Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis?

Leung, Patrick S.C.; Lam, Kit S.; Kurth, Mark J.; Coppel, Ross L.; Gershwin, M. Eric

doi:10.1016/j.molmed.2012.07.005

Cited by 16 publications

(15 citation statements)

References 66 publications

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“…Antibody responses to environmental xenobiotics that bear structural similarity to host autoantigens have been proposed as a mechanism for the breach of tolerance to PDC‐E2 . This is supported by our previous finding that sera from primary biliary cirrhosis (PBC) patients react not only with the primary autoantigen PDC‐E2, but also with environmental chemicals that are structurally related to lipoic acid . It is at present unclear whether the serum antibody against PDC‐E2 in PBC results from de novo activated autoantigen‐specific B cells, or from B cells previously primed by xenobiotics when self‐tolerance was originally compromised.…”

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confidence: 83%

Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis

Zhang

Leung

et al. 2014

Hepatology

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The serologic hallmark of primary biliary cirrhosis (PBC), the antimitochondrial response to the E2 component of the pyruvate dehydrogenase complex (PDC-E2), has unique features, including continuous high titers of IgM and IgG reactivity throughout all stages of disease, capable not only of target enzyme inhibition, but also cross-reactive with chemical xenobiotics that share molecular homology with the inner lipoyl domain of PDC-E2; such chemicals have been proposed as potential etiological agents. We have used flow cytometry and ELISPOT to examine B cell subsets in 59 subjects, including 28 with PBC, 13 with PSC and 18 healthy controls. Strikingly, in PBC, although there were no significant differences in B cell phenotype subpopulations, 10% of the total IgG and IgA plasmablast population and 23% of the IgM plasmablast population were uniquely reactive with PDC-E2, detected in the CXCR7+CCR10low plasmablast population. In contrast, plasmablast reactivity to a control antigen, tetanus toxoid, was minimal and similar in all groups. Additionally, we isolated plasmablast-derived polyclonal antibodies and compared reactivity with plasma-derived antibodies and noted a distinct non-circulating tissue source of xenobiotic cross-reacting antibodies. The high levels of autoantigen specific peripheral plasmablasts indicate recent activation of naive or memory B cells and a continuous and robust activation. The presence of CXCR7+CCR10low PDC-E2-specific ASCs suggests a mechanistic basis for the migration of circulating antigen specific plasmablasts to the mucosal epithelial ligands CXCL12 and CCL28. In conclusion, our findings suggest a sustained rigorous B cell response in PBC, likely activated and perpetuated by cognate autoantigen.

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confidence: 83%

Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis

Zhang

Leung

et al. 2014

Hepatology

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“…Accumulating evidence implicates that the loss of tolerance to the 2-OADC E2 subunits is pivotal in the initiation event of PBC and that AMA specificities reflect aspects to the induction phase of the disease (7, 8). Recent data further suggest that chemical modification of the PDC-E2 lipoic acid, via an electrophilic attack on the lipoic acid disulfide bond, triggers the breakage of tolerance to PDC-E2 (9, 10). Such modifications could substantially affect the conformation of the PDC-E2 lipoyl domain and its immunogenicity in genetically susceptible hosts.…”

Section: Introductionmentioning

confidence: 99%

Antimitochondrial Antibody Recognition and Structural Integrity of the Inner Lipoyl Domain of the E2 Subunit of Pyruvate Dehydrogenase Complex

Wang

Budamagunta

Voss

et al. 2013

The Journal of Immunology

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Antimitochondrial autoantibodies (AMA), the serological hallmark of primary biliary cirrhosis (PBC) are directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2). However, comprehensive analysis of the amino acid residues of PDC-E2 lipoyl beta sheet with AMA specificity is lacking. Herein, we postulated that specific residues within the lipoyl domain are critical to AMA recognition by maintaining conformational integrity. We systematically replaced each of 19 residue peptides of the inner lipoyl domain with alanine and analyzed these mutants for reactivities against 60 PBC and 103 control sera. Based on these data, we then constructed mutants with 2, 3, or 4 replacements and, in addition, probed the structure of the substituted domains using thiol-specific spin labeling and electron paramagnetic resonance (EPR) of a 5Ile-> Ala and 12Ile->Ala double mutant. Single alanine replacement at 5Ile, 12Ile and 15Glu significantly reduced AMA recognition. In addition, mutants with 2, 3, or 4 replacements at 5Ile, 12Ile and 15Glu reduced AMA reactivity even further. Indeed, EPR reveals a highly flexible structure within the 5Ile and 12Ile double-alanine mutant. Autoreactivity is largely focused on specific residues in the PDC-E2 lipoyl domain critical in maintaining the lipoyl loop conformation necessary for AMA recognition. Collectively, the AMA binding studies and EPR analysis demonstrate the necessity of the lipoyl beta sheet structural conformation in anti-PDC-E2 recognition.

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“…2‐OA and SAc have the ability to modify the lipoyl domain of PDC‐E2, resulting in the formation of neoantigens. SAc is a modified form of LA in which both sulfur atoms of the disulfide bond of the lipoyl ring are modified by acetyl groups, thereby maintaining PDC‐E2 in a reduced state by preventing disulfide bond formation . Our study demonstrates that a subpopulation of anti‐PDC‐E2 autoantibodies, encoded with fewer mutated variable region transcripts, exhibits cross‐reactivity to chemical xenobiotics including 2‐OA and SAc.…”

Section: Discussionmentioning

confidence: 79%

Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics

et al. 2017

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A major problem in autoimmunity has been identification of the earliest events that lead to breach of tolerance. Although there have been major advances in dissecting effector pathways and the multi-lineage immune responses to mitochondrial self-antigens in primary biliary cholangitis (PBC), the critical links between environmental factors and tolerance remain elusive. We hypothesized that environmental xenobiotic modification of the E2 subunit of the pyruvate dehydrogenase (PDC-E2) inner lipoyl domain can lead to loss of tolerance to genetically susceptible hosts. Previously we demonstrated that serum anti-PDC-E2 autoantibodies cross-react with the chemical xenobiotics 2-octynoic acid (2-OA) and 6,8-bis (acetylthio) octanoic acid (SAc) and further that there is a high frequency of PDC-E2 specific peripheral plasmablasts. Herein we generated 104 recombinant mAbs based on paired heavy- and light-chain variable regions of individual plasmablasts derived from PBC patients. We identified 32 mAbs reactive with native PDC-E2, including 20 specific for PDC-E2 and 12 cross-reactive with both PDC-E2 and 2-OA and SAc. A lower frequency of replacement somatic hypermutations, indicating lower level of affinity maturation, was observed in the complementarity-determining regions (CDR) of the cross-reactive mAbs in comparison to mAbs exclusively recognizing PDC-E2 or those for irrelevant antigens. In particular, when the highly mutated heavy chain gene of a cross-reactive mAb was reverted to the germline sequence, the PDC-E2 reactivity was reduced dramatically whereas the xenobiotics reactivity was retained. Importantly, cross-reactive mAbs also recognized lipoic acid (LA), a mitochondrial fatty acid that is covalently bound to PDC-E2. Our data reflect that chemically modified LA or LA itself, via molecular mimicry, is the initial target that leads to the development of PBC.

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Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis?

Cited by 16 publications

References 66 publications

Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis

Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis

Antimitochondrial Antibody Recognition and Structural Integrity of the Inner Lipoyl Domain of the E2 Subunit of Pyruvate Dehydrogenase Complex

Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics

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