PMID- 27808577
OWN - NLM
STAT- MEDLINE
DCOM- 20171222
LR  - 20180831
IS  - 1607-842X (Electronic)
IS  - 0891-6934 (Linking)
VI  - 49
IP  - 8
DP  - 2016 Dec
TI  - Topoisomerase I peptide-loaded dendritic cells induce autoantibody response as 
      well as skin and lung fibrosis.
PG  - 503-513
AB  - DNA Topoisomerase I (TopoI) is a candidate autoantigen for diffuse cutaneous 
      systemic sclerosis (dcSSc) associated with fatal lung disease. Dendritic cells 
      (DCs) contribute to bleomycin-induced lung fibrosis. However, the possibility 
      that TopoI-loaded DCs are involved in the initiation and/or perpetuation of dcSSc 
      has not been explored. Here, we show that immunization with TopoI peptide-loaded 
      DCs induces anti-TopoI autoantibody response and long-term fibrosis. Mice were 
      repeatedly immunized with unpulsed DCs or DCs loaded with either TOPOIA or TOPOIB 
      peptides, selected from different regions of TopoI. At week 12 after initial DC 
      immunization, TOPOIA DCs but not TOPOIB DCs immunization induced mixed 
      inflammation and fibrosis in lungs and skin. At a late time point (week 18), both 
      TOPOIA DCs and TOPOIB DCs groups displayed increased alpha-smooth muscle actin 
      expression in lungs and dermis along with skin fibrosis distal from the site of 
      injection when compared with unpulsed DCs. Both TopoI peptide-DC-immunized groups 
      developed IgG2a anti-TopoI autoantibody response. At week 10, signs of 
      perivascular, peribronchial, and parenchymal pulmonary inflammation were already 
      observed in the TOPOIA DCs group, together with transient elevation in 
      bronchoalveolar lavage cell counts, IL-17A expression, and CXCL4 production, a 
      biomarker of early human dcSSc. Collectively, TopoI peptide DCs induce 
      progressive autoantibody response as well as development of protracted skin and 
      lung dcSSc-like disease. Pronounced lung inflammation, transient IL-17A, and 
      CXCL4 expression precede fibrosis development. Our immunization strategy, that 
      uses self immune system and autoantigen, will help to further investigate the 
      pathogenesis of this complex autoimmune disorder with unmet medical needs.
FAU - Mehta, Heena
AU  - Mehta H
AD  - a Immunoregulation Laboratory and.
FAU - Goulet, Philippe-Olivier
AU  - Goulet PO
AD  - a Immunoregulation Laboratory and.
FAU - Nguyen, Vinh
AU  - Nguyen V
AD  - a Immunoregulation Laboratory and.
FAU - Perez, Gemma
AU  - Perez G
AD  - b Laboratory for Research in Autoimmunity , Center de Recherche du Center 
      Hospitalier de l'Universite de Montreal (CRCHUM) , Montreal , Quebec , Canada.
FAU - Koenig, Martial
AU  - Koenig M
AD  - b Laboratory for Research in Autoimmunity , Center de Recherche du Center 
      Hospitalier de l'Universite de Montreal (CRCHUM) , Montreal , Quebec , Canada.
FAU - Senecal, Jean-Luc
AU  - Senecal JL
AD  - b Laboratory for Research in Autoimmunity , Center de Recherche du Center 
      Hospitalier de l'Universite de Montreal (CRCHUM) , Montreal , Quebec , Canada.
FAU - Sarfati, Marika
AU  - Sarfati M
AD  - a Immunoregulation Laboratory and.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20161103
PL  - England
TA  - Autoimmunity
JT  - Autoimmunity
JID - 8900070
RN  - 0 (Actins)
RN  - 0 (Autoantibodies)
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (Peptides)
RN  - EC 5.99.1.2 (DNA Topoisomerases, Type I)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Autoantibodies/*immunology
MH  - Autoimmunity
MH  - Biomarkers
MH  - Biopsy
MH  - Bronchoalveolar Lavage Fluid/immunology
MH  - Cytokines/metabolism
MH  - DNA Topoisomerases, Type I/chemistry/*immunology
MH  - Dendritic Cells/*immunology/metabolism
MH  - Fibrosis
MH  - Immunization
MH  - Lung/*immunology/metabolism/*pathology
MH  - Mice
MH  - Peptides/*immunology
MH  - Skin/*immunology/metabolism/*pathology
OTO - NOTNLM
OT  - Systemic sclerosis
OT  - anti-Topoisomerase I
OT  - dendritic cells
OT  - fibrosis
OT  - inflammation
EDAT- 2016/11/04 06:00
MHDA- 2017/12/23 06:00
CRDT- 2016/11/04 06:00
PHST- 2016/11/04 06:00 [pubmed]
PHST- 2017/12/23 06:00 [medline]
PHST- 2016/11/04 06:00 [entrez]
AID - 10.1080/08916934.2016.1230848 [doi]
PST - ppublish
SO  - Autoimmunity. 2016 Dec;49(8):503-513. doi: 10.1080/08916934.2016.1230848. Epub 
      2016 Nov 3.