Mast cells are associated with the onset and progression of celiac disease.
BACKGROUND
Celiac disease (CD) is an immune-mediated disorder characterized by an accumulation of immune cells in the duodenal mucosa as a consequence of both adaptive and innate immune responses to undigested gliadin peptides. Mast cells (MCs) are innate immune cells that are a major source of costimulatory signals and inflammatory mediators in the intestinal mucosa. Although MCs have previously been associated with CD, functional studies have never been performed.


OBJECTIVE
We aimed at evaluating the role of MCs in the pathogenesis of CD.


METHODS
Intestinal biopsy specimens of patients with CD were scored according to the Marsh classification and characterized for leukocyte infiltration and MC distribution. Moreover, MC reactivity to gliadin and its peptides was characterized by using in vitro assays.


RESULTS
Infiltrating MCs were associated with the severity of mucosal damage, and their numbers were increased in patients with higher Marsh scores. MCs were found to directly respond to nonimmunodominant gliadin fragments by releasing proinflammatory mediators. Immunohistochemical characterization of infiltrating MCs and the effects of gliadin peptides on intestinal MCs indicated an increase in proinflammatory MC function in advanced stages of the disease. This was also associated with increased neutrophil accumulation, the prevalence of M1 macrophages, and the severity of tissue damage.


CONCLUSIONS
We provide a description of the progressive stages of CD, in which MCs are the hallmark of the inflammatory process. Thus the view of CD should be revised, and the contribution of MCs in the onset and progression of CD should be reconsidered in developing new therapeutic approaches.
Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
Barbara
B
Frossi
Department of Health Science, University Hospital of Palermo, Palermo, Italy.
Claudio
C
Tripodo
Department of Health Science, University Hospital of Palermo, Palermo, Italy.
Carla
C
Guarnotta
Department of Internal Medicine and Specialist, University Hospital of Palermo, Palermo, Italy.
Antonio
A
Carroccio
Second Unit of Internal Medicine, University of Udine, Udine, Italy.
Marco
M
De Carli
Second Unit of Internal Medicine, University of Udine, Udine, Italy.
Stefano
S
De Carli
Department of Gastroenterology and Digestive Endoscopy, University Hospital of Udine, Udine, Italy.
Marco
M
Marino
Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University Hospital of Florence, Florence, Italy; Tuscany Referral Center for Adult Coeliac Disease, AOU Careggi, Florence, Italy.
Antonino
A
Calabrò
Department of Medical and Biological Sciences, University of Udine, Udine, Italy. Electronic address: carlo.pucillo@uniud.it.
Carlo E
CE
Pucillo
D000818:Animals; D002446:Celiac Disease / Q000276:immunology* / Q000473:pathology*; D015550:Cell Degranulation / Q000276:immunology; D018450:Disease Progression; D005260:Female; D005455:Fluorescent Antibody Technique; D005903:Gliadin / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000276:immunology
D010446:Peptide Fragments; C549457:gliadin p31-43; D005903:Gliadin
Celiac disease; gliadin immunology; mast cell; p31-43 fragment