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Introduction
Overview - Microbiome and Development of Adaptive Immunity
Gut Microbiome and Immune Dysregulation in CVID
The Gut Microbiome in APECED
PATIENTS WITH CTLA-4 INSUFFICIENCY HAVE DISTINCT INTESTINAL MICROBIOME SIGNATURES
Abstract
Background and Aims
CTLA-4 insufficiency is a monogenetic condition caused by heterozygous mutations in CTLA4 that is characterized by immune dysregulation, including autoimmune enteropathy. The disease presents with a reduced (~70%) penetrance, so we hypothesized that affected and unaffected CTLA4 mutation carriers have distinct intestinal microbiome signatures compared to each other and to healthy controls, and that the microbiome may identify patients with disease-related organ involvements.
Methods
We collected stool samples and clinical data from healthy donors (HDs, n=178), affected (n=33) and unaffected CTLA-4 patients (n=8) and performed 16S rRNA sequencing. We also compared samples from patients with and without a history of specific organ involvement (enteropathy, splenomegaly, lymphadenopathy, GLILD).
Results
Affected patients had a significantly decreased alpha-diversity (Shannon), compared to unaffected carriers and HDs. Moreover, CTLA-4 patients with a history of specific organ involvement had decreased alpha-diversity (not significant). Additionally, we identified significantly different taxa in affected and unaffected CTLA-4 mutation carriers. We found that the Proteobacteria were significantly enriched in affected patients, compared to unaffected carriers and controls. Furthermore, we could identify various taxa that are the main drivers of the differences between affected and unaffected mutation carriers. In affected individuals Veillonella, Escherichia, and Haemophilus were enriched, in unaffected individuals Ruminococcacease, Tenericutes, and Lachnospiraceae were expanded. Some of these taxa are known to be correlated with inflammatory bowel disease.
Conclusions
Here we show, that affected CTLA4 mutation carriers have distinct intestinal microbiome structures, and that the microbiome may be a relevant disease modifier. Our results could serve as a basis for further interventional studies.
INTERFERON-DRIVEN IMMUNE DYSREGULATION IN COMMON VARIABLE IMMUNODEFICIENCY ASSOCIATED ENTEROPATHY IS EXACERBATED BY NOROVIRUS INFECTION
Abstract
Background and Aims
About 15% of patients with common variable immunodeficiency (CVID) develop a small intestinal enteropathy, resembling celiac disease with regard to histopathology but evolves from a distinct and poorly defined pathogenesis that has been linked in some cases to chronic norovirus infection. While Interferon-driven inflammation is known as a prominent feature of CVID enteropathy, it still remains unknownit still remains unknown whether norovirus (NV) infection may contribute to it.
Methods
Duodenal biopsies of CVID patients, stratified according to enteropathy with and without villous atrophy (VA), the presence of IgA+ plasma cells and the NV status were investigated by flow-cytometry, multi-epitope-ligand cartography (MELC), bulk RNA sequencing and RT-qPCR.
Results
In our study the development of severe enteropathy in forms of VA, was connected with the lack of intestinal (IgA+) plasma cells (PC), a T helper 1 (TH1)/T helper 17 (TH17) cell imbalance and increased recruitment of Granzyme+CD8+ T cells and pro-inflammatory macrophages to the affected site. An Interferon (IFN)-signature occurred in early enteropathy stages and aggravated with increasing severity of histopathological changes. Chronic NV infection exacerbated this signature when compared to stage-matched NV-negative samples.
Conclusions
Our study suggests that IFN signaling and T-cell cytotoxicity are driving mechanisms during the development of CVID enteropathy. NV infection induces locally high IFN-driven inflammation, usually only seen in VA, already at less severe histological stages. Thus, revealing the impact of the different drivers of the pathological IFN signature may allow for more targeted treatment strategies in CVID enteropathy and supports the goal of viral elimination.