PMID- 31604370
OWN - NLM
STAT- MEDLINE
DCOM- 20200721
LR  - 20200721
IS  - 1365-2249 (Electronic)
IS  - 0009-9104 (Print)
IS  - 0009-9104 (Linking)
VI  - 199
IP  - 2
DP  - 2020 Feb
TI  - Monoclonal anti-dsDNA antibody 2C10 escorts DNA to intracellular DNA sensors in 
      normal mononuclear cells and stimulates secretion of multiple cytokines 
      implicated in lupus pathogenesis.
PG  - 150-162
LID - 10.1111/cei.13382 [doi]
AB  - There have been many studies on the mechanisms of internalization of DNA-anti-DNA 
      immune complexes by cells, including the one used for rheumatoid 
      factor-expressing mouse B cells. In parallel, studies on the role of 
      intracellular DNA sensors in the pathogenesis of systemic lupus erythematosus 
      (SLE) have been conducted, including the one using a mouse model lacking one of 
      the sensors. These and other data have established a framework for understanding 
      the pathogenic role of anti-DNA antibodies, but studies on normal cells are 
      limited. Here, we used the monoclonal anti-dsDNA antibody 2C10, 2-kbp dsDNA and 
      healthy human peripheral blood mononuclear cells (PBMCs) to test whether and how 
      2C10 and/or DNA cause pathology in normal cells. We found that on culture with 
      PBMCs, 2C10 preferentially entered monocytes and that DNA enhanced this 
      internalization. In contrast, DNA alone was not significantly internalized by 
      monocytes, but 2C10 facilitated its internalization. This was suppressed by 
      cytochalasin D, but not by methyl-beta-cyclodextrin, chloroquine or an Fc blocker, 
      suggesting the involvement of macropinocytosis in this process. Internalization 
      of 2C10 and DNA together resulted in production of interferon (IFN)-alpha, IFN-gamma, 
      tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein-1 (MCP-1), 
      interleukin (IL)-1beta, IL-6, IL-10 and IL-33 by PBMCs. Cytokine production was 
      suppressed by chloroquine and shikonin, but not by RU.521, suggesting dependence 
      on activation of the Toll-like receptor (TLR)-9 and absent in melanoma 2 (AIM-2) 
      pathways. These results established a simple model to demonstrate that anti-DNA 
      antibodies can cause dysregulation of cytokine network mimicking systemic lupus 
      erythematosus in culture of normal PBMCs, and emphasize again the importance of 
      maintaining anti-DNA antibodies at low levels by treatment.
CI  - (c) 2019 The Authors. Clinical & Experimental Immunology published by John Wiley & 
      Sons Ltd on behalf of British Society for Immunology.
FAU - Inoue, K
AU  - Inoue K
AUID- ORCID: 0000-0003-1388-4717
AD  - Department of Microbiology and Immunology, Graduate School of Health Care 
      Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
FAU - Ishizawa, M
AU  - Ishizawa M
AD  - Department of Immunopathology, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
FAU - Kubota, T
AU  - Kubota T
AUID- ORCID: 0000-0003-1021-7898
AD  - Department of Immunopathology, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191029
PL  - England
TA  - Clin Exp Immunol
JT  - Clinical and experimental immunology
JID - 0057202
RN  - 0 (Antibodies, Antinuclear)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Cell-Free Nucleic Acids)
RN  - 0 (Cytokines)
SB  - IM
MH  - Antibodies, Antinuclear/*immunology
MH  - Antibodies, Monoclonal/*immunology
MH  - Cell-Free Nucleic Acids/*immunology
MH  - Cytokines/*immunology
MH  - Humans
MH  - Leukocytes, Mononuclear/*immunology/pathology
MH  - Lupus Erythematosus, Systemic/*immunology/pathology
MH  - THP-1 Cells
PMC - PMC6954677
OTO - NOTNLM
OT  - anti-DNA antibodies
OT  - endocytosis
OT  - macropinocytosis
OT  - systemic lupus erythematosus
COIS- All the authors have no conflicts of interest to disclose.
EDAT- 2019/10/12 06:00
MHDA- 2020/07/22 06:00
PMCR- 2019/10/29
CRDT- 2019/10/12 06:00
PHST- 2019/10/07 00:00 [accepted]
PHST- 2019/10/12 06:00 [pubmed]
PHST- 2020/07/22 06:00 [medline]
PHST- 2019/10/12 06:00 [entrez]
PHST- 2019/10/29 00:00 [pmc-release]
AID - CEI13382 [pii]
AID - 10.1111/cei.13382 [doi]
PST - ppublish
SO  - Clin Exp Immunol. 2020 Feb;199(2):150-162. doi: 10.1111/cei.13382. Epub 2019 Oct 
      29.