Increased TLR4 expression and downstream cytokine production in immunosuppressed adults compared to non-immunosuppressed adults.
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.
Dunne
Dana W
DW
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America. dana.dunne@yale.edu
Shaw
Albert
A
Bockenstedt
Linda K
LK
Allore
Heather G
HG
Chen
Shu
S
Malawista
Stephen E
SE
Leng
Lin
L
Mizue
Yuka
Y
Piecychna
Marta
M
Zhang
Lin
L
Towle
Virginia
V
Bucala
Richard
R
Montgomery
Ruth R
RR
Fikrig
Erol
E
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*
D016207:Cytokines; D051197:Toll-Like Receptor 4