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Immunologic aspects of the pathogenesis of human onchocerciasis
Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
Responsible organisation
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Onchocerciasis, or river blindness, is a parasitic disease that affects more than 20 million people globally. The induction of pathology is directly related to the presence and destruction of the microfilarial stages (mf) of this filarial nematode. The disease presents clinically with a wide spectrum of dermal and ocular manifestations, the basis of the variation is believed to involve the immune system. The clinical presentations of infected hosts relate to the intensity of the reactions against the parasite. Anti-microfilarial drugs are also thought to somehow involve the immune system in their pharmacological action. In this study we have investigated some of the factors that might contribute to the pathogenesis, with the aim of gaining a better understanding of the role of immune response in these host inflammatory reactions to Onchocerca volvulus parasite. In the first study we have highlighted the clinically most severe form of dermal onchocerciasis, known as reactive onchocercal dermatitis (ROD), one that is often ignored and has not been properly identified. This form has special characteristics and important biological information that could greatly assist the general understanding of the disease as a whole. Amongst the three major foci of the disease in the study country, Sudan, the prevalence of ROD was found to be associated with different environmental and epidemiological characteristics; strikingly higher in the hypo-endemic areas. Including ROD cases in the prevalence will upgrade the level of endemicity of a locality, and often bring patients much in need of treatment into mass treatment programs that currently only treat localities with medium to high levels of endemicity. In the following research studies, we tried to address the immunological characteristics of the clinically different onchocerciasis patients. Then we also investigated the role of genetic polymorphism in the gene encoding receptor that links innate and adaptive immunity, namely, FcγRIIa.

Patients with either of two major forms of the clinical spectrum-mild and severe dermatopathology were studied by assaying the antigen-driven proliferation of peripheral blood mononuclear cells and the ability of patients’ serum antibodies to promote cytoadherence activity to mf in vitro. Immune responses of those with severe skin disease were found to be stronger compared with the mild dermatopathology group. Mectizan® treatment was followed by an increase in immune responsiveness in those with initially poor responses. Thus the degree of dermatopathology is related to the host’s immune response against mf and immunocompetence may be necessary for Mectizan® to clear the infection efficiently.

The infection has also been associated with increased levels of circulating immune complexes (CIC) containing parasite antigens and a cytokine response that involves both pro-and anti-inflammatory cytokines. Our fourth paper investigated the effect of IC from the O. volvulus infected patients on the production of pro-and anti-inflammatory cytokines. CIC were increased in all patients studied. The precipitate from plasma treated with polyethylene glycol (PEG) were added to peripheral blood mononuclear cell (PBMC) cultures, and the levels of IL-10, tumor necrosis factor TNF-α, IL-1β and their endogenous antagonists soluble TNF-Rp75 and IL-1-receptor antagonist (IL-1ra) were measured. A significant induction of all cytokines measured occurred in the onchocerciasis patients compared to healthy controls. However, the IL-1ra level was suppressed. The suppression of the production of IL-1ra suggests that the IC containing antigens may have a selectively suppressive effect on the production of this anti-inflammatory cytokine; thus implicating its possible role in counteracting inflammatory responses associated with the disease, and suggesting a potential therapeutic significance.

