year of publishing :1999
Number:47
Number of Pages:49
Publisher:Swedish University of Agricultural Sciences
ISBN for printed version:91-576-5415-8
ISSN:1401-6257
Language:English
Publication Type:Doctoral thesis
Article category:Other scientific
Version:Published version
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Immunology in the medical area
(A) Swedish standard research categories 2011 > 4 Agricultural Sciences > 403 Veterinary Science > Pathobiology
Keywords:type I interferon, dendritic cells, systemic lupus erythematosus, interferon inducer, immunostimulatory DNA, autoimmunity, herpes simplex virus, Sendai virus
URN:NBN:urn:nbn:se:slu:epsilon-p-117449
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-117449
ID Code:28330
Faculty:VH - Faculty of Veterinary Medicine and Animal Science
Department:(VH) > Institutionen för veterinärmedicinsk mikrobiologi
Deposited By: SLUpub Connector
Deposited On:14 Jun 2022 14:25
Metadata Last Modified:14 Jun 2022 14:35

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