epiglucan and Lupus-Erythematosus--Systemic

The influence of gut-leakage or gut-microbiota upon lupus progression was explored in 2 lupus mouse models. Pristane, administered in 4-wk-old wild-type (WT) female mice, induced lupus characteristics at 24-wk-old similar to the lupus-onset in FcGRIIb-/- mice. Gut-microbiota alteration was induced by co-housing together with the gavage of feces from 40-wk-old FcGRIIb-/- mice (symptomatic lupus). On the other hand,  gut-leakage was induced  by dextran sulfate solution (DSS). DSS and gut-microbiota alteration induced high serum anti-dsDNA immunoglobulin (Ig) as early as 30 days post-DSS only in FcGRIIb-/- mice. DSS, but not gut-microbiota alteration, enhanced lupus characteristics (serum creatinine and proteinuria) in both lupus models (but not in WT) at 60 days post-DSS. Indeed, DSS induced the translocation of molecular components of gut-pathogens as determined by bacterial burdens in mesenteric lymph node (MLN), endotoxemia (gut-bacterial molecule) and serum (1→3)-β-D-glucan (BG) (gut-fungal molecule) as early as 15 days post-DSS together with enhanced MLN apoptosis in both WT and lupus mice. However, DSS induced spleen apoptosis in FcGRIIb-/- and WT mice at 30 and 60 days post-DSS, respectively, suggesting the higher impact of gut-leakage against spleen of lupus mice. In addition, macrophages preconditioning with LPS plus BG were susceptible to starvation-induced apoptosis, predominantly in FcGRIIb-/- cell, implying the influence of gut-leakage upon cell stress. In summary, gut-leakage induced gut-translocation of organismal-molecules then enhanced the susceptibility of stress-induced apoptosis, predominantly in lupus. Subsequently, the higher burdens of apoptosis in lupus mice increased anti-dsDNA Ig and worsen lupus severity through immune complex deposition. Hence, therapeutic strategies addressing gut-leakage in lupus are interesting.

Topics: Animals; beta-Glucans; Cytokines; Dextran Sulfate; Disease Models, Animal; Disease Progression; Feces; Female; Lupus Erythematosus, Systemic; Mice; Receptors, IgG; Terpenes

We investigated the influence of spontaneous gut leakage upon polymicrobial sepsis in a lupus model with Fc gamma receptor IIb-deficient (FcGRIIb-/-) mice aged 8 and 40 weeks, as representing asymptomatic and symptomatic lupus, respectively. Spontaneous gut leakage, determined by (i) the presence of FITC-dextran, (ii) elevated serum endotoxin, and (iii) elevated serum (1→3)-β-D-glucan (BG), was demonstrated in symptomatic lupus but not in the asymptomatic group. In parallel, spontaneous gut leakage, detected by elevated serum BG without fungal infection, was demonstrated in patients with active lupus nephritis. Gut leakage induced by dextran sulfate solution (DSS) or endotoxin administration together with BG or endotoxin alone, but not BG alone, enhanced the severity of cecal ligation and puncture (CLP) sepsis more prominently in 8-week-old FcGRIIb-/- mice. Additionally, the bone marrow-derived macrophages of FcGRIIb-/- mice produced higher cytokine levels when coexposed to endotoxin and BG, when compared to wild-type mice. In summary, spontaneous gut leakage was demonstrated in symptomatic FcGRIIb-/- mice and the induction of gut permeability worsened sepsis severity. Gut translocation of endotoxin and BG had a minor effect on wild-type mice, but the synergistic effect of BG and endotoxin was prominent in FcGRIIb-/- mice. The data suggest that therapeutic strategies addressing gut leakage may be of interest in sepsis conditions in patients with lupus.

Topics: Adult; Animals; beta-Glucans; Cytokines; Dextran Sulfate; Disease Models, Animal; Endotoxins; Female; Gastrointestinal Tract; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Macrophages; Mice; Permeability; Proteoglycans; Receptors, IgG; Sepsis; Survival Analysis

Beta-glucans are naturally occurring polysaccharides that exert important immunostimulatory activities. In the present study, we evaluated whether beta-glucans could modulate the development and the course of systemic lupus erythematosus (SLE). To this aim, we employed the classical model of SLE represented by the F1 hybrid between the NZB and NZW mouse strains which develop severe lupus-like phenotypes comparable to that of SLE patients. The administration of beta-glucan was associated to a more aggressive development of the disease and a worse prognosis, as observed from the clinical, biochemical and histopathological data. This finding implies that restraint should be practised in the possible use of beta-glucans as immunomodulators in human therapy in the context of SLE.

Topics: Animals; beta-Glucans; Disease Models, Animal; Female; Lupus Erythematosus, Systemic; Mice; Mice, Inbred NZB; Prognosis; Severity of Illness Index; Species Specificity