FcgRIIa receptors are involved in many important biological responses, and considered as important mediators of inflammation. A polymorphism in the gene encoding this receptor, that is either arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses. We therefore hypothesized that this polymorphism might be one of the underlying mechanisms to the varied clinical presentations seen in this disease. FcgRIIa genotyping was carried out by gene specific polymerase chain reaction (PCR) and allele-specific restriction enzyme digestion of DNA from clinically characterized patients. The genotype R/R frequencies were found to be significantly higher among patients with the severe form of the disease (including ROD), and it was particularly associated with one tribe (Masaleet) compared to Fulani. Moreover, the H allele was found to be associated with lower risk of developing the severe form. As no significant difference was seen between onchocerciasis cases and controls, the study also implies that this polymorphism influences protection from developing the severe form rather than being related to protection from the infection.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi , 2006. , 68 p.
National Category
Immunology
Identifiers
URN: urn:nbn:se:su:diva-793ISBN: 91-7155-202-2 (print)OAI: oai:DiVA.org:su-793DiVA: diva2:199307
Public defence
2006-02-02, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00
Opponent
Supervisors
Available from: 2006-01-12 Created: 2006-01-12Bibliographically approved
List of papers
1. Reactive onchocercal dermatitis (Sowda) in Sudan: definition and prevalence
Open this publication in new window or tab >>Reactive onchocercal dermatitis (Sowda) in Sudan: definition and prevalence
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2005 In: Acta Trop.Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:su:diva-25274 (URN)
Note
Part of urn:nbn:se:su:diva-793Available from: 2006-01-12 Created: 2006-01-12Bibliographically approved
2. Immune responses directed against microfilariae correlate with severity of clinical onchodermatitis and treatment history
Open this publication in new window or tab >>Immune responses directed against microfilariae correlate with severity of clinical onchodermatitis and treatment history
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2003 In: Journal of Infectious Diseases, Vol. 187, no 4, 714-717 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25275 (URN)
Note
Part of urn:nbn:se:su:diva-793Available from: 2006-01-12 Created: 2006-01-12Bibliographically approved
3. Immunocompetence may be important in the effectiveness of Mectizan® (ivermectin) in the treatment of human onchocerciasis
Open this publication in new window or tab >>Immunocompetence may be important in the effectiveness of Mectizan® (ivermectin) in the treatment of human onchocerciasis
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2002 In: Acta Tropica, Vol. 84, no 1, 49-53 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25276 (URN)
Note
Part of urn:nbn:se:su:diva-793Available from: 2006-01-12 Created: 2006-01-12Bibliographically approved
4. Stimulation of TNF-a, IL-1ß and IL-10 production, but suppression of production of IL-1ra by high molecular weight immune complexes from Onchocerca volvulus-infected Sudanese patients: implications for disease pathogenesis and therapy
Open this publication in new window or tab >>Stimulation of TNF-a, IL-1ß and IL-10 production, but suppression of production of IL-1ra by high molecular weight immune complexes from Onchocerca volvulus-infected Sudanese patients: implications for disease pathogenesis and therapy
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2005 Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:su:diva-25277 (URN)
Note
Part of urn:nbn:se:su:diva-793Available from: 2006-01-12 Created: 2006-01-12Bibliographically approved
5. FcγRIIa (CD32) polymorphism and onchocercal skin disease: implications for the development of severe reactive onchodermatitis (ROD)
Open this publication in new window or tab >>FcγRIIa (CD32) polymorphism and onchocercal skin disease: implications for the development of severe reactive onchodermatitis (ROD)
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2007 (English)In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, Vol. 77, no 6, 1074-1078 p.Article in journal (Refereed) Published
Abstract [en]

The pathologic manifestations of Onchocerca volvulus infection depend on the interplay between the host and the parasite. A genetic single nucleotide polymorphism in the FcγRIIa gene, resulting in arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses and may influence the clinical variations seen in onchocerciasis. This study investigated the relationship between this polymorphism and disease outcome. FcγRIIa genotyping was performed on clinically characterized onchocerciasis patients (N = 100) and healthy controls (N = 74). FcγRIIa genotype R/R131 frequencies were significantly higher among patients with severe dermatopathology (P < 0.001). Increased risk of developing this form was mostly associated with one tribe (Masalit) (OR = 3.2, 95% CI 1-9.9, P = 0.042). The H131 allele was found to be significantly associated with a reduced risk of having the severe form of the disease (adjusted OR = 0.26, 95% CI = 0.13-0.46, P < 0.001). Our findings suggest that the polymorphism influences the clinical outcome of onchocerciasis.

Keyword
Eye disease ; Africa ; Infection ; Parasitosis ; Helminthiasis ; Nematode disease ; Filariosis ; Sudan ; Tropical medicine ; Human ; Severe ; Disease development ; Polymorphism ; Skin disease ; Onchocerciasis ;
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:su:diva-25278 (URN)000252123200016 ()
Note
Part of urn:nbn:se:su:diva-793Available from: 2006-01-12 Created: 2006-01-12 Last updated: 2010-08-09Bibliographically approved

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