title: Structural and Functional Changes in the Tight Junctions of Asymptomatic and Serology-negative First-degree Relatives of Patients With Celiac Disease.
abstract: Ten to 15% of first-degree relatives (FDRs) of celiac disease (CeD) patients develop CeD. Although intestinal barrier functions (intestinal permeability) are abnormal in the subset of serology-negative FDRs, what leads to the abnormal barrier function is not known.
  
  
  
  To study the ultrastructure and functions of tight junctions in serology-negative FDRs of CeD patients.
  
  
  
  The intestinal permeability was measured in 97 asymptomatic and anti-tissue transglutaminase antibody (anti-tTG Ab)-negative FDRs (using the lactulose mannitol ratio) and in 75 controls. The ultrastructure of tight junctions using transmission electron microscopy, and the expression of key tight junction proteins (claudin-2, claudin-3, occludin, JAM-A, and ZO-1) and zonulin using real-time PCR and immunohistochemistry were assessed in anti-tTG Ab-negative, HLA-DQ2/-DQ8-positive FDRs having normal villi and in disease controls. In addition, the serum zonulin level was measured in 172 anti-tTG Ab-negative FDRs and 198 controls.
  
  
  
  The intestinal permeability was significantly increased in FDRs than in controls. Ultrastructural abnormalities such as dilatation of the tight junction (P=0.004) and loss of the pentalaminar structure (P=0.001) were more common in FDRs than in disease controls. There was significant underexpression of tight junction proteins ZO-1 (P=0.040) and occludin (P=0.041) in FDRs. There was no significant difference in the serum zonulin level between FDRs and controls (P=0.154).
  
  
  
  Even asymptomatic, anti-tTG-Ab-negative FDRs with a normal villous histology have both ultrastructural and functional abnormalities in tight junctions. These findings are indirect evidence of the presence of tight junction abnormalities before the onset of the disease and may have therapeutic implications.
authors.affiliation: Departments of *Gastroenterology and Human Nutrition ‡Anatomy †Biostatistics §Pathology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Asha
authors.initials: A
authors.lastname: Mishra
authors.forename: Shyam
authors.initials: S
authors.lastname: Prakash
authors.forename: Vishnubhatla
authors.initials: V
authors.lastname: Sreenivas
authors.forename: Taposh K
authors.initials: TK
authors.lastname: Das
authors.forename: Vineet
authors.initials: V
authors.lastname: Ahuja
authors.forename: Siddhartha D
authors.initials: SD
authors.lastname: Gupta
authors.forename: Govind K
authors.initials: GK
authors.lastname: Makharia
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002446:Celiac Disease / Q000473:pathology*; D002772:Cholera Toxin / Q000378:metabolism*; D005192:Family Health; D005260:Female; D006242:Haptoglobins; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D062793:Occludin / Q000378:metabolism / Q000648:ultrastructure; D010539:Permeability; D011498:Protein Precursors; D060888:Real-Time Polymerase Chain Reaction; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure; D055815:Young Adult; D062826:Zonula Occludens-1 Protein / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D006242:Haptoglobins; D062793:Occludin; D011498:Protein Precursors; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C408043:zonulin; D002772:Cholera Toxin