T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is characterized by loss of tolerance against ubiquitously expressed mitochondrial autoantigens followed by biliary and salivary gland epithelial cell (BEC and SGEC) destruction by autoreactive T cells. It is unclear why BECs and SGECs are targeted. Previous work demonstrated that the reduced form of the major PBC autoantigen predominated in apoptotic BECs and SGECs as opposed to an oxidized form in other apoptotic cells. This led to the hypothesis that presentation of novel self-peptides from phagocytosed apoptotic BECs might contribute to BEC targeting by autoreactive T cells. The effect of autoantigen redox status on self-peptide formation was examined along with the phagocytic ability of BECs. Oxidation of PBC autoantigens first was shown to be due to protein S-glutathionylation of lipoyllysine residues. Absence of protein S-glutathionylation generated novel self-peptides and affected T cell recognition of a lipoyllysine containing peptide. Liver biopsy staining revealed BEC phagocytosis of apoptotic BECs (3.74+/-2.90% of BEC) was present in PBC (7 of 7 cases) but not in normal livers (0 of 3). BECs have the ability to present novel mitochondrial self-peptides derived from phagocytosed apoptotic BECs. Apoptotic cell phagocytosis by non-professional phagocytes may influence the tissue specificity of autoimmune diseases.
Allina
Jorge
J
Department of Medicine, The Mount Sinai School of Medicine, New York, NY, USA.
Hu
Bin
B
Sullivan
Daniel M
DM
Fiel
Maria Isabel
MI
Thung
Swan N
SN
Bronk
Steven F
SF
Huebert
Robert C
RC
van de Water
Judy
J
LaRusso
Nicholas F
NF
Gershwin
M E
ME
Gores
Gregory J
GJ
Odin
Joseph A
JA
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry; D051379:Mice; D010084:Oxidation-Reduction; D010447:Peptide Hydrolases / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology*; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology*; D008063:Thioctic Acid / Q000031:analogs & derivatives / Q000737:chemistry
D001324:Autoantigens; C067769:lipoyllysine; D008063:Thioctic Acid; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D010447:Peptide Hydrolases; D002401:Cathepsin B; D005978:Glutathione; D008239:Lysine