High levels of soluble CTLA-4 are present in anti-mitochondrial antibody positive, but not in antibody negative patients with primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease frequently characterized by anti-mitochondrial autoantibodies (AMA). A minority of patients are AMA-negative. Cytotoxic-T-Lymphocyte-Antigen-4 (CTLA-4) is a surface molecule expressed on activated T-cells delivering a critical negative immunoregulatory signal. A soluble form of CTLA-4 (sCTLA-4) has been detected at high concentrations in several autoimmune diseases, and its possible functional meaning has been suggested. We aimed to evaluate sCTLA-4 concentration in sera of patients with PBC and to correlate it to immunological abnormalities associated with the disease. Blood samples were collected from 82 PBC-patients diagnosed according to international criteria (44 AMA-positive/MIT3-positive and 38 AMA-negative-MIT3-negative), and 65 controls. sCTLA-4 levels were evaluated by ELISA and Western blot. Increased sCTLA-4 concentrations were found in all AMA-positive PBC-patients, but in none of the AMA-negative ones, nor in normal controls or in controls with unrelated liver diseases. sCTLA-4 presence was associated with autoantibodies against MIT3, but not with nuclear autoantibodies (sp100, gp210). This is the first study to demonstrate that levels of sCTLA-4 are elevated in sera of PBC patients. However, they are clearly restricted to patients with AMA positivity, suggesting an immunological difference with respect to AMA-negative ones.
Department of Experimental Medicine - Section of Human Anatomy, University of Genova, Genova, Italy.
Daniele
D
Saverino
Autoimmunity Unit, Department of Internal Medicine, University of Genova, Genova, Italy.
Giampaola
G
Pesce
Autoimmunity Unit, Department of Internal Medicine, University of Genova, Genova, Italy.
Princey
P
Antola
Department of Internal Medicine, University of Siena, Siena, Italy.
Brunetta
B
Porcelli
Department of Clinical Pathology, Buccheri La Ferla Hospital, Palermo, Italy.
Ignazio
I
Brusca
Allergology and Clinical Immunology, S. Maria degli Angeli Hospital, Pordenone, Italy.
Danilo
D
Villalta
Laboratory of Clinical Pathology, University Hospital, Bari, Italy.
Marilina
M
Tampoia
Clinical Pathology, Department of Laboratory Medicine, S. Maria degli Angeli Hospital, Pordenone, Italy.
Renato
R
Tozzoli
Immunopathology and Allergology Unit, S. Maria della Misericordia Hospital, Udine, Italy.
Elio
E
Tonutti
Department of Laboratory Medicine, Biochemistry Laboratory, Riuniti Hospital, Bergamo, Italy.
Maria Grazia
MG
Alessio
Autoimmunity Unit, Department of Internal Medicine, University of Genova, Genova, Italy.
Marcello
M
Bagnasco
Laboratory of Clinical Pathology, San Antonio Hospital, Tolmezzo, Udine, Italy.
Nicola
N
Bizzaro
D000328:Adult; D034961:Antigens, Nuclear / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000097:blood / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000276:immunology*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology; D015854:Up-Regulation
D034961:Antigens, Nuclear; D001323:Autoantibodies; D001324:Autoantigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C558283:MIT3 fusion protein; C063865:NUP210 protein, human; D028861:Nuclear Pore Complex Proteins; D011993:Recombinant Fusion Proteins; C066642:SP100 protein, human