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Helicobacter pylori Infection Increased Anti-dsDNA and Enhanced Lupus Severity in Symptomatic Fc?RIIb-Deficient Lupus Mice.

ABSTRACT: The defect on Fc gamma receptor IIb (Fc?RIIb), the only inhibitory Fc?R, has been identified as one of the genetic factors increasing susceptibility to lupus. The prevalence of Helicobacter pylori (HP) and Fc?RIIb dysfunction-polymorphisms are high among Asians, and their co-existence is possible. Unfortunately, the influence of HP against lupus progression in patients with lupus is still controversial. In this study, the interactions between these conditions were tested with HP infection in 24-week-old Fc?RIIb-/- mice (symptomatic lupus). HP induced failure to thrive, increased stomach bacterial burdens and stomach injury (histology and cytokines) in both wild-type and Fc?RIIb-/- mice. While the severity of HP infection, as determined by these parameters, was not different between both strains, antibodies production (anti-HP, anti-dsDNA and serum gammaglobulin) were higher in Fc?RIIb-/- mice compared to wild-type. Accordingly, HP infection also accelerated the severity of lupus as determined by proteinuria, serum creatinine, serum cytokines, renal histology, and renal immune complex deposition. Although HP increased serum cytokines in both wild-type and Fc?RIIb-/- mice, the levels were higher in Fc?RIIb-/- mice. As such, HP also increased spleen weight and induced several splenic immune cells responsible for antibody productions (activated B cell, plasma cell and follicular helper T cell) in Fc?RIIb-/- mice, but not in wild-type. These data describe the different systemic responses against localized HP infection from diverse host genetic background. In conclusion, the mutual interactions between HP and lupus manifestations of Fc?RIIb-/-mice were demonstrated in this study. With the prominent immune responses from the loss of inhibitory signaling in Fc?RIIb-/- mice, HP infection in these mice induced intense chronic inflammation, increased antibody production, and enhanced lupus severity. Thus, the increased systemic inflammatory responses due to localized HP inducing gastritis in some patients with lupus may enhance lupus progression. More studies are needed.

SUBMITTER: Surawut S

PROVIDER: S-EPMC6043646 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Project description:Fc? receptors (Fc?Rs) are classified as activating (Fc?RI, III, and IV) and inhibitory (Fc?RII) receptors. We have reported that deletion of activating Fc?Rs in apolipoprotein E (apoE) single knockout mice attenuated atherosclerosis. In this report, we investigated the hypothesis that deficiency of inhibitory Fc?RIIb exacerbates atherosclerosis.ApoE-Fc?RIIb double knockout mice, congenic to the C57BL/6 (apoE-Fc?RIIbB6 (-/-)), were generated and atherosclerotic lesions were assessed. In contrary to our hypothesis, when compared with apoE single knockout mice, arterial lesions were significantly decreased in apoE-Fc?RIIbB6 (-/-) male and female mice fed chow or high-fat diets. Chimeric mice generated by transplanting apoE-Fc?RIIbB6 (-/-) marrow into apoE single knockout mice also developed reduced lesions. CD4(+) T cells from apoE-Fc?RIIbB6 (-/-) mice produced higher levels of interleukin-10 and transforming growth factor-? than their apoE single knockout counterparts. As our findings conflict with a previous report using apoE-Fc?RIIb129/B6 (-/-) mice on a mixed genetic background, we investigated whether strain differences contributed to the anti-inflammatory response. Macrophages from Fc?RIIb129/B6 (-/-) mice on a mixed genetic background produced more interleukin-1? and MCP-1 (monocyte chemoattractant protein-1) in response to immune complexes, whereas congenic Fc?RIIbB6 (-/-) mice generated more interleukin-10 and significantly less interleukin-1?. Interestingly, the expression of lupus-associated slam genes, located in proximity to fcgr2b in mouse chromosome 1, is upregulated only in mixed Fc?RIIb129/B6 (-/-) mice.Our findings demonstrate a detrimental role for Fc?RIIb signaling in atherosclerosis and the contribution of anti-inflammatory cytokine responses in the attenuated lesions observed in apoE-Fc?RIIbB6 (-/-) mice. As 129/sv genome-derived lupus-associated genes have been implicated in lupus phenotype in Fc?RIIb129/B6 (-/-) mice, our findings suggest possible epistatic mechanism contributing to the decreased lesions.

Project description:BackgroundThe protozoan parasite Giardia intestinalis and the pathogenic bacterium Helicobacter pylori are well known for their high prevalences in human hosts worldwide. The prevalence of both organisms is known to peak in densely populated, low resource settings and children are infected early in life. Different Giardia genotypes/assemblages have been associated with different symptoms and H. pylori with induction of cancer. Despite this, not much data are available from sub-Saharan Africa with regards to the prevalence of different G. intestinalis assemblages and their potential association with H. pylori infections.Methodology/principal findingsFecal samples from 427 apparently healthy children, 0-12 years of age, living in urban Kampala, Uganda were analyzed for the presence of H. pylori and G. intestinalis. G. intestinalis was found in 86 (20.1%) out of the children and children age 1<5 years had the highest rates of colonization. H. pylori was found in 189 (44.3%) out of the 427 children and there was a 3-fold higher risk of concomitant G. intestinalis and H. pylori infections compared to non-concomitant G. intestinalis infection, OR = 2.9 (1.7-4.8). No significant association was found in the studied population with regard to the presence of Giardia and gender, type of toilet, source of drinking water or type of housing. A panel of 45 G. intestinalis positive samples was further analyzed using multi-locus genotyping (MLG) on three loci, combined with assemblage-specific analyses. Giardia MLG analysis yielded a total of five assemblage AII, 25 assemblage B, and four mixed assemblage infections. The assemblage B isolates were highly genetically variable but no significant association was found between Giardia assemblage type and H. pylori infection.Conclusions/significanceThis study shows that Giardia assemblage B dominates in children in Kampala, Uganda and that the presence of H. pylori is an associated risk factor for G. intestinalis infection.

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Helicobacter pylori Infection Increased Anti-dsDNA and Enhanced Lupus Severity in Symptomatic Fc?RIIb-Deficient Lupus Mice.

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