Unique Cholangiocyte-Targeted IgM Autoantibodies Correlate With Poor Outcome in Biliary Atresia.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
revised:
27
06
2020
received:
07
01
2020
accepted:
12
07
2020
pubmed:
9
8
2020
medline:
6
1
2022
entrez:
9
8
2020
Statut:
ppublish
Résumé
The etiology of biliary atresia (BA) is not known and is likely multifactorial, including a genetic predisposition, a viral or environmental trigger, an aberrant autoimmune response targeting cholangiocytes, and unique susceptibilities of the neonatal bile ducts to injury. Damaged cholangiocytes may express neo self-antigens and elicit autoreactive T-cell-mediated inflammation and B-cell production of autoantibodies. The aim of this study was to discover autoantibodies in BA that correlated with outcomes. An autoantigen microarray encompassing approximately 9,500 autoantigens was used to screen for serum immunoglobulin M (IgM) and immunoglobulin G (IgG) autoantibodies in patients with BA or other liver disease controls. Validation of candidate autoantibodies by enzyme-linked immunosorbent assay on a second cohort of subjects (6-12 months following Kasai portoenterostomy) and correlations of autoantibodies with outcomes were performed (serum bilirubin levels and need for liver transplant in first 2 years of life). Mean anti-chitinase 3-like 1 (CHI3L1), anti-delta-like ligand (DLL-4), and antisurfactant protein D (SFTPD) IgM autoantibodies in BA were significantly higher compared with controls, and IgM autoantibody levels positively correlated with worse outcomes. Immunofluorescence revealed cholangiocyte-predominant expression of CHI3L1, DLL-4, and SFTPD. The humoral autoantibody response was associated with C3d complement activation and T-cell autoimmunity, based on detection of cholangiocyte-predominant C3d co-staining and peripheral blood autoreactive T cells specific to CHI3L1, DLL-4 and SFTPD, respectively. BA is associated with cholangiocyte-predominant IgM autoantibodies in the first year after Kasai portoenterostomy. Anti-CHI3L1, anti-DLL-4, and anti-SFTPD IgM autoantibody correlations with worse outcomes and the detection of C3d on cholangioctyes and antigen-specific autoreactive T cells suggest that autoimmunity plays a role in the ongoing bile duct injury and progression of disease.
Sections du résumé
BACKGROUND AND AIMS
The etiology of biliary atresia (BA) is not known and is likely multifactorial, including a genetic predisposition, a viral or environmental trigger, an aberrant autoimmune response targeting cholangiocytes, and unique susceptibilities of the neonatal bile ducts to injury. Damaged cholangiocytes may express neo self-antigens and elicit autoreactive T-cell-mediated inflammation and B-cell production of autoantibodies. The aim of this study was to discover autoantibodies in BA that correlated with outcomes.
APPROACH AND RESULTS
An autoantigen microarray encompassing approximately 9,500 autoantigens was used to screen for serum immunoglobulin M (IgM) and immunoglobulin G (IgG) autoantibodies in patients with BA or other liver disease controls. Validation of candidate autoantibodies by enzyme-linked immunosorbent assay on a second cohort of subjects (6-12 months following Kasai portoenterostomy) and correlations of autoantibodies with outcomes were performed (serum bilirubin levels and need for liver transplant in first 2 years of life). Mean anti-chitinase 3-like 1 (CHI3L1), anti-delta-like ligand (DLL-4), and antisurfactant protein D (SFTPD) IgM autoantibodies in BA were significantly higher compared with controls, and IgM autoantibody levels positively correlated with worse outcomes. Immunofluorescence revealed cholangiocyte-predominant expression of CHI3L1, DLL-4, and SFTPD. The humoral autoantibody response was associated with C3d complement activation and T-cell autoimmunity, based on detection of cholangiocyte-predominant C3d co-staining and peripheral blood autoreactive T cells specific to CHI3L1, DLL-4 and SFTPD, respectively.
CONCLUSIONS
BA is associated with cholangiocyte-predominant IgM autoantibodies in the first year after Kasai portoenterostomy. Anti-CHI3L1, anti-DLL-4, and anti-SFTPD IgM autoantibody correlations with worse outcomes and the detection of C3d on cholangioctyes and antigen-specific autoreactive T cells suggest that autoimmunity plays a role in the ongoing bile duct injury and progression of disease.
Identifiants
pubmed: 32767570
doi: 10.1002/hep.31504
pmc: PMC7867668
mid: NIHMS1648867
doi:
Substances chimiques
Autoantibodies
0
Immunoglobulin M
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1855-1867Subventions
Organisme : NIDDK NIH HHS
ID : U01 DK062481
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062470
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062436
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062466
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK084575
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK084536
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062456
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK067009
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK103149
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK084538
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062453
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK094937
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK062456
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062500
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062497
Pays : United States
Informations de copyright
© 2020 by the American Association for the Study of Liver Diseases.
Références
Am J Pathol. 2016 Jul;186(7):1874-1889
pubmed: 27171900
Liver Transpl. 2017 Jan;23(1):96-109
pubmed: 27650268
OMICS. 2015 Jun;19(6):339-45
pubmed: 26415140
Environ Health Perspect. 2000 Jun;108 Suppl 3:463-73
pubmed: 10852846
Hepatology. 2018 Nov;68(5):1890-1904
pubmed: 29679373
Hepatology. 2006 Nov;44(5):1231-9
pubmed: 17058262
J Autoimmun. 2009 Nov-Dec;33(3-4):270-4
pubmed: 19398190
Curr Opin Allergy Clin Immunol. 2016 Dec;16(6):523-529
pubmed: 27755185
Histopathology. 1981 Mar;5(2):217-21
pubmed: 7216182
J Immunol. 2014 Nov 1;193(9):4448-56
pubmed: 25225671
Sci Rep. 2016 Oct 14;6:35282
pubmed: 27739482
J Clin Invest. 2007 Mar;117(3):712-8
pubmed: 17332892
PLoS One. 2013 Aug 21;8(8):e73644
pubmed: 23991203
Bioanalysis. 2016 May;8(10):1105-26
pubmed: 27097564
J Pediatr Surg. 2015 Feb;50(2):297-300
pubmed: 25638623
Pediatr Dev Pathol. 2018 Jan-Feb;21(1):29-40
pubmed: 28474973
J Clin Invest. 2015 Jun;125(6):2194-202
pubmed: 25938780
Gastroenterology. 2010 Nov;139(5):1753-61
pubmed: 20659472
Gastroenterology. 2007 Jul;133(1):278-87
pubmed: 17631149
Mol Cell Proteomics. 2012 Dec;11(12):1885-97
pubmed: 22997428
Hepatology. 2018 Feb;67(2):721-735
pubmed: 28880403
World J Gastroenterol. 2018 Jan 21;24(3):387-396
pubmed: 29391761
PLoS One. 2018 Aug 8;13(8):e0200818
pubmed: 30089176
Inflamm Bowel Dis. 2011 Jun;17(6):1291-300
pubmed: 21560193
Pediatr Surg Int. 2017 Dec;33(12):1233-1241
pubmed: 29063959
J Neuroinflammation. 2017 Jun 19;14(1):120
pubmed: 28629465
Int Rev Immunol. 2000;19(2-3):265-87
pubmed: 10763712
Hepatology. 2018 Sep;68(3):1163-1173
pubmed: 29604222
Clin Cancer Res. 2007 Dec 15;13(24):7243-6
pubmed: 18094402