Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis.

Abstract

The immunodominant antimitochondrial antibody response in patients with primary biliary cirrhosis (PBC) is directed against the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Based on our earlier observations regarding peripheral blood mononuclear cell (PBMC) T cell epitopes, we reasoned that a comparative analysis of the precursor frequencies of PDC-E2 163-176-specific T cells isolated from PBMC, regional hepatic lymph nodes, and from the liver of PBC patients would provide insight regarding the role of T cells in PBC. Results showed a diseasespecific 100-150-fold increase in the precursor frequency of PDC-E2 163-176-specific T cells in the hilar lymph nodes and liver when compared with PBMC from PBC patients. Interestingly, autoreactive T cells and autoantibodies from PBC patients both recognize the same dominant epitope. In addition, we demonstrated cross-reactivity of PDC-E2 peptide 163-176-specific T cell clones with PDC-E2 peptide 36-49 and OGDC-E2 peptide 100-113 thereby identifying a common T cell epitope "motif" ExETDK. The peptide 163-176-specific T cell clones also reacted with purified native PDC-E2, suggesting that this epitope is not a cryptic determinant. These data provide evidence for a major role for PDC-E2 peptide 163-176 and/or peptides bearing a similar motif in the pathogenesis of PBC. ( J. Clin. Invest. 1998. 102: 1831-1840 . )

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

“…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.…”

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

“…21 Such patients may have IgM AMAs, which may participate in the pathogenesis of mucosal lesions; pathogenic CD4 and CD8 T cells may also play a role. [22][23][24][25] Hence, we do not mean to imply that IgA AMA are the sole pathogenic mechanism involved in biliary cell destruction. In fact, we believe that the biliary cell is an innocent victim of an orchestrated immune response involving several limbs of the immune system.…”

“…Over time, the functional reserve of the tissue to replace itself is lost, perhaps because of loss of the local stem cell population, or because of synergistic activity of other immune effectors including CD4 and CD8 lymphocytes. [22][23][24][25] Eventually, the ducts are destroyed and the liver becomes cirrhotic. Although AMAs of the IgA isotype are not found in every patient's bile, saliva, or urine, we have been impressed by the significant frequency of detection in fluids that are difficult to analyze because of volume, dilution issues, the presence of detergents, and proteases.…”

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

“…The pathogenic role of these antibodies, however, has been poorly investigated so far and remains unknown. 41 ) T-cell antigen receptor-ab 1 and CD8 1 T cells are most commonly seen in portal tracts, in particular around damaged bile ducts in the liver tissue of PBC patients, strongly suggesting the involvement of cellular immune mechanisms in biliary damage, [74][75][76][77][78][79][80][81] as suggested by liver tolerance. 82 In past decades, the nature and the role of cellular adaptive immune responses in PBC have been extensively characterized, showing that both CD4 and CD8 T cells participate in liver tissue damage.…”