Fine Specificity of T Cells Reactive to Human PDC-E2 163-176 Peptide, the Immunodominant Autoantigen in Primary Biliary Cirrhosis: Implications for Molecular Mimicry and Cross-Recognition Among Mitochondrial Autoantigens

Abstract

The anti-mitochondrial antibody response in primary biliary cirrhosis (PBC) is primarily directed at E2 components of PDC, OGDC, and BCOADC, and E3BP. Previous work has shown that the immunodominant autoreactive T-cell epitope is the PDC-E2 163-176 peptide, restricted by HLA DR53. To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls. Interestingly, fine specificities were unique for every single T-cell clone, but the clones could be categorized into two distinct groups based on recognition motifs of the T-cell receptor ( Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease characterized by the presence of anti-mitochondrial antibodies (AMAs) and inflammation of interlobular bile ducts. 1 The major mitochondrial antigens recognized by AMAs have been identified as E2 components of the 2-oxo acid dehydrogenase complexes including PDC-E2, OGDC-E2 and BCOADC-E2, and E3BP, all localized to the inner membrane of mitochondria. 2-10 Previously, we showed that the human PDC-E2 163-176 peptide (GDLLAEIETDKATI) is an immunodominant T-cell epitope restricted by HLA DR53 (DRA1*0101/DRB4*0101) in patients with PBC. 11 The frequency of T cells in the peripheral blood with specificity for this epitope was significantly higher in patients with PBC as compared with healthy subjects. 12 Of particular interest, the precursor frequency of PDC-E2 163-176 -reactive T cells is 100-to 150-fold higher in the liver and regional hepatic lymph nodes as compared with peripheral blood mononuclear cells (PBMCs) in patients with PBC. 13 Furthermore, these cloned T-cell lines proliferated in response to the purified native PDC-E2 protein, indicating that PDC-E2 163-176 is not a cryptic epitope. 13 Collectively, these data provide suggestive evidence for a major role of the PDC-E2 163-176 peptide in the pathogenesis of PBC. [11][12][13] T cells specific to self-antigens are incriminated in the pathogenesis of various human autoimmune diseases. Molecular mimicry between foreign and self-antigens have been implicated as a possible mechanism for the activation of these self-reactive T cells. 14-19 Previously, we illustrated the evidence of molecular mimicry at the T-cell clonal level in PBC; one molecular mimicry peptide derived from Escherichia coli PDC-E2 activated a human PDC-E2 163-176 -reactive cloned T-cell line generated from a patient with PBC. 11 In addition, we illustrated the evidence of cross-recognition of human OGDC-E2 100-113 peptide (DEVVCEIETDKTSV), which is a distinct but related mitochondrial antigen recognized by some AMAs, by human PDC-E2 163-176 -reactive cloned T-cell lines established from PBC patients. 13 In the present study, to address questions related to molecular mimicry, sharing of recognition motifs among mitochondrial antigens, T-cell receptor (TCR) antagonism or anergy, and the role of complementarity-...

A comparative study of antibody expressions in primary biliary cirrhosis and autoimmune cholangitis using phage display

“…The epitope does not appear to include the conserved lipoyl-binding lysine (K 173 ) although the 2 B-cell epitope regions flank the PDC-E2 163 to 176 peptide that constitutes the immunodominant autoreactive T-cell epitope. 45,46 The alignment of AIC-selected phagotopes to the PBC-specific branches of the peptide guide tree gives clear evidence that PBC and AIC are companion diseases, serologically at least, even though varying contributions to a multiplex pathogenesis may provide clinical individuality. Finally, our study illustrates the applicability of phage display coupled with multiple sequence alignments to the analysis of multifactorial immune-mediated diseases, with the promise of uncovering environmental agent(s) as the elusive trigger for the self-perpetuating pathology of PBC.…”

β-Glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis

“…Because the aetiology of PBC remains unclear, the goal in treating early-stage PBC is to slow the progression of disease and alleviate symptoms. Accumulated evidence by our group has demonstrated that autoreactive T cells that proliferate in response to mitochondrial autoantigens play a critical role in the destruction of the BECs [3][4][5][6][7]. Additionally, CD8 + T cells have been shown to predominate in the cellular infiltrates of portal tracts [3].…”

Emerging Issues in the Immunopathogenesis, Diagnosis and Clinical Management of Primary Biliary Cirrhosis Associated with Systemic Sclerosis

“…E. coli has been strongly associated with PBC (Bogdanos et al, 2010;Burroughs et al, 1984), largely due to the high occurrence of recurrent urinary tract infections in women with PBC (Corpechot et al, 2010;Gershwin et al, 2005). Experimental data support the presence of cross-reactive immune responses between human and E. coli PDC-E2 at the CD4 and CD8 T-cell level (Shigematsu et al, 2000;Van de Water et al, 2001). Several studies have demonstrated cross reactivity between the human PDC-E2 autoepitope (GDLLAEIETDKATI), and that of E. coli (EQSLITVEGDKASM) at the CD4 T cell level (Shimoda et al, 1995).…”