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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Autoimmunitet)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Autoimmunitet)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Autoimmunitet)
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2007 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 178, no 8, 5383-5389 p.Article 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.

Place, publisher, year, edition, pages
2007. Vol. 178, no 8, 5383-5389 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-14035ISI: 000245605300084PubMedID: 17404324OAI: oai:DiVA.org:uu-14035DiVA: diva2:41805
Available from: 2008-01-28 Created: 2008-01-28 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Functional Role of Immune Complexes in Rheumatic and Parasitic Diseases
Open this publication in new window or tab >>Functional Role of Immune Complexes in Rheumatic and Parasitic Diseases
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. 68 p.
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:nbn:se:uu:diva-139529 (URN)978-91-554-7981-7 (ISBN)
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: 2011-03-11Bibliographically approved
2. The Immunopathology of Rheumatoid Arthritis and Leishmania donovani Infection in Sudan
Open this publication in new window or tab >>The Immunopathology of Rheumatoid Arthritis and Leishmania donovani Infection in Sudan
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Immune complexes (IC) and antibody production against self-antigens play a pathological key role in the development of autoimmunity that occurs in patients with parasitic infections and rheumatic diseases. My studies have targeted two groups of patients from Sudan; patients with visceral leishmaniasis (VL) and patients with rheumatoid arthritis (RA).

In VL patients I studied the functional role of IC and IC-induced cytokine production in the pathogenesis of the disease and their effect on kidney functions. For the Sudanese RA cohort, I performed a comparative study with Swedish RA patients. I also investigated the Sudanese RA cohort for the occurrence of RA-associated autoantibodies (rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA)) and the diagnostic and prognostic impact of these autoantibodies on the clinical outcome.

In the VL project, I demonstrated that Sudanese VL patients had elevated serum levels of IC and of IC-induced cytokine levels in vitro. GM-CSF levels were increased in acute VL patients and in VL patients with ongoing sodium stibogluconate treatment, and the only cytokine that correlated to a high degree with circulating IC levels. Cystatin C was shown to be a superior marker of glomerular function as compared to serum creatinine in VL patients. For the RA project, a comparative study was performed in collaboration with the rheumatology unit at Gävle hospital. We concluded that the clinical picture of RA in Sudan was more severe, with more widespread joint involvement and stronger laboratory signs of inflammation when compared to the Swedish RA patients.

ACPA and RF are both included in the new 2010 RA classification criteria. In many RA studies over the world the occurrence of ACPA and RF varies considerably, this may be due to both geographical differences and lack of standardization for RF and anti-CCP in the RA criteria. But in this study we aligned all antibodies to the same diagnostic specificity compared to Sudanese healthy controls. When doing so we determined that IgA RF had the highest diagnostic sensitivity, a finding that differs from Caucasian studies in which IgM RF predominates. IgG RF was also the autoantibody most strongly associated with early age of disease onset and hand deformities, a clinical picture that differs in most Caucasian studies in which ACPA are the strongest markers for bad prognosis. Thus data from this Sudanese RA cohort implies significant clinical and immunological differences compared to Caucasian RA patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 919
National Category
Medical and Health Sciences
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-204392 (URN)978-91-554-8710-2 (ISBN)
Public defence
2013-09-18, Rudbecksalen, Dept of Immunology, Uppsala University Rudbeck Laboratory, 751 85 Uppsala, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-08-28 Created: 2013-08-01 Last updated: 2014-01-07

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Åhlin, ErikMathsson, LindaRönnelid, Johan

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