Why Serological Responses during Cystitis are Limited

Abstract

The high frequency of urinary tract infections (UTIs), some of which appear to be endogenous relapses rather than reinfections by new isolates, point to defects in the host's memory immune response. It has been known for many decades that, whereas kidney infections evoked an antibody response to the infecting bacteria, infections limited to the bladder failed to do so. We have identified the existence of a broadly immunosuppressive transcriptional program associated with the bladder, but not the kidneys, during infection of the urinary tract that is dependent on bladder mast cells. This involves the localized secretion of IL-10 and results in the suppression of humoral immune responses in the bladder. Mast cell-mediated immune suppression could suggest a role for these cells in critically balancing the needs to clear infections with the imperative to prevent harmful immune reactions in the host.

Keywords: cystitis; defects in memory response; mast cells; recurrent UTI; serology.

Figure 1

Failure of humoral responses in bladder during uropathogenic E. coli (UPEC) infection. Serum geometric mean titers (GMT) of UPEC antibodies were measured. (First arrow) 1 × 10⁸ CFU UPEC was transurethrally given to mice bladder for inducing cystitis-only or pyelonephritis. (Second arrow) both groups were infected through cystitis-only. * p < 0.05; ** p < 0.01; *** p < 0.001. n = 4–7. Dotted line: detection threshold. This figure is a reproduction from [16].

Figure 2

UPEC infection specifically enhanced Il10 transcription as an anti-inflammatory response in the bladder. Il10 transcription levels (real-time PCR) in the bladder and kidney measured at various times p.i. * p < 0.05; ** p < 0.01. This figure is a reproduction from [16].

Figure 3

IL10 suppresses the activation of dendritic cells during cystitis. (Left) Upon cystitis or pyelonephritis, MHC-II⁺CD11c⁺ population of DCs were measured by flow cytometry after 24 h p.i.; (Right) Increased population of MHC-II⁺CD11c⁺CD86⁺ DCs of WT in RLN or Il10^−/− in ILN and RLN. ILN: iliac lymph node; RLN: renal lymph node; * p < 0.05; ** p < 0.01; n = 3–7. This figure is a reproduction from [16].

Figure 4

Localization of mast cells in the epithelium of the bladder. Bladder of Mcpt5-Cre tdTomato^fl/fl mouse was whole-mounted and stained. Green: superficial epithelial cells (wheat germ agglutinin); Blue: blood vessels (anti CD31 antibody); Red: mast cells (tdTomato); Scale bar: 30 µm. Upper figure is a top view image showing spatial distribution of mast cells relative to superficial epithelial cells and blood vessels. Lower figure is a side view image revealing the close proximity of mast cells to the superficial epithelium and blood vessels, where immune cells are recruited from.

Figure 5

Bladder mast cells express IL10 during UPEC infection. Individual group of mice were infected with UPEC, and at 24 h p.i. Il10 expression (real time PCR) was measured. ** p < 0.01. This figure is a reproduction from [16].

Figure 6

UPEC-specific IgG production is no longer suppressed in mice whose mast cells fail to secrete IL-10. Serum UPEC-specific IgG was detected in Mcpt5-Cre Il10^fl/fl mice 7days p.i. but not in wild type mice. n = 5; Error bars represent the 95% confidence level. This figure is a reproduction from [16].