title: Defective thymopoiesis and poor peripheral homeostatic replenishment of T-helper cells cause T-cell lymphopenia in cirrhosis.
abstract: OBJECTIVE
  Depletion of circulating CD4(+) T-helper (Th) lymphocytes, especially naive Th cells, is common in cirrhosis. Little is known about the pathogenetic mechanisms involved in Th-cell depletion in cirrhosis. We investigated the mechanisms involved in circulating Th-cell lymphopenia in cirrhosis.
  
  
  METHODS
  Circulating naive and memory Th cells were analyzed by flow cytometry in 60 patients with cirrhosis and 40 sex- and age-matched healthy controls. Thymopoiesis, apoptosis, cell activation, and proliferation were assessed through CD31, annexin-V, HLA-DR and Ki-67 expression, respectively. Lipopolysaccharide (LPS)-binding protein (LBP) and spleen size were measured as indicators of bacterial translocation and splenic pooling, respectively.
  
  
  RESULTS
  Compared to controls, patients showed reduced numbers of Th cells involving a greater depletion of the naive than memory Th-cell compartment (2.7- vs. 1.5-fold, respectively). Recent thymic emigrants were diminished (p < 0.01), and each patient had a lower number of CD31(+) naive Th cells than the matched-control. Spontaneous and induced apoptosis (Annexin-V(+)) of Th cells was increased in patients. Activated (HLA-DR(+)) and proliferating (Ki-67(+)) memory Th cells were increased in patients (p < 0.01), and they directly correlated with plasma LBP (p < 0.05) and negatively with naive Th cells (p < 0.01), respectively. Naive Th cells were inversely correlated (p < 0.01) with their frequencies of apoptosis and of activated memory Th cells, LBP, and spleen size. On multivariate analysis, defective thymic generation of naive Th cells, increased memory Th-cell activation, and splenomegaly were independently associated with Th-cell depletion.
  
  
  CONCLUSIONS
  Th-cell immunodeficiency in cirrhosis is explained by a universal defect in thymopoiesis exacerbated by splenic pooling and activation-driven cell-death induced by bacterial translocation.
authors.affiliation: Departamento de Medicina, Universidad de Alcalá, Madrid, Spain.
authors.forename: Margaret
authors.initials: M
authors.lastname: Lario
authors.forename: Leticia
authors.initials: L
authors.lastname: Muñoz
authors.forename: María
authors.initials: M
authors.lastname: Ubeda
authors.forename: María-José
authors.initials: MJ
authors.lastname: Borrero
authors.forename: Javier
authors.initials: J
authors.lastname: Martínez
authors.forename: Jorge
authors.initials: J
authors.lastname: Monserrat
authors.forename: David
authors.initials: D
authors.lastname: Díaz
authors.forename: Melchor
authors.initials: M
authors.lastname: Alvarez-Mon
authors.forename: Agustín
authors.initials: A
authors.lastname: Albillos
mesh_terms: D000209:Acute-Phase Proteins / Q000276:immunology; D017209:Apoptosis; D002352:Carrier Proteins / Q000276:immunology; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D006706:Homeostasis; D006801:Humans; D007156:Immunologic Memory; D008103:Liver Cirrhosis / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008231:Lymphopenia / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D008875:Middle Aged; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011446:Prospective Studies; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000099231:Lipopolysaccharide-Binding Protein
keywords: Bacterial translocation; IGF-l; IQR; LBP; LPS; Naive Th cells; PBMCs; PHA; Peripheral homeostatic proliferation; Recent thymic emigrants; T-cell receptor; T-cytotoxic; T-helper; TCR; TNF-α; Tc; Th; Th-cell depletion; insulin-like growth factor-1; interquartile range; lipopolysaccharide; lipopolysaccharide binding protein; mAbs; monoclonal antibodies; peripheral blood mononuclear cells; phytohemagglutinin; tumor necrosis factor-alpha