Gastrointestinal Autoimmunity Associated With Loss of Central Tolerance to Enteric α-Defensins

Dobeš, Jan; Neuwirth, Aleš; Dobešová, Martina; Vobořil, Matouš; Balounová, Jana; Ballek, Ondřej; Lebl, Jan; Meloni, Antonella; Krohn, Kai; Kluger, Nicolas; Ranki, Annamari; Filipp, Dominik

doi:10.1053/j.gastro.2015.05.009

Cited by 35 publications

(35 citation statements)

References 39 publications

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“…Increasing numbers of observations suggest that gastrointestinal involvement in APECED has been underestimated, and recent data, although very limited, suggest that the composition of the intestinal flora may be altered in the patients (36). The data reported in the present study indicate that AIRE is an important regulator of intestinal homeostasis, although it is likely that the regulation is indirect.…”

Section: Discussionmentioning

confidence: 47%

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

Hetemäki

Jarva

Kluger

et al. 2016

The Journal of Immunology

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Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the AIRE gene. Although mainly an endocrine disease, a substantial fraction of patients have gastrointestinal manifestations. In this study, we have examined the role of anticommensal responses and their regulation. APECED patients had increased levels of Abs against Saccharomyces cerevisiae (p < 0.0001) and against several species of commensal gut bacteria, but not against species predominantly associated with other locations. The anticommensal Ab levels did not correlate with gastrointestinal autoantibodies, neutralizing anti–IL-17 or –IL-22 Abs, or gastrointestinal symptoms, although scarcity of the available clinical data suggests that further study is required. However, the anti–S. cerevisiae Ab levels showed a significant inverse correlation with FOXP3 expression levels in regulatory T cells (Treg), previously shown to be dysfunctional in APECED. The correlation was strongest in the activated CD45RO+ population (ρ = −0.706; p < 0.01). APECED patients also had decreased numbers of FOXP3+ cells in gut biopsies. These results show that APECED patients develop early and sustained responses to gut microbial Ags in a pattern reminiscent of Crohn’s disease. This abnormal immune recognition of gut commensals is linked to a systemic Treg defect, which is also reflected as a local decrease of gut-associated Treg. To our knowledge, these data are the first to show dysregulated responses to non-self commensal Ags in APECED and indicate that AIRE contributes to the regulation of gut homeostasis, at least indirectly. The data also raise the possibility of persistent microbial stimulation as a contributing factor in the pathogenesis of APECED.

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Section: Discussionmentioning

confidence: 47%

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

Hetemäki

Jarva

Kluger

et al. 2016

The Journal of Immunology

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“…This is the first report on the oral microbiota in APS-1, and only a few studies have investigated the gut microbiota in patients [17,22,23]. A comparative analysis of the intestinal microbiota of APS-1 patients with gastrointestinal manifestations showed significant enrichment of segmented filamentous bacteria [17], which are Gram-positive commensal bacteria with the potential to adhere to epithelial cells and induce T helper (Th) 17 responses.…”

Section: Discussionmentioning

confidence: 99%

“…A comparative analysis of the intestinal microbiota of APS-1 patients with gastrointestinal manifestations showed significant enrichment of segmented filamentous bacteria [17], which are Gram-positive commensal bacteria with the potential to adhere to epithelial cells and induce T helper (Th) 17 responses. Another study reported that APS-1 patients develop early and sustained responses to gut microbial antigens reminiscent to Crohn’s disease [23] linked to defects in Tregs.…”

Section: Discussionmentioning

confidence: 99%

“…These oral manifestations probably interfere with the homeostasis of the oral microbiota. Furthermore, autoimmunity against defensins and other antimicrobial substances as observed in APS-1 could change the microbiota [17]. Reduced salivary flow rate changes the oral microbiota [18] and in a study of patients with severe Sjögren’s syndrome Streptococcus salivarius, Neisseria pharyngis, Veillonella species, and Micrococcus mucilaginosus were reduced and the number of Staphylococcus aureus and Candida species were increased compared to healthy controls [19].…”

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confidence: 99%

“…In APS-1, no information exists regarding the oral microbiota and only a few studies of the gut microbiota have been reported [17,22,23]. In this study, we characterized the bacterial profile in whole unstimulated saliva of patients by high throughput sequencing, a technique which recovers both cultivated and not-yet-cultivated bacteria, thus giving an in-depth overview of bacteria present.…”

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Oral microbiota in autoimmune polyendocrine syndrome type 1

Bruserud

Siddiqui

Marthinussen

et al. 2018

Journal of Oral Microbiology

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Background: Autoimmune polyendocrine syndrome type-1 (APS-1) is a rare, childhood onset disease caused by mutations in the Autoimmune Regulator gene. The phenotypic expression is highly variable and includes disease manifestations in the oral cavity, including mucocutaneous candidiasis. Increasing evidence suggests a potential role of the skin, oral and gut microbiotas in the pathogenesis of autoimmunity. To date, no information exists regarding the oral microbiota in APS-1. Objective: To assess the bacterial microbiota of whole saliva in APS-1 patients by using high throughput sequencing. Design: Whole unstimulated saliva was collected from 10 APS-1 patients and 17 healthy controls and examined by high throughput sequencing of the hypervariable region V1-V2 of 16S rRNA using the 454 GS Junior system. Metastats (http://cbcb.umd.edu/software/metastats) was used to analyse the pyrosequencing reads. Results: A reduction in the total number of bacterial genera and species was detected in APS-1 compared to healthy controls. The proportion of the major phyla Firmicutes was higher (60% vs 41%, p = 0.002) and Bacteroidetes lower (15% vs 28%, p = 0.007) in APS-1 compared to healthy controls. On the genus level, Streptococcus and Gemella were prevalent in APS-1. Conclusion: Our findings indicate a significantly altered oral microbiota in APS-1.

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