title: Role of intestinal myofibroblasts in HIV-associated intestinal collagen deposition and immune reconstitution following combination antiretroviral therapy.
abstract: OBJECTIVE
  To investigate the potential role of mucosal intestinal myofibroblasts (IMFs) in HIV and associated fibrosis in gut-associated lymphoid tissue.
  
  
  METHODS
  Profibrotic changes within the secondary lymphoid organs and mucosa have been implicated in failed immune reconstitution following effective combination antiretroviral therapy (cART). Microbial translocation is believed to be sustaining these systemic inflammatory pathways. IMFs are nonprofessional antigen-presenting cells with both immunoregulatory and mesenchymal functions that are ideally positioned to respond to translocating microbial antigen.
  
  
  METHODS
  Duodenal biopsies, obtained from patients naive to cART, underwent trichrome staining and were examined for tissue growth factor-beta (TGF-β) expression. Combined immunostaining and second harmonic generation analysis were used to determine IMF activation and collagen deposition. Confocal microscopy was performed to examine IMF activation and Toll-like receptor (TLR)4 expression. Finally, primary IMF cultures were stimulated with lipopolysaccharide to demonstrate the expression of the inflammatory biomarkers.
  
  
  RESULTS
  The expression of the fibrosis-promoting molecule, TGF-β1, is significantly increased in duodenal biopsies from HIV patients naïve to cART, and negatively correlated with subsequent peripheral CD4(+) recovery. The increase in TGF-β1 coincided with an increase in collagen deposition in the duodenal mucosa in the tissue area adjacent to the IMFs. We also observed that IMFs expressed TLR4 and had an activated phenotype since they were positive for fibroblast activation protein. Finally, stimulation of IMFs from HIV patients with TLR4 resulted in significantly increased expression of profibrotic molecules, TGF-β1, and interleukin-6.
  
  
  CONCLUSIONS
  Our data support the hypothesis that activated IMFs may be among the major cells contributing to the profibrotic changes, and thus, the establishment and maintenance of systemic inflammation interfering with immune reconstitution in HIV patients.
authors.affiliation: aUniversity of California Davis Medical Center, Sacramento, California bUniversity of Texas Medical Branch, Galveston, Texas cVeteran's Administration Northern California Healthcare System, Sacramento dCalifornia National Primate Research Center, Davis, California, USA. *David M. Asmuth and Irina V. Pinchuk contributed equally to the writing of this article.
authors.forename: David M
authors.initials: DM
authors.lastname: Asmuth
authors.forename: Irina V
authors.initials: IV
authors.lastname: Pinchuk
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Gracie
authors.initials: G
authors.lastname: Vargas
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Chen
authors.forename: Surinder
authors.initials: S
authors.lastname: Mann
authors.forename: Anthony
authors.initials: A
authors.lastname: Albanese
authors.forename: Zhong-Min
authors.initials: ZM
authors.lastname: Ma
authors.forename: Ramez
authors.initials: R
authors.lastname: Saroufeem
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Melcher
authors.forename: Paolo
authors.initials: P
authors.lastname: Troia-Cancio
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Torok
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Miller
authors.forename: Don W
authors.initials: DW
authors.lastname: Powell
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers; D018791:CD4 Lymphocyte Count; D003094:Collagen / Q000378:metabolism*; D004386:Duodenum / Q000166:cytology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000097:blood*; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D058628:Myofibroblasts / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D003094:Collagen