Antibody Linked to Celiac Disease That Does Not Respond To Gluten-Free Diet

A new study, with contributions made from two CDF Medical Advisory Board Members, Martin Kagnoff and Joseph A. Murray, has identified antibody biomarkers that can be potentially used to diagnose nonresponsive celiac disease.

Celiac disease (CD) is an autoimmune condition where those genetically susceptible individuals with the disease have an immune system that damages the intestines in reaction to gluten, a protein found in wheat, or similar proteins in rye and barley. Currently, the only effective treatment for CD is a strict gluten-free diet for life. However, not every CD patient responds to a gluten-free diet. An estimated 10-19% of these patients have non-responsive CD (NRCD), where the intestinal lining damaged by the immune system does not recover even after a year of a gluten-free diet.

The most common reason for NRCD is when the gluten-free diet is not being followed strictly enough (36-45%). For those who have NRCD and do follow the strict diet, their poor response may be caused by other coexisting conditions like irritable bowel syndrome, lactose intolerance, and small intestine bacterial overgrowth, or by refractory CD (RCD).

Refractory CD is a rare version of CD occurring in about 4% of CD patients where a strict gluten-free diet doesn’t lead to intestinal healing and recovery and all other possible causes such as accidental exposure to gluten and coexisting conditions have been ruled out. These patients are typically treated with steroids and immunosuppressants.

The usual serological assays used to test for CD are for autoantibodies against tissue transglutaminase (tTG) or endomysial tissue (EMA). These antibodies dissipate after the patient is on a gluten-free diet, but previous studies have found no link between the disappearance of tTG and EMA antibodies and intestinal recovery.

The need for a non-invasive method for tracking intestinal recovery is apparent, which was exactly the purpose of a recent study published in Alimentary Pharmacology & Therapeutics in its February issue of 2014. The study, titled “Persistence of Elevated Deamidated Gliadin Peptide Antibodies on a Gluten-Free Diet Indicates Nonresponsive Celiac Disease” relied on a technique called bacterial display coupled with fluorescence-activated cell sorting (FACS).

The authors, Bradley N. Spatola, Katri Kaukinen, Pekka Collin, Martin Kagnoff, and Patrick S. Daugherty got their methodology from a previous paper published a year earlier in Analytical Chemistry. That paper, titled “Antibody Repertoire Profiling Using Bacterial Display Identifies Reactivity Signatures of Celiac Disease”, was written by many of the same authors, and describes how to quantitatively identify peptide mimotopes — small protein chains that mimic the antigen surface that antibodies typically bind — from a random peptide library that captures disease-specific antibodies present in a patient’s blood serum.

In this most recent study, the authors compared three groups: 15 patients with NRCD, 45 patients with normal and responsive CD, as well as a non-CD control group. After multiple rounds of sorting were completed, several suitable peptide sequences were found.  They determined these peptides were mimicking deamidated gliadin peptide (dGP) and concluded that dGP IgG antibody assays would be effective for testing CD patients for NRCD.

For the NRCD and responsive CD groups, the sensitivity of the assay was 87% while the specificity was 89%. The assay still needs to be tested in larger groups to more accurately determine its positive and negative predictive values.

The authors also found that the results of the assay correlated with how badly the patient’s intestines were damaged when categorized by Marsh classifications. The difference in dGP IgG titres was not statistically significant for a one level difference like between Marsh 0 and Marsh 1 or Marsh 2 and Marsh 3a/3b, but for a two or more level difference, like between Marsh 0 and Marsh 2 or Marsh 1 and Marsh 3a/3b, results were significant. When comparing fully recovered Marsh 0 patients with Marsh 3c NRCD patients, the accuracy in classifying patients of the assay improves to greater than 90%.

One explanation the authors offer for why antibodies for dGP stay in the blood for so long in NRCD patients is “the presence of T-cell clones that have evolved antigen independence and continue to stimulate dGP antibody-secreting plasma cells.” This phenomenon, previously studied, has shown that even when a particular antigen has long been absent, memory cells in the immune system can be maintained for years. It’s also been found that plasma cells can secrete antibodies even after the memory cells have disappeared. However, until NRCD has been further studied, the exact mechanism for the endurance of IgG antibodies for dGP will remain unknown.

From these promising results, the authors suggest including the assay for IgG dGP antibodies in the diagnostic algorithm for celiac disease follow-up. After one year or more on a strict gluten-free diet the physician should order dGP IgG serology and if it’s negative, NRCD is unlikely and normal follow-up can resume. If it’s positive, and adherence to the gluten-free diet is confirmed, the patient should be tested again several months later. If the patient still has positive dGP IgG serology, NRCD is likely and a duodenal biopsy to confirm poor intestinal response can be used to confirm.

With IgG DGP serology, physicians can more efficiently detect and diagnose NRCD, which can require different treatments than responsive CD and can help reduce the risk for mortality and other diseases associated with NRCD.

 

The papers discussed in this article, “Persistence of Elevated Deamidated Gliadin Peptide Antibodies On a Gluten-Free Diet Indicates Nonresponsive Celiac Disease” and “Antibody Repertoire Profiling Using Bacterial Display Identifies Reactivity Signatures of Celiac Disease” can be found here and here, respectively.