title: Down-regulated NOD2 by immunosuppressants in peripheral blood cells in patients with SLE reduces the muramyl dipeptide-induced IL-10 production.
abstract: BACKGROUND
  Pattern recognition receptors (PRRs) such as Toll-like receptors are aberrantly expressed of peripheral blood mononuclear cells (PBMCs) in systemic lupus erythematosus (SLE) patients, for playing immunopathological roles.
  
  
  RESULTS
  We investigated the expression and function of the PRR nucleotide-binding oligomerization domain (NOD2) in SLE. NOD2 expression in T, B lymphocytes, monocytes, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) was assessed in SLE patients and healthy controls (HCs) using flow cytometric analysis. Ex vivo production of cytokines from PBMCs upon NOD2 agonist muramyl dipeptide (MDP) stimulation was assessed using Cytometric Bead Array. Over-expression of NOD2 in monocytes was observed in immunosuppressant naïve SLE patients, and was positively associated with longer disease duration. Immunosuppressive therapy was an independent explanatory variable for downregulating NOD2 expression in CD8+ T, monocytes, mDCs and pDCs. Ex vivo basal productions of cytokines (IL-6, IL-8 and IL-10) were significantly increased in immunosuppressant naïve patients and patients with active disease despite immunosuppressants compared with HCs. Upon MDP stimulaiton, relative induction (%) of cytokines (IL-1β) from PBMC was significantly increased in immunosuppressant naïve patients with inactive disease, and patients with active disease despite immunosuppressant treatment compared with HCs. Immunosuppressant usage was associated with a decreased basal production and MDP induced relative induction (%) of IL-10 in patients with inactive disease compared with immunosuppressant naïve patients and HCs.
  
  
  CONCLUSIONS
  Bacterial exposure may increase the NOD2 expression in monocytes in immunosuppressant naïve SLE patients which can subsequently lead to aberrant activation of PBMCs to produce proinflammatory cytokines, implicating the innate immune response for extracellular pathogens in the immunopathological mechanisms in SLE. Immunosuppressant therapy may downregulate NOD2 expression in CD8+ T lymphocytes, monocytes, and DCs in SLE patients which subsequently IL-10 reduction, contributing towards the regulation of immunopathological mechanisms of SLE, at the expense of increasing risk of bacterial infection.
authors: Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
authors: Shui-Lian
authors: SL
authors: Yu
authors: Chun-Kwok
authors: CK
authors: Wong
authors: Purple Tsz-Yan
authors: PT
authors: Wong
authors: Da-Peng
authors: DP
authors: Chen
authors: Cheuk-Chun
authors: CC
authors: Szeto
authors: Edmund K
authors: EK
authors: Li
authors: Lai-Shan
authors: LS
authors: Tam
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology*; D000328:Adult; D001419:Bacteria; D001773:Blood Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000473:pathology; D007113:Immunity, Innate; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis*; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000276:immunology; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000187:drug effects* / Q000235:genetics; D055815:Young Adult
chemical_list: D016207:Cytokines; C508609:IL10 protein, human; D007166:Immunosuppressive Agents; D053473:Nod2 Signaling Adaptor Protein; D016753:Interleukin-10; D000119:Acetylmuramyl-Alanyl-Isoglutamine