title: Dysregulated B-cell TLR2 expression and elevated regulatory B-cell frequency precede the diagnosis of AIDS-related non-Hodgkin lymphoma.
abstract: OBJECTIVE
  In antiretroviral therapy (ART)-treated patients, to determine if AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is preceded by: elevated frequency of potentially malignant abnormal activated/germinal center-like B cells, elevated serum prevalence of B-cell stimulatory Toll-like receptor (TLR) ligands resulting from HIV infection-associated microbial translocation, dysregulated B-cell TLR expression/signaling, and perturbations in the frequency of immunoregulatory cells.
  
  
  METHODS
  A case-control study nested with a cohort study of HIV-infected women.
  
  
  METHODS
  Prediagnostic AIDS-NHL cases (n = 12, collected 1-12 months before diagnosis) and controls (n = 42) from the Women's Interagency HIV Study cohort, were matched for HIV and ART status, age, race, and CD4 lymphocyte count. Serum levels of TLR ligands, the prevalence of malignancy-associated abnormal activated/germinal center-like (CD19CD10CD71CD86AID) B cells, TLR2 expression on B cells, expression of TLR2-modulating micro-RNA, and the frequency of regulatory T and B cells were assessed.
  
  
  RESULTS
  Diagnosis of AIDS-NHL was preceded by a significantly elevated frequency of activated/germinal center-like CD19CD10CD71CD86AID B cells (P = 0.0072), elevated serum prevalence of the TLR2 ligand, and significantly elevated B-cell TLR2 expression (P = 0.0015), positively correlating with the frequency of activated/germinal center-like B cells (rho = 0.7273, P = 0.0144). In cases, a purified subset of activated/germinal center-like B cells exhibited decreased expression of microRNAs that modulate TLR2 signaling, including miR-21, 146a, 146b, and 155. Finally, cases also exhibited significantly elevated frequencies of antitumor immunity inhibitory regulatory B cells (P = 0.0024), but not regulatory T cells.
  
  
  CONCLUSIONS
  Our findings suggest that increased microbial translocation and dysregulated TLR expression/signaling, coupled with an elevated frequency of regulatory B cells, precede the diagnosis of AIDS-NHL in HIV-infected ART-treated patients.
authors.affiliation: aRush University Medical Center bDepartments of Medicine, Stroger Hospital and Rush University, Chicago, Illinois cDepartment of Clinical Pharmacy, University of California San Francisco, San Francisco dCity of Hope National Medical Center, Duarte eUCLA AIDS Institute, University of California, California, USA.
authors.forename: Basile
authors.initials: B
authors.lastname: Siewe
authors.forename: Joey T
authors.initials: JT
authors.lastname: Pham
authors.forename: Mardge
authors.initials: M
authors.lastname: Cohen
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Hessol
authors.forename: Alexandra
authors.initials: A
authors.lastname: Levine
authors.forename: Otoniel
authors.initials: O
authors.lastname: Martinez-Maza
authors.forename: Alan
authors.initials: A
authors.lastname: Landay
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000473:pathology*; D000328:Adult; D016175:B-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D018988:Bacterial Translocation / Q000276:immunology; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D008228:Lymphoma, Non-Hodgkin / Q000175:diagnosis*; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000032:analysis*
chemical_list: D035683:MicroRNAs; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2