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. 2018 Mar;48(3):464-470.
doi: 10.1002/eji.201747209. Epub 2017 Dec 11.

IL-22 neutralizing autoantibodies impair fungal clearance in murine oropharyngeal candidiasis model

Rudolf Bichele  1 , Jaanika Kärner  1 , Kai Truusalu  2 , Imbi Smidt  2 , Reet Mändar  2 , Heather R Conti  3   4 , Sarah L Gaffen  3 , Pärt Peterson  1 , Martti Laan  1 , Kai Kisand  1
Affiliations

IL-22 neutralizing autoantibodies impair fungal clearance in murine oropharyngeal candidiasis model

Rudolf Bichele et al. Eur J Immunol. 2018 Mar.

Abstract

Protection against mucocutaneous candidiasis depends on the T helper (Th)17 pathway, as gene defects affecting its integrity result in inability to clear Candida albicans infection on body surfaces. Moreover, autoantibodies neutralizing Th17 cytokines have been related to chronic candidiasis in a rare inherited disorder called autoimmune polyendocriopathy candidiasis ectodermal dystrophy (APECED) caused by mutations in autoimmune regulator (AIRE) gene. However, the direct pathogenicity of these autoantibodies has not yet been addressed. Here we show that the level of anti-IL17A autoantibodies that develop in aged Aire-deficient mice is not sufficient for conferring susceptibility to oropharyngeal candidiasis. However, patient-derived monoclonal antibodies that cross-react with murine IL-22 increase the fungal burden on C. albicans infected mucosa. Nevertheless, the lack of macroscopically evident infectious pathology on the oral mucosa of infected mice suggests that additional susceptibility factors are needed to precipitate a clinical disease.

Keywords: Aire; Cytokine autoantibodies; IL-22; Oropharyngeal candidiasis; Th17.

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Conflict of interest statement

Conflict of Interest

KK and PP are co-cofounders and shareholders of ImmunoQure AG. All other authors declare no financial or commercial conflict of interest.

Figures

Figure 1
Figure 1. The impact of Aire-deficiency on the susceptibility for oropharyngeal candidiasis
Binding autoantibodies to IL-17A were quantified from mouse serum samples using ELISA (A) and their biological activity was tested using cell-based neutralization assay (B). The tests were performed three times in two replicates. Control mice (BALB/c, n=5) were treated with cortisone at day −1, 1 and 3, and were subjected to OPC at day 0 together with aged Aire-deficient mice (BALB/c, n=16, >1.5 years of age) and their wild type littermates (n=22). Weight loss was calculated daily (C). Tongues were harvested on day 3-4 (cortisone-treated mice) or 6 for fungal burden enumeration. Dotted line indicates LOD (50 CFU/g) (D). Data were pooled from three independent experiments13 −15 mice per experiment. Mean and SD are depicted in the graphs. Unpaired two-tailed t-test (A and B) and Dunn’s multiple comparison test (C) were used. *** p< 0.001
Figure 2
Figure 2. The impact of IL-22 neutralization on the susceptibility for oropharyngeal candidiasis
APECED patient derived recombinant monoclonal antibodies were compared for their capacity to neutralize human (A) or mouse (B) IL-22. Inhibitory concentration 50 (IC50) values are indicated as calculated from the dose-response curves using nonlinear regression. The experiments were performed at least three times with two parallel measurements. Intra-peritoneal injection of 30G1 at days −1, 1, 3 and 5 resulted in measurable anti-IL-22 activity in mouse serum samples at day 6 as measured using luciferase based immunoprecipitation systems (C). Weight loss after C. albicans infection was recorded in cortisone (BALB/c, n=5), 30G1 (BALB/c, n=17) or IgG (BALB/c, n=15) treated mice (D). Tongues were harvested on day 3-4 (cortisone-treated mice) or 6 for fungal burden enumeration. Dotted line indicates LOD (50 CFU/g) (E). Data were pooled from three independent experiments with 8-18 mice per experiment. Mean and SD are depicted in the graphs. * p<0.05, *** p< 0.001 determined by unpaired two-tailed t-test (C) or Dunn’s multiple comparison test (E).
Figure 3
Figure 3. Th17 cytokine related gene expression in tongue tissue at day 6 after oropharyngeal C. albicans infection
Aire-deficient (BALB/c, n=8, >1.5 years of age) and wild type littermates(n=9) mice were compared in panel A, and 30G1 (BALB/c, n=8) and IgG (BALB/c, n=8) treated mice in panel B for Il22 and Il17a, and their downstream gene expression relative to B2m with the comparative Ct (ΔΔCt) method. Data are pooled from four different experiments with 8-18 mice per experiment. Mean and SD are depicted in the graphs. Two-tailed unpaired t-test was used. * p<0.05, ** p< 0.01, *** p< 0.001
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