Helicobacter pylori Infection Increased Anti-dsDNA and Enhanced Lupus Severity in Symptomatic FcγRIIb-Deficient Lupus Mice

Abstract

The defect on Fc gamma receptor IIb (FcγRIIb), the only inhibitory FcγR, has been identified as one of the genetic factors increasing susceptibility to lupus. The prevalence of Helicobacter pylori (HP) and FcγRIIb 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 FcγRIIb-/- mice (symptomatic lupus). HP induced failure to thrive, increased stomach bacterial burdens and stomach injury (histology and cytokines) in both wild-type and FcγRIIb-/- 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 FcγRIIb-/- 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 FcγRIIb-/- mice, the levels were higher in FcγRIIb-/- 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 FcγRIIb-/- 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 FcγRIIb-/-mice were demonstrated in this study. With the prominent immune responses from the loss of inhibitory signaling in FcγRIIb-/- 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.

Increased Risk of Systemic Lupus Erythematosus in Patients With Helicobacter pylori Infection: A Nationwide Population-Based Cohort Study

“…Yamanishi et al have demonstrated B-1-cell activation using HP urease, leading to the creation of anti-ssDNA antibodies (16). In a recent animal study, Surawut et al found that HP infection increased anti-dsDNA and lupus severity in the symptomatic FcγRIIb-deficient lupus mouse model (23). Few clinical studies have been conducted to understand the correlation between HP infection and SLE.…”

Helicobacter pylori and its association with autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis and Sjögren syndrome

“…In FcγRIIb−/− mice, a polymorphism associated with SLE development, H. pylori infection was associated with increased SLE severity, higher levels of anti- H. pylori and anti-dsDNA antibodies, and increased production of splenic autoimmune cells compared with wild-type mice [ 53 ]. Urease induced the production of anti-ssDNA antibodies in animal models [ 31 ].…”

Leaky-gut enhanced lupus progression in the Fc gamma receptor-IIb deficient and pristane-induced mouse models of lupus

“…11-13) despite the similar level of LPS and BG in blood (Fig. 4D,E) emphasizing the hyper-immune responses due to the inhibitory-signaling defect of FcGRIIb−/− group 3,23 . However, proteinuria, histopathology score and immunoglobulin deposition in glomeruli were not different between FcGRIIb−/− and pristane mice ( Figs.…”

“…Spleen apoptosis was detected by immunohistochemistry with anti-active caspase 3 antibody (Cell Signaling Technology, Beverly, MA, USA) (expressed as positive cells per high-power field) 22 and flow cytometry. The fluorochrome-conjugated antibodies against different molecules were used including; i) apoptosis indicators, annexin V and propidium iodide (PI), ii) B220 (B cell) and iii) F4/80 (macrophage) (BioLegend, San Diego, CA, USA) with FlowJo software 23 . www.nature.com/scientificreports www.nature.com/scientificreports/ Mesenteric lymph node analysis.…”

“…Because FcGRIIb−/− mice developed proteinuria as early as 24-wk-old 23 , DSS was administered in 24-wk-old FcGRIIb−/− (and pristane) mice to explore the influence of leaky-gut in symptomatic lupus condition. At 30 days post-DSS, anti-dsDNA Ig, serum Cr and serum IL-6 in FcGRIIb−/− mice was higher than pristane ( Figs.…”