This problem focusses on a subgroup of immune cells belonging to the innate immune system, neutrophils, that are involved in the first phase of inflammation by their quick recruitment to the site of injury, in order to keep damage local and under control. For this purpose these cells interact with the other immune cells. In celiac disease, gluten-containing cereals (wheat, rye, barley) trigger an auto-immune response with intestinal damage as a result. Diagnosis is currently made by serological testing of celiac specific markers in the peripheral blood. Positive serological test needs confirmation by examining an intestinal biopsy for signs of gut damage. Once the diagnosis is made, the only therapy now available is a life-long strict gluten-free diet.
In recent years, clinic recognizes patients with another gluten-related disorder, non-celiac gluten sensitivity. Individuals present similar symptoms as celiac patients, but diagnosis for celiac disease is excluded. Gluten consumption impacts the health of a substantial number of people.
The peptide in gluten that is causing the trigger to disease is gliadin. In experimental setting we have shown that gliadin peptides appear to have chemoattractant properties for neutrophils similar to peptides derived from bacteria. Moreover, the cells use the same receptor to sense bacterial peptides and gliadin peptides. This means that neutrophils sense gliadin as if it were a bacteria and migrate in the direction of it. This migratory behavior to a stimulus is essential for the recruitment of neutrophils.
This response was studied in neutrophils from individuals who do not have problems when eating gluten. In a preliminary study we observed that neutrophils from celiac patients respond differently to gliadin with respect to their migratory behavior.
For many people gluten consumption leads to health concerns. Knowledge about the pathogenesis of these disorders will provide possibilities to advance in understanding of pathogenesis, prevention, diagnosis and eventually treatment. The few information until now suggests that immune activation in non-celiac gluten sensitivity is mostly confined to activation of the innate immune system. Neutrophil function therefore will help us to find extended information on the early steps in celiac disease pathogenesis as well as information on non-celiac gluten sensitivity.
Novel diagnostic tools that are more rapid, less invasive and less costly are patient-friendly, medically relevant and economically advantageous. Since biopsy is an elaborate, costly and for the patient unpleasant intervention, a novel assay that combines improvements at level of invasiveness, time and cost, provided that such assay can confirm serology with equivalent power will be of great benefit for society.
This study was concerned with the following objectives:
-To obtain extended basic knowledge about the neutrophil subset and its role in gluten-related disorders, Celiac disease and non-celiac gluten sensitivity.
-To apply this knowledge in the development of a novel, rapid and less invasive diagnostic tool for Celiac disease and possibly non-celiac gluten sensitivity.
Conclusions of the action
Due to the corona outbreak we have not been able to perform the clinical part of the study. Since the beginning of the year, it has not been allowed to ask individuals to volunteer for this study and to draw blood for the experiments. The work of the Medical Ethical Committee (MEtC) that has the task to approve the design of the clinical approaches and therewith the inclusion of volunteers or patients for experimental studies as proposed in this grant, has been postponed since all activity on clinical studies has been postponed. Likewise, the laboratories were only open to routine diagnostics but closed for the research that is needed to answer the questions for this study.
During Summer and before the second wave of corona, we have been working on approval of MEtC and the approval phase is in the last episode. Still, however, with the second wave ongoing and the slow and even stagnating decrease of the number of infections, we have no perspective on when we will be able to ask volunteers to participate in the study. It may not be feasible to conduct this project prior to vaccination to corona.
We have the experimental design that we are going to employ and have a thorough plan how to perform the study once it can start. Despite the delays with regard to possibility to make use of laboratory equipment for experimental studies as described in this proposal, we have been able to start preparation of the stimuli for the in vitro experiments. An ultimate check will be done in the weeks to come and with that the stimuli will be ready for use.
