Antibodies against multiple post-translationally modified proteins aid in diagnosis of autoimmune hepatitis and associate with complete biochemical response to treatment

Abstract

Background(Auto)immune mediated and cholestatic liver disease (AILD) includes autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Especially AIH is characterized by the presence of autoantibodies and elevated serum immunoglobulins. In rheumatoid arthritis, autoantibodies against post-translational modifications (PTMs) such as citrullination (Cit) and carbamylation (CarP) are used as diagnostic and prognostic markers, respectively. We studied the presence of six anti-PTM antibodies in patients with the three AILDs and non-AILD.MethodsAntibodies against six PTMs (malondialdehyde–acetaldehyde adducts (MAA), advanced glycation end-products (AGE), CarP, acetylation (AL), Cit, and nitration (NT)) were tested in sera of patients with AILD (n = 106), non-AILD (n = 101) and compared with healthy controls (HC) (n = 100). Levels and positivity were correlated with clinical and biochemical features in a well-defined cohort of untreated AIH patients.ResultsAnti-PTM antibodies were more often detectable in sera from AILD patients compared with HCs (anti-MAA: 67.9% vs. 2.0%, anti-AGE: 36.8% vs. 4.0%, anti-CarP: 47.2% vs. 5.0% and anti-AL: 18.9% vs. 5.0%). In untreated AIH, time to complete biochemical response (CBR) was associated with anti-MAA, anti-AGE, anti-CarP and anti-AL antibodies. Significantly more patients with at least three anti-PTM antibodies attained CBR at 12 months of treatment (13 vs. 3 p = 0.01).ConclusionAnti-PTM antibodies are frequently present in AILD. The presence of anti-MAA, anti-AGE and anti-CarP antibodies correlates with the presence of AIH within this cohort. In AIH, harboring at least three anti-PTM antibody responses is positively associated with CBR. Determination of anti-PTM antibodies in liver disease may have diagnostic and prognostic value.

Commentary: Antibodies against multiple post-translationally modified proteins aid in diagnosis of autoimmune hepatitis and associate with complete biochemical response to treatment

“…We read with great interest the article “ Antibodies against multiple post-translationally modified proteins aid in diagnosis of autoimmune hepatitis and associate with complete biochemical response to treatment ” by van den Beukel et al ( 1 ). First of all, we would like to congratulate the authors on their interesting finding that immunoglobulin G (IgG) against post-translationally modified (PTM) proteins are also found in autoimmune liver diseases and especially in untreated autoimmune hepatitis (AIH) and not only in rheumatologic autoimmune diseases.…”

“…That is, IgG from patients with untreated AIH were significantly more reactive against multiple foreign protein and non-protein antigens, as well as against multiple autoantigens, than patients with non-AIH liver diseases or healthy controls in adults and children ( 2 , 3 ). We identified pIgG with a similar solid phase ELISA immunoassay using the same plastic ELISA plates (Nunc Maxisorb) with the same blocking reagent bovine serum albumin (BSA) as van den Beukel et al ( 1 ). In addition, IgG from AIH patients showed increased binding to these BSA-blocked ELISA plates even without the addition of foreign antigens or autoantigens to the ELISA plates.…”

Commentary: Commentary: Antibodies against multiple post-translationally modified proteins aid in diagnosis of autoimmune hepatitis and associate with complete biochemical response to treatment

“…We read with great interest the commentary of Taubert et al ( 1 ) on our article “Antibodies against multiple post-translationally modified proteins aid in diagnosis of autoimmune hepatitis and associate with complete biochemical response to treatment ( 2 ).” In their kind commentary the authors bring up the very important and relevant subject of polyreactive IgG (pIgG) as they have described to occur in autoimmune hepatitis (AIH) ( 3 ). The team of Taubert have identified such pIgG using an experimental set up roughly similar to the enzyme-linked immunosorbent assay (ELISA) setup as we have used for the detection of the antibodies against post-translationally modified proteins (anti-PTM).…”

“…The authors raise interesting questions regarding the nature of the antibody response to the PTM proteins. As can be seen in supplementary figure 1 of the manuscript ( 2 ), we studied how often the different anti-PTM antibodies can be found together in the same patients, as this may be an indication of either co-induction or cross-reactivity. We clearly observe different patterns with some individuals positive for one anti-PTM and other positive for several others ( 2 ), again indicating that the different assays are clearly identifying different antibodies.…”

“…As can be seen in supplementary figure 1 of the manuscript ( 2 ), we studied how often the different anti-PTM antibodies can be found together in the same patients, as this may be an indication of either co-induction or cross-reactivity. We clearly observe different patterns with some individuals positive for one anti-PTM and other positive for several others ( 2 ), again indicating that the different assays are clearly identifying different antibodies. Additionally, while between some anti-PTM responses we do observe a correlation [as observed before ( 4 , 6 )] for other anti-PTM responses we do not detect any correlations.…”