Emergence of an adaptive immune paradigm to explain celiac disease: a perspective on new evidence and implications for future interventions and diagnosis

ABSTRACT

Introduction

Recent patient studies have shown that gluten-free diet is less effective in treating celiac disease than previously believed, and additionally patients remain vulnerable to gluten-induced acute symptoms and systemic cytokine release. Safe and effective pharmacological adjuncts to gluten-free diet are in preclinical and clinical development. Clear understanding of the pathogenesis of celiac disease is critical for drug target identification, establishing efficacy endpoints and to develop noninvasive biomarkers suitable to monitor and potentially diagnose celiac disease.

Areas covered

The role and clinical effects of CD4+ T cells directed against deamidated gluten in the context of an ‘adaptive immune paradigm’ are reviewed. Alternative hypotheses of gluten toxicity are discussed and contrasted. In the context of recent patient studies, implications of the adaptive immune paradigm for future strategies to prevent, diagnose, and treat celiac disease are outlined.

Expert Opinion

Effective therapeutics for celiac disease are likely to be approved and necessitate a variety of new clinical instruments and tests to stratify patient need, monitor remission, and confirm diagnosis in uncertain cases. Sensitive assessments of CD4+ T cells specific for deamidated gluten are likely to play a central role in clinical management, and to facilitate research and pharmaceutical development.

KEYWORDS:

• Celiac
• T cell
• diagnosis
• treatment
• prevention
• pathogenesis
• pharmaceutical
• interleukin-2

Article highlights

• The recent increase in high-quality translational immunology research motivated by drug development has challenged established understanding of celiac disease, and future studies promise to consolidate clearer understanding of CD4+ T cell function and regulation.

• Conventional histology has substantially underestimated residual intestinal injury in apparently well-controlled celiac disease treated by gluten-free diet alone.

• In patients, CD4+ T cell activation after administering deamidated gluten peptides, and after gluten ingestion is rapid and accounts for early gastrointestinal symptoms that had previously been attributed to innate immune properties of gluten.

• The new and unexpected finding of consistently rapid, and sometimes substantial elevations in plasma cytokines and chemokines, in particular interluekin-2, after gluten ingestion offers a range of new biomarkers to quantify and characterize ‘whole-body’ gluten immunity, but future studies should seek to understand whether T cells in the gut are responsible.

• Reliance on ex vivo, in vitro and non-human studies, and absence of replication studies has led to key aspects of pathogenesis, potential drug targets, and clinical correlates of adaptive immunity driven by CD4+ T cells being overlooked.

• Effective therapeutics for celiac disease are likely to be approved and necessitate a variety of new clinical instruments and tests to stratify patient need, monitor remission, and confirm diagnosis in uncertain cases.

• Sensitive blood-based assessments of CD4+ T cells specific for deamidated gluten are likely to play a central role in clinical management, and to facilitate research and pharmaceutical development.

• There is a pressing need to collate and critically analyse research findings to establish a broadly agreed paradigm on the relationship between biological and chemical effects of gluten and celiac disease.

Declaration of interest

R Anderson is a shareholder and director of Novoviah Pharmaceuticals Pty Ltd., a named inventor of, but has no financial interest in patents relating to celiac disease diagnostics and therapies. R Anderson is a consultant to Takeda Pharmaceutical Company Ltd/Millennium Pharmaceuticals, GSK, Bristol-Myers Squibb Australia Pty Ltd, Allero Therapeutics BV, Kanyos Bio Inc, TregTherapeutics, Inc, Bioniz Therapeutics, Inc, AdAlta, Ltd, Immunic AG, and Atheneum Partners GmbH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.