title: Increased TLR4 expression and downstream cytokine production in immunosuppressed adults compared to non-immunosuppressed adults.
abstract: BACKGROUND
  An increasing number of patients have medical conditions with altered host immunity or that require immunosuppressive medications. While immunosuppression is associated with increased risk of infection, the precise effect of immunosuppression on innate immunity is not well understood. We studied monocyte Toll-like receptor (TLR) expression and cytokine production in 137 patients with autoimmune diseases who were maintained on immunosuppressive medications and 419 non-immunosuppressed individuals.
  
  
  RESULTS
  Human peripheral blood monocytes were assessed for surface expression of TLRs 1, 2, and 4. After incubation with TLR agonists, in vitro production of the cytokines IL-8, TNFalpha, and MIF were measured by ELISA as a measure of TLR signaling efficiency and downstream effector responsiveness. Immunosuppressed patients had significantly higher TLR4 surface expression when compared to non-immunosuppressed adults (TLR4 %-positive 70.12+/-2.28 vs. 61.72+/-2.05, p = 0.0008). IL-8 and TNF-alpha baseline levels did not differ, but were significantly higher in the autoimmune disease group following TLR stimulation. By contrast, baseline MIF levels were elevated in monocytes from immunosuppressed individuals. By multivariable analyses, IL-8 and TNFalpha, but not MIF levels, were associated with the diagnosis of an underlying autoimmune disease. However, only MIF levels were significantly associated with the use of immunosuppressive medications.
  
  
  CONCLUSIONS
  Our results reveal that an enhanced innate immune response is a feature of patients with autoimmune diseases treated with immunosuppressive agents. The increased risk for infection evident in this patient group may reflect a dysregulation rather than a simple suppression of innate immunity.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America. dana.dunne@yale.edu
authors.forename: Dana W
authors.initials: DW
authors.lastname: Dunne
authors.forename: Albert
authors.initials: A
authors.lastname: Shaw
authors.forename: Linda K
authors.initials: LK
authors.lastname: Bockenstedt
authors.forename: Heather G
authors.initials: HG
authors.lastname: Allore
authors.forename: Shu
authors.initials: S
authors.lastname: Chen
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Malawista
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Yuka
authors.initials: Y
authors.lastname: Mizue
authors.forename: Marta
authors.initials: M
authors.lastname: Piecychna
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Virginia
authors.initials: V
authors.lastname: Towle
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Montgomery
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
mesh_terms: D000328:Adult; D016207:Cytokines / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007121:Immunocompetence; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051197:Toll-Like Receptor 4