Transient coeliac disease autoimmunity: natural history and immunological mechanisms

Grant: 002/2024

• Title: Transient coeliac disease autoimmunity: natural history and immunological mechanisms.
• Duration: 2 Years Project
• Principal Investigator: Roberta Mandile, University Federico II, Naples, Italy

THE STUDY

Background

Celiac disease (CD) is characterized by highly specific autoatibodies directed against transglutaminase 2 (anti-TG2), found both in blood and small intestine, where they are produced. They disappear from serum after the beginning of a gluten-free diet (GFD) and they are routinely used in clinical practice to monitor patients in remission. However, spontaneous disappearance of anti-TG2, despite a gluten containing diet, has been reported in a subgroup of patients with potential celiac
disease (PCD), a condition characterized by the presence of autoantibodies in sera and a normal mucosal architecture at the duodenal biopsy.

Hypothesis, Rationale and Aims

The observation that patients who immunologically recognize gluten can spontaneously stop producing autoantibodies despite on a gluten free diet suggests that  autoimmunity/loss of tolerance can be a reversible process in some cases.

Aim 1. Characterize long term natural history of patients that stop producing anti-TG2 overtime
1.1 Define the presence of biomarkers able to predict since their first observation future disappearance of CD-associated autoantibodies
1.2 Demonstrate the duration of serum anti-TG2 negativity and the nutritional status at the longest follow-up available

Aim 2. Investigate immunological features that sustain this condition by:

2.1 the presence of anti-TG2 antibodies in the intestinal mucosa despite disappearance in sera
2.2 the presence of immunological stigmata of CD still present in the biopsies despite anti-TG2 seronegativization (e.g. increased density of γδ intraepithelial lymphocytes)
2.3 the presence (or not), the phenotype and the secretory profile of gluten specific T cells at the time of anti-TG2 seronegativization.

Research Plan (Experimental design and Methodologies)

To test our hypothesis, we will take advantage of a very big longitudinal cohort of asymptomatic PCD patients prospectively followed-up on a gluten containing diet with periodical serological and endoscopic evaluations. Those who remain “potential” (no development of symptoms/villous atrophy) are divided in two groups:

1. a) PCD who show normalization of anti-TG2 levels overtime, seronegativized PCD (PCD-neg);
2. b) PCD who show persistently increased levels of anti-TG2 overtime, persistently positive (PCD-pp).

We will compare clinical, genetical (HLA haplotype), histological (Marsh grade and histomorphometry) and immunohistochemical (CD3+, γδ+, CD25 + cells) features as well as the levels of anti-TG2 antibodies both on sera and on the intestinal mucosa between PCD-neg and PCD-pp, in order to evaluate if there is any clue at the time of their first observation that predicts anti-TG2 disappearance overtime.

In a subset of 20 PCD-neg patients we will repeat the analysis of intestinal biopsies at the time of anti-TG2 seronegativization looking for the persistence (or not) of immunological stigmata of CD, including gluten-specific T cell lines and clones.

Expected results and Impact on Celiac disease

We expect that PCD-neg patients maintain some stigmata of the disease at the intestinal level, but may activate immunoregulatory pathways able to shift gluten specific T cells from a proinflammatory to a regulatory direction. The comprehension of the mechanisms behind this could pave the way to interventions aimed to stop the progression of the disease. Moreover, from a clinical point of view, it is important to understand if these patients are still at risk to later develop the disease or the autoimmune process is completely and permanently reverted.