Evidence for a locally driven mucosal response and the presence of mitochondrial antigens in saliva in primary biliary cirrhosis

Reynoso-Paz, Sandra; Leung, Patrick S.C.; Water, Judith A Van de; Tanaka, Atsushi; Muñoz, Santiago J.; Bass, Nathan M.; Lindor, Keith D.; Donald, Paul J.; Coppel, Ross L.; Ansari, Aftab A.; Gershwin, M. Eric

doi:10.1002/hep.510310106

Cited by 77 publications

(48 citation statements)

References 33 publications

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“…These data and the recent evidence of the presence of IgG and IgA AMA in the saliva of PBC patients 24 together support the earlier observation and hypothesis that a PDC-E2 molecule might be aberrantly expressed in the salivary glands of PBC patients, and the possible association of Sjö gren's syndrome with PBC. 23 In a previous study, the V, D, and J segment utilization in XenoMouse animals was shown to be nearly identical to the gene segment utilization reported for humans.…”

Section: Discussionsupporting

confidence: 89%

Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse

Sasaki¹

2001

Hepatology

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Antimitochondrial antibodies (AMA) are detected in Ͼ95% of sera from patients with primary biliary cirrhosis (PBC) and recognize the highly conserved mitochondrial 2-oxo-acid dehydrogenase complex (OADC enzyme complex), including the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the E2 subunit of the branched-chain 2-oxo-acid dehydrogenase complex (BCOADC-E2), the E2 subunit of the 2-oxoglutarate dehydrogenase complex (OGDC-E2), and E3BP (E3-binding protein or protein X). [1][2][3][4] We hypothesized that utilization of specific members of the human immunoglobulin (Ig) repertoire plays a critical role in specific epitope recognition of PDC-E2 and initiates a cascade of mucosal autoimmune responses against mitochondrial autoantigens, as a result of specific structural features of the autoantigens or of specific oddities of the etiologic process. To address this issue, we have taken advantage of a unique transgenic animal, XenoMouse (Abgenix Inc., Fremont, CA), that contains the human heavy (H) and light chain loci cloned on yeast artificial chromosomes. 5,6 The yeast artificial chromosomes in XenoMouse include approximately 66 V H (ϳ80%) and 32 V (ϳ75%) gene regions, rendering these mice capable of producing high-affinity, fully functional IgM and IgG2 antibodies, which closely resemble those seen in humans, to multiple antigens. 7,8 Moreover, the Ig gene usage toward immunizing antigens has been shown to be quite diverse. 7 Therefore, the production of human antibodies in XenoMouse provides a valuable tool to investigate the nature and specificity of the human antibody response to autoantigens. Here, we report the successful generation and characterization of human mAbs (HmAbs) to the major mitochondrial autoantigens in PBC, together with a comparison of Ig gene usage with that found in patients with PBC. 9-11 Our data have implications for identifying the causative agent of PBC.Abbreviations: AMA, antimitochondrial antibody; PBC, primary biliary cirrhosis; OADC, the E2 component of the 2-oxo-acid dehydrogenase complex; PDC-E2, the E2 component of pyruvate dehydrogenase; BCOADC-E2, the E2 component of the branched-chain 2-oxo-acid dehydrogenase complex; OGDC-E2, the E2 component of the 2-oxoglutarate dehydrogenase complex; E3BP, E3-binding protein; Ig, immunoglobulin; HmAbs, human monoclonal antibody; r, recombinant; KLH, keyhole limpet hemocyanin; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; RT, room temperature; HRP, horseradish peroxidase; SDS, sodium dodecyl sulfate; ILD, inner lipoyl domain; PSC, primary sclerosing cholangitis; DIG, digoxigenin.From the

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Section: Discussionsupporting

confidence: 89%

Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse

Sasaki¹

2001

Hepatology

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“…It is possible that these differences reflect a much higher titer of autoantibodies to PDC-E2 compared to OGDC-E2 or BCOADC-E2 not only in the sera, but also in the secretions in PBC. 7,8,42,43 It would be interesting to prospectively study patients ranked on their capacity to induce caspase activation in this system and determine whether this predicts their progression of disease. Fig.…”

Section: Discussionmentioning

confidence: 99%

Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis

et al. 2004

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“…111 Further, the PDC-E2 amino acids E, D, and K are essential for the recognition of the epitope by HLA-restricted T-cell clones, similar to that observed for AMA. PDC-E2 [163][164][165][166][167][168][169][170][171][172][173][174][175][176] -specific CD4 þ Tcell clones also react with other AMA-specific mitochondrial autoantigens, including the E2 subunits of OGDC and BCOADC, as well as E3BP. 112,113 In all these molecules, interestingly, the epitopes include a lipoylated domain.…”

Section: Immunopathogenesis Of Pbcmentioning

confidence: 99%

“…The study of TCR b gene rearrangements of cell clones obtained from PBC liver biopsies demonstrated different degrees of oligoclonality of the infiltrating T cells. 114,115 The use of TCR Vb or Jb genes by PDC-E2 [163][164][165][166][167][168][169][170][171][172][173][174][175][176] -reactive T-cell clones is also highly diverse with GXG or GXS motifs found within the complementaritydetermining region 3 (CDR3) of all T-cell clones. 116 When autoreactive T-cell frequencies are compared among different tissues of patients with PBC, PDC-E2 163-176 -reactive precursor T cells are 100-150-fold more represented in the hilar lymph nodes and the liver compared to the peripheral blood, possibly with changes in different disease stages.…”

Section: Immunopathogenesis Of Pbcmentioning

confidence: 99%

Genes and (auto)immunity in primary biliary cirrhosis

et al. 2005

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Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease most commonly encountered in postmenopausal women; it is characterized by high-titer serum autoantibodies to mitochondrial antigens, elevated serum IgM, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. The cytopathic mechanisms leading to the selective destruction of intrahepatic cholangiocytes are still largely unknown. The current theory on the pathogenesis of PBC indicated that environmental factors might trigger autoimmunity in genetically susceptible individuals. In fact, genetic predisposition is critical to disease onset and progression, yet peculiar among autoimmune diseases, as indicated by the lack of a strong association with major histocompatibility complex haplotypes. Further, the recently reported concordance rate among monozygotic twins strenghtens the importance of genetic factors, while also indicating that additional factors, possibly infectious agents or xenobiotics, intervene to trigger the disease. In this review, the available data regarding the genetic factors associated with PBC susceptibility and progression, as well as the available evidence regarding the immunomediated pathogenesis of PBC, will be critically illustrated and discussed.

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Evidence for a locally driven mucosal response and the presence of mitochondrial antigens in saliva in primary biliary cirrhosis

Abstract: Primary biliary cirrhosis (PBC) is often considered to be

Cited by 77 publications

References 33 publications

Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse

Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse

Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis

Genes and (auto)immunity in primary biliary cirrhosis

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