Anti-tissue transglutaminase antibodies from celiac patients are responsible for trophoblast damage via apoptosis in vitro.
OBJECTIVE
The association between maternal celiac disease (CD) and both reduced fertility and increased risk of adverse pregnancy-related events has been long documented. However, no evidences are available regarding the pathogenic mechanisms of this link. The aim of this study was to determine whether anti-tissue transglutaminase (anti-tTG) antibodies are involved in the damage of trophoblastic cells in vitro.


METHODS
Human primary trophoblastic cells, isolated from term placenta, were exposed to anti-tTG immunoglobulin G (IgG) antibodies, both commercially available and separated from sera of three untreated celiac women. The ability of anti-tTG antibodies to bind to trophoblastic cells, invasiveness of placental cells through a layer of extracellular matrix, and the activity of cellular matrix metalloprotease (MMP) and cellular apoptosis were evaluated, as indicators of trophoblast damage, by TdT-mediated dUTP digoxigenin nick end labeling (TUNEL) and annexin V expression.


RESULTS
Anti-tTG IgG showed a specific dose- and time-dependent binding to human trophoblast. In addition, trophoblastic cells, after being exposed to anti-tTG IgG antibodies, both commercially available and separated from sera of celiac women, showed an impaired invasiveness, a decreased activity of cellular MMP, and a greater percentage of TUNEL positivity and annexin V positivity.


CONCLUSIONS
We showed that the binding of anti-tTG antibodies to trophoblast might represent a key mechanism by which the embryo implantation and pregnancy outcome are impaired in untreated celiac pregnant women. Because healthy trophoblast development is essential for placental and fetal development, these data provide a novel mechanism for CD-induced infertility, early pregnancy loss, and intrauterine growth retardation.
Di Simone
Nicoletta
N
Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Rome, Italy.
Silano
Marco
M
Castellani
Roberta
R
Di Nicuolo
Fiorella
F
D'Alessio
Maria C
MC
Franceschi
Francesco
F
Tritarelli
Alessandra
A
Leone
Antonio M
AM
Tersigni
Chiara
C
Gasbarrini
Giovanni
G
Silveri
Nicolò G
NG
Caruso
Alessandro
A
Gasbarrini
Antonio
A
D000888:Antibodies, Anti-Idiotypic; D017209:Apoptosis / Q000276:immunology*; D002446:Celiac Disease / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D019204:GTP-Binding Proteins; D006801:Humans; D020287:In Situ Nick-End Labeling; D010920:Placenta / Q000276:immunology / Q000473:pathology; D011247:Pregnancy; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000276:immunology*; D014327:Trophoblasts / Q000276:immunology* / Q000473:pathology
D000888:Antibodies, Anti-Idiotypic; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins