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. 2015 Mar 20;10(3):e0121776.
doi: 10.1371/journal.pone.0121776. eCollection 2015.

Humoral Immunity Links Candida Albicans Infection and Celiac Disease

Free PMC article

Humoral Immunity Links Candida Albicans Infection and Celiac Disease

Marion Corouge et al. PLoS One. .
Free PMC article


Objective: The protein Hwp1, expressed on the pathogenic phase of Candida albicans, presents sequence analogy with the gluten protein gliadin and is also a substrate for transglutaminase. This had led to the suggestion that C. albicans infection (CI) may be a triggering factor for Celiac disease (CeD) onset. We investigated cross-immune reactivity between CeD and CI.

Methods: Serum IgG levels against recombinant Hwp1 and serological markers of CeD were measured in 87 CeD patients, 41 CI patients, and 98 healthy controls (HC). IgA and IgG were also measured in 20 individuals from each of these groups using microchips sensitized with 38 peptides designed from the N-terminal of Hwp1.

Results: CI and CeD patients had higher levels of anti-Hwp1 (p=0.0005 and p=0.004) and anti-gliadin (p=0.002 and p=0.0009) antibodies than HC but there was no significant difference between CeD and CI patients. CeD and CI patients had higher levels of anti-transglutaminase IgA than HC (p=0.0001 and p=0.0039). During CI, the increase in anti-Hwp1 paralleled the increase in anti-gliadin antibodies. Microchip analysis showed that CeD patients were more reactive against some Hwp1 peptides than CI patients, and that some deamidated peptides were more reactive than their native analogs. Binding of IgG from CeD patients to Hwp1 peptides was inhibited by γIII gliadin peptides.

Conclusions: Humoral cross-reactivity between Hwp1 and gliadin was observed during CeD and CI. Increased reactivity to Hwp1 deamidated peptide suggests that transglutaminase is involved in this interplay. These results support the hypothesis that CI may trigger CeD onset in genetically-susceptible individuals.

Conflict of interest statement

Competing Interests: Co-author VS is affiliated with the private company Innobiochips. VS participated in the design, data collection, analysis and preparation of the manuscript for publication. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.


Fig 1
Fig 1. (A) Analysis of rNtermHwp1 purification by SDS-PAGE and immunoblotting.
After migration in polyacrylamide gels, only a single band was stained with Coomassie blue in the sample containing purified rNtermHwp1 (lane 1). This band was detected with anti-HisTag (lane 2) and mAb 16B1 (lane 3) antibodies, showing purity of the sample. As deduced from its amino acid sequence, rNtermHwp1 has a theoretical molecular mass of 19.5 kDa but migrates in SDS PAGE as a 45 kDa protein. This molecular mass shift is a result of the rigid coiled structure of Hwp1. (B) Photomicroscopy. (1) Bright field microscopy of C. albicans yeast forms producing germ tubes. (2) Same microscopic field as (1) using immunofluorescence staining with mAb 16B1, which selectively binds to the surface of germ tubes. (C) Reactivity of mAb 16B1 with rNterm Hwp1 by ELISA, expressed as optical density.
Fig 2
Fig 2. Distribution of antibodies in patients with Celiac disease (CeD), invasive Candida infection (CI), and healthy controls (HC).
(A) Anti-Hwp1 IgG; (B) anti-gliadin IgA and IgG; (C) anti-transglutaminase IgG; (D) anti-transglutaminase IgA; (E) anti-deamidated gliadin IgA and IgG. Anti-Hwp1 IgG, anti-gliadin IgA and IgG results are expressed as optical density (450 nm), and anti-transglutaminase IgG and IgA as log of arbitrary units (log AU) and anti-deamidated IgA and IgG results as arbitrary units (AU). The significance of discrimination between the different groups is represented below each figure as the p value.
Fig 3
Fig 3. Kinetics of anti-Hwp1 and anti-gliadin antibody responses.
(A) Anti-Hwp1 and (B) anti-gliadin antibodies in five patients with invasive C. albicans infection (CI) selected for having an increase in anti-Hwp1 IgG during infection. Each number represents a patient and the results are expressed as optical density. The anti-Hwp1 response parallels the anti-gliadin response (Box Plots) except in one patient (no. 5).
Fig 4
Fig 4. Antibody reactivity of sera from Celiac disease (CeD) patients according to adherence to a gluten-free diet (GFD).
(A) Anti-Hwp1 IgG; (B) anti-gliadin IgA and IgG; (C) anti-transglutaminase IgG; (D) anti-transglutaminase IgA; (E) anti-deamidated gliadin IgA and IgG. Anti-Hwp1 IgG, anti-gliadin IgA and IgG results are expressed as optical density (450 nm) anti-tTG IgG as log of arbitrary units (log AU) anti-IgA tTG and anti-deamidated gliadin as arbitrary units (AU). YES: strict adherence to a GFD in the previous 2 months. NO: no strict adherence in the previous 2 months.
Fig 5
Fig 5. Percentage of sera giving positive IgA (A) and IgG (B) signals, respectively, on the 38 synthetic peptides (with color code according to their design*) as a function of the nature of the sera (CeD in green, CI in red, and HC in blue).
* Red: native peptide; blue all Q changed for E; yellow: combinatory changes for one Q/E (Glutamine/Glutamic acid). (C) Reduction of signal resulting from the addition of 10-5 M of a 20-mer sequence mimicking γ gliadin (γ III) to different Hwp1 peptides. (D) Nature of Hwp1 peptides reacting with mAb 16B1 (epitope mapping) (HC in blue, Ac16B1 in grey).
Fig 6
Fig 6. (A) Reduction of fluorescent signal associated with the binding of patient’s IgG to P17 as a function of different molarities of neighboring overlapping peptides P15,16,18 (deamided or not) (B1, B2).
Representative examples of inhibition of CeD serum reactivity to P17 and P18 using the homologous peptides and N1 and γ III gliadin sequences.

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Grant support

This work received the following grant support: Unit U995-2 INSERM- Lille2 University; the European Community’s 7th Framework program (FP7-2007-2013) grant agreement N° Health F2-2010-260338 (ALLFUN); Digest Science Foundation. Co-author VS is affiliated to Innobiochips. Innobiochips provided support in the form of salary for author VS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Innobiochips played an indirect role through the participation of the co-author VS. The specific role of this author is articulated in the ‘author contributions’ section.