title: Mucosal plasma cell barrier disruption during intestine transplant rejection.
abstract: BACKGROUND
  Intestinal allograft mucosa undergoes repopulation with host immunocytes. However, critical changes within key immunocyte subsets are not known.
  
  
  METHODS
  To explain acute cellular rejection after intestine transplantation (ITx) on the basis of altered mucosal immunocytes, rejecting and rejection-free ITx allografts (n=17) were compared with genome-wide expression arrays. Cells identified by cell/lineage-specific genes were evaluated by immunohistochemistry. The corresponding phenotype and donor-specific alloreactivity were characterized in peripheral blood. Time-dependent changes in candidate cell(s) were evaluated in biopsies from an independent cohort of 12 children with ITx.
  
  
  RESULTS
  Among 107 differentially expressed genes, three B-cell lineage-specific genes, CCR10, STAP1, and IGLL1, were down-regulated during ITx rejection and were selected for and achieved technical quantitative reverse transcription polymerase chain reaction replication. Down-regulation of the immunoglobulin (Ig)A+ plasma cell-specific CCR10 gene correlated with decreased mature mucosal CD138+ plasma cell numbers in corresponding biopsy specimens (r=0.761, P=0.006) and inversely correlated with enhanced alloreactivity of CD154+ T-cytotoxic memory cells (r=-0.56, P=0.031), which predict acute cellular rejection with high sensitivity. An independent cohort of serial biopsy specimens from 12 ITx recipients (1) confirmed relative CD138+ plasma cell depletion during rejection (P=0.042) and (2) showed increased IgG+-to-IgA+ cell ratios within 4 hr of reperfusion in rejection-prone allografts (P=0.037) and during ITx rejection (P=0.025), compared with rejection-free allografts. No differences existed late after ITx. Increased peripheral IgG+ CD27+ CD19+ memory B cells (P=0.004) were seen during ITx rejection in archived peripheral blood lymphocyte from test and replication cohorts.
  
  
  CONCLUSIONS
  Protracted depletion of the mucosal CD138+ plasma cell barrier and early mucosal infiltration with memory IgG+ cells characterize the rejection-prone intestine allograft. Mucosal IgA+ plasma cell barrier reconstitution may augur resolution of ITx rejection.
authors.affiliation: Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, USA.
authors.forename: Mylarappa
authors.initials: M
authors.lastname: Ningappa
authors.forename: Chethan
authors.initials: C
authors.lastname: Ashokkumar
authors.forename: Sarangarajan
authors.initials: S
authors.lastname: Ranganathan
authors.forename: Lori
authors.initials: L
authors.lastname: Schmitt
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.forename: Qing
authors.initials: Q
authors.lastname: Sun
authors.forename: Maria
authors.initials: M
authors.lastname: Branca
authors.forename: George
authors.initials: G
authors.lastname: Mazariegos
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
authors.forename: Kareem
authors.initials: K
authors.lastname: Abu-Elmagd
authors.forename: Robert
authors.initials: R
authors.lastname: Squires
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rudolph
authors.forename: Feras
authors.initials: F
authors.lastname: Alissa
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sindhi
mesh_terms: D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001706:Biopsy; D019070:Cell Lineage / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007146:Immunoglobulin lambda-Chains / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology*; D007422:Intestines / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D008297:Male; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D054447:Receptors, CCR10 / Q000235:genetics; D053668:Syndecan-1 / Q000378:metabolism; D014184:Transplantation, Homologous; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018941:Antigens, CD19; C515706:CCR10 protein, human; D007146:Immunoglobulin lambda-Chains; D054447:Receptors, CCR10; C400186:STAP1 protein, human; D053668:Syndecan-1; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7