Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Functional Role of Immune Complexes in Rheumatic and Parasitic Diseases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Immune complexes (IC) have key pathological roles in both autoimmune and infectious diseases. In this thesis functional mechanisms behind IC-driven inflammation in rheumatic diseases and tropical infections have been studied, with special focus on the contribution of autoantibodies and cytokine-inducing properties of IC. In the autoimmune disease SLE, increased levels of IC-induced cytokines were associated with both increased classical complement activation and the occurrence of the autoantibodies anti-SSA and anti-SSB, both directed against RNA-associated antigens. In addition, complement activation and anti-SSA synergistically predisposed to higher levels of IC in sera. In the following study it was demonstrated that also other autoantibodies against RNA-associated autoantigens were more enriched than anti-dsDNA in SLE IC.

Sudanese Visceral Leishmaniasis (VL) patients had elevated IC levels, and precipitated IC induced higher levels of GM-CSF, IL10, IL6 and IL1RA than control IC. Levels of IC were especially prominent in severely ill patients receiving antimony treatment, and a parallel association with IC induction of GM-CSF was demonstrated. Leishmania-infected patients were often rheumatoid factor (RF) positive and a substantial number displayed reactivity towards cyclic citrullinated peptide (CCP) antigens. Contrary to what was seen in Sudanese RA sera, the CCP reactivity was not restricted to citrulline but reacted equally well with arginine-containing control peptides. Levels of anti-CCP among VL patients were not due to cross-reactions with, or CCP-reactivity bound to IC.

I have demonstrated that IC are associated with the presence of autoantibodies in both SLE and in Leishmania infection. In SLE, autoantibodies against RNA-associated antigens were more prone to form circulating IC than anti-dsDNA. In Leishmania infection false reactivity against the CCP-autoantigen correlated to IC levels although the IC themselves did not contain such reactivity. In both diseases higher IC levels were associated with a more active disease, and purified IC induced key cytokines in disease pathogeneses.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 636
National Category
Immunology in the medical area
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-139529ISBN: 978-91-554-7981-7 (print)OAI: oai:DiVA.org:uu-139529DiVA, id: diva2:382529
Public defence
2011-02-17, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-01-27 Created: 2010-12-28 Last updated: 2018-01-12Bibliographically approved
List of papers
1. Cytokine induction by circulating immune complexes and signs of in-vivo complement activation in systemic lupus erythematosus are associated with the occurrence of anti-Sjögren's syndrome A antibodies
Open this publication in new window or tab >>Cytokine induction by circulating immune complexes and signs of in-vivo complement activation in systemic lupus erythematosus are associated with the occurrence of anti-Sjögren's syndrome A antibodies
Show others...
2007 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 147, no 3, p. 513-520Article in journal (Refereed) Published
Abstract [en]

Circulating immune complexes (IC) and levels of IC-induced cytokines have been correlated with complement activation and autoantibody profiles in systemic lupus erythematosus (SLE). SLE sera were analysed concerning levels of immune complexes (IC), classical complement function and different antinuclear and anti-C-reactive protein (CRP) autoantibodies. Blood mononuclear cells from healthy donors were stimulated with isolated IC and production of interleukin (IL)-10, IL-6 and IL-12p40 was measured. Functional experiments revealed that increased levels of IC-induced cytokines were associated with both increased classical complement activation and the occurrence of anti-Sjögren's syndrome A (SSA) and anti-SSB but not other autoantibodies. Biochemical measurement of circulating IC showed that the degree of complement activation and the occurrence of anti-SSA were synergistically associated with levels of circulating IC in SLE sera, as complement activation was a prerequisite for the enhancing effect of anti-SSA. Anti-CRP was associated with complement activation, but not with other autoantibodies. Our results indicate that anti-SSA and possibly anti-SSB antibodies influence IC formation and subsequent IC-induced cytokine induction, and that they thereby participate in the inflammatory process in active SLE.

Keywords
Complement, Cytokines, Immune complex, Systemic lupus erythematosus
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-14037 (URN)10.1111/j.1365-2249.2006.03313.x (DOI)000243928900016 ()17302901 (PubMedID)
Available from: 2008-01-28 Created: 2008-01-28 Last updated: 2018-02-27Bibliographically approved
2. Autoantibodies associated with RNA are more enriched than anti-dsDNA antibodies in circulating immune complexes in SLE
Open this publication in new window or tab >>Autoantibodies associated with RNA are more enriched than anti-dsDNA antibodies in circulating immune complexes in SLE
Show others...
2012 (English)In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 21, no 6, p. 586-595Article in journal (Refereed) Published
Abstract [en]

To what extent different autoantibodies accumulate in systemic lupus erythematosus (SLE) immune complexes (ICs), and whether such accumulation is associated with disease activity has been investigated. ICs were isolated from SLE sera by both polyethylene glycol (PEG) precipitation and C1q-binding. Autoantibody specificities were determined using a lineblot assay quantified by densitometry. To compare the relative levels of autoantibodies, levels were normalized to the total levels of IgG measured by ELISA in sera and parallel ICs. Samples were investigated both in a cross-sectional design as well as in a paired design with samples obtained during both active and inactive SLE. All investigated autoantibody specificities except anti-dsDNA were enriched in circulating ICs as compared with parallel sera. The group of antibodies against RNA-associated antigens (anti-RNP/Sm, anti-Sm, anti-SSA/Ro60, anti-SSA/Ro52, anti-SSB/La) all exhibited higher median enrichment than the DNA-associated (anti-dsDNA, anti-histones, anti-nucleosomes) or cytoplasmic (anti-ribosomal P) antigens. In particular autoantibodies against RNP/Sm and SSA/Ro52 had the highest degree of enrichment in SLE PEG precipitates. These findings were corroborated by analysis of autoantibody content in C1q-bound ICs. There was no difference in degree of IC accumulation of the investigated autoantibodies during active and inactive SLE. Our findings demonstrate a difference in enrichment between autoantibodies against RNA- and DNA-associated autoantigens in isolated SLE IC, suggesting that the RNA-associated autoantibodies are more prone to form circulating ICs in SLE, in contrast to antibodies against DNA-associated autoantigens such as dsDNA. These finding have implications in understanding mechanisms of differential autoantibody accumulation in target organs in SLE.

