Metalloelastase (MMP-12) is upregulated in the gut of pediatric patients with potential celiac disease and in type 1 diabetes.
OBJECTIVE
A slight to moderate increase in autoantibodies to transglutaminase 2 (TG2), but no morphological evidence of villous atrophy to confirm the diagnosis of celiac disease (CD) poses a challenge for clinicians. Our aim was to study the matrix metalloproteinase (MMP) profile, proliferative and apoptotic characteristics of jejunal biopsies obtained from such pediatric patients in order to find markers predictive of early changes in extracellular matrix degrading enzymes in the development of CD.


METHODS
Twenty-eight children with positive screening tests (increase in transglutaminase and/or endomysium antibodies), but minor histological changes in the gut (Marsh grade 0-2), were studied and followed up for 2-3 years. In situ hybridizations for MMP-1, -3 and -12 were performed and sections were immunostained for MMP-19 and -26. Proliferating cells were identified by Ki-67 immunostaining and apoptotic cells using the TUNEL technique.


RESULTS
MMP-12 was detected in macrophages in 16/28 samples and its expression was associated with increased autoantibodies for TG2 and densities of CD3 and gammadelta positive T-cells in the epithelium. The number of stromal MMP-26 positive cells was high in patients with high TG2 titers. Expression of MMP-12, MMP-1 and -3 clustered in children with type 1 diabetes (T1D) and the proportion of apoptotic mucosal cells was increased in patients with T1D compared to the others. When children with CD were compared to those who did not develop it, the numbers of IEL, cryptal Ki-67, CD-3, and MMP-12 positive cells were higher and showed the most significant differences.


CONCLUSIONS
In pediatric patients, increased numbers of MMP-12 positive macrophages in lamina propria associate with high titers of antibodies to TG2 and proness to CD. A stage of mild inflammation may contribute to the upregulation of MMPs in the gut of patients with T1D.
Bister
Ville
V
Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland.
Kolho
Kaija-Leena
KL
Karikoski
Riitta
R
Westerholm-Ormio
Mia
M
Savilahti
Erkki
E
Saarialho-Kere
Ulpu
U
D000293:Adolescent; D000906:Antibodies / Q000097:blood; D016022:Case-Control Studies; D002446:Celiac Disease / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D007583:Jejunum / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000276:immunology; D011503:Transglutaminases / Q000276:immunology
D000906:Antibodies; D011503:Transglutaminases; D020782:Matrix Metalloproteinases