Neutrophil recruitment and barrier impairment in celiac disease: a genomic study.
OBJECTIVE
Celiac disease is an enteropathy featuring villous atrophy, crypt hyperplasia, and lymphocytosis. Tissue remodeling is driven by an inflammatory reaction to gluten in genetically susceptible individuals. The adaptive pathway is considered the major immune response but recent evidence has indicated the involvement of innate immunity as well. To assess the contribution of either immune response we performed global gene expression profiling of the regenerating mucosa.


METHODS
Microarray hybridizations were performed with biopsy samples from 13 untreated patients, 31 patients on a gluten-free diet in various stages of remission, and 21 controls. Additional data were generated using low-density array and conventional quantitative reverse-transcription polymerase chain reaction, and immunohistochemistry.


RESULTS
A total of 108 differentially expressed immune-related genes were identified (50 innate, 43 adaptive, 9 both innate/adaptive, and 6 immunoregulatory). Expression levels showed a gradual change as opposed to the discrete histological transitions. In addition to details provided on the adaptive and innate immune pathways used, we observed a chronic recruitment of activated neutrophils. Neutrophil involvement was unabated in otherwise completely normalized remission patients.


CONCLUSIONS
We observed a contribution of both the innate and adaptive immune response in celiac disease pathogenesis. The discrepancy between the histological classification and the observed incremental change in immune-gene expression may have consequences for current diagnostic inclusion criteria. Enhanced neutrophil infiltration in both active and remission patients points to a genetic impairment of the intestinal barrier that may contribute to the cause rather than the consequence of celiac disease.
Diosdado
Begoña
B
Department of Medical Genetics, Division of Biomedical Genetics, University Medical Center, Utrecht, The Netherlands.
van Bakel
Harm
H
Strengman
Eric
E
Franke
Lude
L
van Oort
Erica
E
Mulder
Chris J
CJ
Wijmenga
Cisca
C
Wapenaar
Martin C
MC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D007408:Intestinal Absorption / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020556:Neutrophil Infiltration / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000502:physiology