Keywords
SLE, Immune complexes, anti-SSA, anti-SSB, Ro52, Ro60, anti-dsDNA, ANA
National Category
Rheumatology and Autoimmunity Immunology in the medical area
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-139527 (URN)10.1177/0961203311434938 (DOI)000302915200002 ()
Available from: 2010-12-28 Created: 2010-12-28 Last updated: 2018-02-27
3. Circulating immune complexes (IC) and IC-induced levels of GM-CSF are increased in sudanese patients with acute visceral Leishmania donovani infection undergoing sodium stibogluconate treatment: implications for disease pathogenesis
Open this publication in new window or tab >>Circulating immune complexes (IC) and IC-induced levels of GM-CSF are increased in sudanese patients with acute visceral Leishmania donovani infection undergoing sodium stibogluconate treatment: implications for disease pathogenesis
Show others...
2007 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 178, no 8, p. 5383-5389Article in journal (Refereed) Published
Abstract [en]

Infection with Leishmania donovani is associated with IL-10 as well as with GM-CSF. Immune complexes (IC) exert important functions by stimulation of monocytes/macrophage-mediated production of pro- and anti-inflammatory cytokines in rheumatic diseases. In this investigation, we have explored IC-induced cytokine production during Leishmania infection. Sera from 43 patients with visceral leishmaniasis (VL), 17 patients with post-kala-azar dermal leishmaniasis, and 20 healthy Sudanese controls were precipitated with polyethylene glycol (PEG). The PEG precipitates were added to serum-free PBMC for 20 h,whereupon supernatant levels of IL-1β, IL-6, IL-10, IL-1 receptor antagonist protein, TNF-α, TNF receptor p75, and GM-CSF were investigated using ELISA. Circulating levels of C1q-binding IC were also measured in the serum samples. PEG precipitates from Leishmania-infected patients induced significantly higher levels of GM-CSF (p = 0.0037) and IL-10 (p < 0.0001), as well as of IL-6 (p < 0.0001) and IL-1 receptor antagonist (p = 0.0238) as compared with PEG precipitates from controls. Patients with acute VL as well as VL patients receiving sodium stibogluconate treatment displayed significantly increased levels of PEG precipitate-induced GM-CSF. The induction of GM-CSF by circulating IC was especially prominent in acute VL patients receiving sodium stibogluconate treatment; ANOVA revealed significant interaction between disease activity and treatment for PEG precipitate-induced levels of GM-CSF (disease activity, p = 0.0006; treatment, p = 0.0005; interaction, p = 0.0046). Parallel associations were determined for C1q-binding immune complexes, but not for any cytokine other than GM-CSF. The importance of IC-induced GM-CSF in leishmaniasis warrants further study.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-14035 (URN)000245605300084 ()17404324 (PubMedID)
Available from: 2008-01-28 Created: 2008-01-28 Last updated: 2018-02-27Bibliographically approved
4. Occurrence of rheumatoid arthritis-associated autoantibodies in Sudanese patients with Leishmania donovani infection
Open this publication in new window or tab >>Occurrence of rheumatoid arthritis-associated autoantibodies in Sudanese patients with Leishmania donovani infection
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective

Our aim with this investigation was to evaluate the occurrence of anti-cyclic citrullinated peptide antibodies (anti-CCP), rheumatoid factor (RF) and circulating immune complexes (IC) in Sudanese patients infected with Leishmania donovani parasite.

Methods

Serum samples were collected from Leishmania infected patients and healthy Sudanese controls. Sudanese anti-CCP positive RA patients were included as positive controls. Data from all analyses were also compared with Swedish healthy control cohorts. Levels of circulating IC and anti-CCP were measured using ELISA and RF using nephelometry. A control plate with cyclic control peptides containing arginine instead of citrulline was used to evaluate citrulline specific reactivity.

Results

We demonstrate that sera from Leishmania infected patients are often RF positive, have elevated IC levels and that a substantial number exhibit antibody reactivity towards CCP. However, contrary to what was evident the in Sudanese RA sera, the CCP reactivity was not restricted to citrulline but reacted equally well with the arginine control peptide.

Conclusions

Our findings stress the importance to interpret a positive CCP test carefully when evaluated in non-rheumatic conditions.

National Category
Infectious Medicine Immunology in the medical area
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-139528 (URN)
Available from: 2010-12-28 Created: 2010-12-28 Last updated: 2018-01-12

Open Access in DiVA

fulltext(3658 kB)1178 downloads
File information
File name FULLTEXT01.pdfFile size 3658 kBChecksum SHA-512
adb6b30fb1cf6dbd4d7ed075d4dbd0e00e77d58dd42778ff0549b6492b4d15e02293ee8c44dc89cc96761f37f712363529febe25f29364a6535d9c28758c7bbb
Type fulltextMimetype application/pdf
Buy this publication >>

Search in DiVA

By author/editor
Åhlin, Erik
By organisation
Clinical Immunology
Immunology in the medical area

Search outside of DiVA

GoogleGoogle Scholar
Total: 1178 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 815 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf