%0 Journal Article
%T Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus
%A Karim Sacre
%A Lindsey A Criswell
%A Joseph M McCune
%J Arthritis Research & Therapy
%D 2012
%I BioMed Central
%R 10.1186/ar3895
%X Peripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-¦Á and tumor necrosis factor alpha (TNF-¦Á) was then analyzed by multiparameter flow cytometry.After TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-¦Á and TNF-¦Á was only observed in pDCs. TLR-7 and TLR-9 induced IFN-¦Á and TNF-¦Á production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-¦Á, P < 0.0001; TLR-9/TNF-¦Á P < 0.0001; TLR-7/TNF-¦Á P = 0.01). TLR-9 and TLR-7 induced IFN-¦Á and TNF-¦Á production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-¦Á, P = 0.0003; impaired TLR-7/IFN-¦Á, P = 0.07; impaired TLR-9/TNF-¦Á, P < 0.009; impaired TLR-7/TNF-¦Á, P < 0.01).Treatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-¦Á and TNF-¦Á upon stimulation with TLR-9 and TLR-7 agonists.A growing body of evidence indicates that type I interferons, such as interferon-¦Á (IFN-¦Á), play a pivotal role in the etiology and pathogenesis of systemic lupus erythematosus (SLE), and single-nucleotide polymorphisms in several key molecules important for IFN-¦Á production and action are associated with SLE [1,2]. Moreover, some of these type I IFN pathway polymorphisms have been shown to impact IFN-¦Á levels and responsiveness in SLE patients in vivo [3].Plasmacytoid dendritic cells (pDCs) have been shown to be the major source of IFN-¦Á production in the peripheral blood [4] and within lymph nodes [5], and these cells produce IFN-¦Á after stimulation across TLR-7 and/or TLR-9 [6-8]. pDCs have also been implicated as key
%U http://arthritis-research.com/content/14/3/R155