A Human Autoimmune Organoid Model Reveals the Role of Interleukin-7 in Coeliac Disease Pathogenesis

핵심 개념

The generation of air-liquid interface duodenal organoids from coeliac disease patient biopsies enables the study of gluten-induced autoimmune responses and the identification of interleukin-7 as a key pathogenic modulator in coeliac disease.

초록

The researchers developed an in vitro model of coeliac disease using air-liquid interface (ALI) duodenal organoids derived from endoscopic biopsies of coeliac disease patients. These organoids preserved the epithelium alongside native mesenchyme and tissue-resident immune cells, allowing for the study of the complex autoimmune interactions in coeliac disease.

The key findings are:

1. The immune diversity of the ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells, and myeloid cells, with extensive T-cell and B-cell receptor repertoires.
2. HLA-DQ2.5-restricted gluten peptides selectively induced epithelial destruction in HLA-DQ2.5-expressing organoids derived from coeliac disease patients, which was antagonized by blocking MHC-II or NKG2C/D.
3. Gluten epitopes stimulated a coeliac disease organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production.
4. Functional studies in coeliac disease organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8+ T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction.
5. Endogenous IL-7 was markedly upregulated in patient biopsies from active coeliac disease compared to remission disease from gluten-free diets, predominantly in lamina propria mesenchyme.

This human in vitro coeliac disease model recapitulates gluten-dependent pathology, enables mechanistic investigation, and establishes a proof of principle for the organoid modeling of autoimmunity.

통계

The immune diversity of the ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells, and myeloid cells.
Endogenous IL-7 was markedly upregulated in patient biopsies from active coeliac disease compared to remission disease from gluten-free diets.

인용구

"HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D."
"Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production."
"Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8+ T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction."

핵심 통찰 요약

A human autoimmune organoid model reveals IL-7 function in coeliac disease - Nature

by Antó... 게시일 www.nature.com 07-24-2024

https://www.nature.com/articles/s41586-024-07716-2

더 깊은 질문

How can the insights from this coeliac disease organoid model be leveraged to develop novel therapeutic interventions targeting the IL-7 pathway?

The insights gained from this coeliac disease organoid model provide a valuable platform for exploring novel therapeutic interventions targeting the IL-7 pathway. Since IL-7 has been identified as a gluten-inducible pathogenic modulator that plays a crucial role in regulating CD8+ T-cell NKG2C/D expression and promoting epithelial destruction in CeD, targeting this pathway could offer promising treatment strategies. By understanding the specific mechanisms through which IL-7 influences immune responses and epithelial damage in CeD organoids, researchers can develop targeted therapies that aim to modulate IL-7 signaling. This could involve the development of IL-7 inhibitors or antagonists to disrupt the IL-7 pathway and prevent the destructive immune responses triggered by gluten peptides in CeD patients. Additionally, the organoid model can be used to screen and test potential therapeutic compounds that target IL-7 or its downstream effectors, providing a more efficient and accurate way to identify effective treatments for CeD.

What are the potential limitations of this in vitro model in fully recapitulating the complex in vivo pathogenesis of coeliac disease?

While the in vitro organoid model of coeliac disease offers significant advantages in studying disease mechanisms and immune responses, there are several limitations that need to be considered when interpreting the results. One major limitation is the complexity of the in vivo microenvironment that cannot be fully replicated in an in vitro setting. The organoid model may lack certain components of the immune system present in the human body, such as the systemic circulation, lymphatic system, and interactions with other organs. This could impact the immune responses and inflammatory processes observed in the organoids, potentially leading to differences in disease progression and outcomes compared to in vivo conditions. Additionally, the organoid model may not fully capture the dynamic and multifaceted interactions between different cell types, signaling pathways, and environmental factors that contribute to the pathogenesis of coeliac disease. Therefore, while the organoid model provides valuable insights into disease mechanisms, researchers should interpret the results with caution and validate findings in animal models or patient samples to ensure their relevance to the in vivo context.

Given the broader implications of this organoid technology, how can it be adapted to study other autoimmune disorders and facilitate the discovery of disease mechanisms and therapeutic targets?

The organoid technology developed for studying coeliac disease can be adapted and applied to investigate other autoimmune disorders, offering a versatile platform for exploring disease mechanisms and identifying therapeutic targets. By utilizing patient-derived tissues and maintaining the complex interactions between epithelial cells, immune cells, and stromal components in organoids, researchers can create disease-specific models that closely mimic the pathophysiology of various autoimmune conditions. This approach enables the study of immune responses, inflammatory processes, and tissue damage in a controlled and reproducible environment, providing valuable insights into the underlying mechanisms of autoimmune diseases. Furthermore, the organoid technology can be used to screen potential therapeutic compounds, test drug efficacy, and personalize treatment approaches based on individual patient responses. By expanding the application of organoids to different autoimmune disorders, researchers can accelerate the discovery of novel therapeutic targets, improve drug development pipelines, and advance precision medicine strategies for treating autoimmune diseases.