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The Immunopathology of Rheumatoid Arthritis and Leishmania donovani Infection in Sudan
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. (Autoimmunity)ORCID iD: 0000-0001-8038-0397
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: urn:nbn:se:uu:diva-204392ISBN: 978-91-554-8710-2 (print)OAI: oai:DiVA.org:uu-204392DiVA: diva2:638738
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
List of papers
1. 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, 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.

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: 2017-12-11Bibliographically approved
2. Cystatin C as a marker of immune complex-associated renal impairment in a sudanese population with visceral leishmaniasis
Open this publication in new window or tab >>Cystatin C as a marker of immune complex-associated renal impairment in a sudanese population with visceral leishmaniasis
2006 (English)In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 75, no 5, 864-868 p.Article in journal (Refereed) Published
Abstract [en]

Renal function was studied in visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL) by means of the specific marker cystatin C and related to circulating immune complexes and cytokine production. Forty patients with VL (23 with sub-acute disease and 17 with acute disease), 17 patients with PKDL, and 22 healthy controls were included. Cystatin C, but not creatinine, was significantly raised in VL (P = 0.004). The highest levels of cystatin C were found in those with acute disease (P < 0.0001). In VL, cystatin C levels were positively correlated to circulating immune complexes and production of granulocyte-macrophage colony stimulating factor (GM-CSF), but negatively correlated to aspartate aminotransferase and lactate dehydrogenase. We conclude that cystatin C is a superior marker of glomerular function in leishmaniasis and that immune complex deposition and GM-CSF are two functions that most likely are causally involved in the mechanisms leading to glomerular dysfunction in leishmaniasis.

National Category
Other Clinical Medicine Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-22998 (URN)000242189100016 ()17123978 (PubMedID)
Available from: 2008-01-28 Created: 2008-01-28 Last updated: 2017-12-07Bibliographically approved
3. Disease severity and treatment of Rheumatoid Arthritis: a comparative study between Sudan and Sweden.
Open this publication in new window or tab >>Disease severity and treatment of Rheumatoid Arthritis: a comparative study between Sudan and Sweden.
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-204381 (URN)
Available from: 2013-08-01 Created: 2013-08-01 Last updated: 2013-08-29
4. Dagnostic and prognostic utility of anti-CCP and RF isotypes in Sudanese patients with rheumatoid arthritis.
Open this publication in new window or tab >>Dagnostic and prognostic utility of anti-CCP and RF isotypes in Sudanese patients with rheumatoid arthritis.
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-204383 (URN)
Available from: 2013-08-01 Created: 2013-08-01 Last updated: 2017-09-11

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