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

Abstract

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.

Interleukin-10 and the pathogenesis of human visceral leishmaniasis

“…Experimental models of VL indicate that B cells and antibodies contribute to parasite persistence because B-cell-deficient mice have enhanced resistance to L. donovani infection [79]. Circulating antibodies and Fc receptors have a crucial role in the pathogenesis of non-healing lesions due to L. mexicana complex parasites in mice [80,81] and immune complexes precipitated from VL serum induce higher levels of IL-10 and other proinflammatory cytokines in PBMCs compared with control sera [70]. Moreover, immune complex formation contributes to high level IL-10 production by both human and mouse macrophages [78,82].…”

“…Apart from being useful in diagnosis of disease, the antibody response in VL patients does not appear to be of benefit to the patient. There are several clinical case reports of autoantibody production and immune complex formation in VL patients [70][71][72][73]. Signs of autoreactivity, such as vasculitis [74,75] and decreased renal function [76,77], have been observed.…”

Electrophoretic and immunoelectrophoretic characteristics of IgG as a constituents of peg precipitable immune complexes in preruminant calves' sera

“…Analysis performed with antiserum to IgG1 subclass showed only one part of serum IgG1 molecules precipitated by PEG. However, serum proteins are not denatured during PEG precipitations, and this method is still used for the isolation and in vitro studies of biological effects of immune complexes (Elshafie et al, 2007;Mathsson et al, 2007). In older calves (two, three and four-months old), as well as in adult cattle, all molecular forms of serum IgG1 were precipitated by PEG.…”

An In Vitro Model of Antibody-Enhanced Killing of the Intracellular Parasite Leishmania amazonensis

“…(1989) demonstrated that soluble ICs can lead to sustained superoxide production [27], [52]. Soluble ICs isolated from Leishmania donovani -infected patients have been shown to modulate macrophage responses in vitro with a significant increase in GM-CSF production [53]. Not surprisingly, the context of the soluble IC/macrophage interaction is important, as some studies using ICs have demonstrated IL-10-dependent immunoregulation [54], [55].…”