HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases.
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TLDR
Six T cell clones specific for pyruvate dehydrogenase complex (PDC)-E2 peptides from four different patients with primary biliary cirrhosis are established using 33 different peptides of 17-20 amino acid residues corresponding to human PDC-E2 as stimulating antigens, demonstrating the presence of molecular mimicry at the T cell clonal level in human autoimmune diseases.Abstract:
We established six T cell clones specific for pyruvate dehydrogenase complex (PDC)-E2 peptides from four different patients with primary biliary cirrhosis using 33 different peptides of 17-20 amino acid residues corresponding to human PDC-E2 as stimulating antigens. The minimal T cell epitopes of these six T cell clones were all mapped to the same region of the PDC-E2 peptide 163-176 (GDLLAEIETDKATI), which corresponds to the inner lipoyl domain of PDC-E2. The HLA restriction molecules for this epitope were all identified as HLA DRB4 0101. The common essential amino acids of this epitope for these T cell clones were E, D, and K at positions 170, 172, and 173, respectively; other crucial amino acids for this epitope differed in each T cell clone. In addition, the alanine-substituted peptides at positions 170 and 173, but not 172, inhibited the proliferation of all T cell clones induced by the original peptide of human PDC-E2 163-176, indicating that amino acid D at position 172 is a critical MHC-binding site for all T cell clones tested. Interestingly, all T cell clones reacted to PDC-E2 peptide 36-49 (GDLIAEVETDKATV), which corresponds to the outer lipoyl domain of human PDC-E2. Furthermore, one T cell clone cross-reacted with exogenous antigens such as Escherichia coli PDC-E2 peptide 31-44/134-147/235-248 (EQSLITVEGDKASM), which has an EXDK sequence. This is a definite demonstration of the presence of molecular mimicry at the T cell clonal level in human autoimmune diseases. It is also considered possible to design peptide-specific immunotherapy based on the findings of T cell autoepitopes in primary biliary cirrhosis.read more
Citations
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Journal ArticleDOI
Primary Biliary Cirrhosis
Keith D. Lindor,M. Eric Gershwin,Raoul Poupon,Marshall M. Kaplan,Nora V. Bergasa,E. Jenny Heathcote +5 more
TL;DR: PBC is a chronic cholestatic liver disease characterized by high-titer serum antimitochondrial autoantibodies (AMAs) and autoimmune-mediated destruction of small and medium-sized intrahepatic bile ducts as discussed by the authors.
Journal ArticleDOI
Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis
Minoru Nakamura,Hisayoshi Kondo,Tsuyoshi Mori,Atsumasa Komori,Mutsumi Matsuyama,Masahiro Ito,Yasushi Takii,Makiko Koyabu,Terufumi Yokoyama,Kiyoshi Migita,Manabu Daikoku,Seigo Abiru,Hiroshi Yatsuhashi,Eiichi Takezaki,Naohiko Masaki,Kazuhiro Sugi,Koichi Honda,Hiroshi Adachi,Hidehiro Nishi,Yukio Watanabe,Yoko Nakamura,Masaaki Shimada,Tatsuji Komatsu,Akira Saito,Takeo Saoshiro,Hideharu Harada,Takeshi Sodeyama,Shigeki Hayashi,Akihide Masumoto,Takehiro Sando,Tetsuo Yamamoto,Hironori Sakai,Masakazu Kobayashi,Toyokichi Muro,Michiaki Koga,Zakera Shums,Gary L. Norman,Hiromi Ishibashi +37 more
TL;DR: Results indicate 2 different progression types in PBC, hepatic failure type and portal hypertension type progression, which may be represented by positive‐anti‐gp210 and positive‐anticentromere antibodies, respectively.
Journal ArticleDOI
Primary biliary cirrhosis: an orchestrated immune response against epithelial cells.
M. Eric Gershwin,Aftab A. Ansari,Ian R. Mackay,Yasuni Nakanuma,Akiyoshi Nishio,Merrill J. Rowley,Ross L. Coppel +6 more
TL;DR: The data so far provide suggestive evidence that PBC is a mucosal disease; this thesis provides a basis for discussion of etiology via the enterohepatic circulation of toxins and/or infection.
Journal ArticleDOI
Liver‐targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis
Ruth Y. Lan,Chunmei Cheng,Zhe-Xiong Lian,Koichi Tsuneyama,Guo Xiang Yang,Yuki Moritoki,Ya-Hui Chuang,Takafumi Nakamura,Shigeru Saito,Shinji Shimoda,Atsushi Tanaka,Christopher L. Bowlus,Yasuo Takano,Aftab A. Ansari,Ross L. Coppel,M. Eric Gershwin +15 more
TL;DR: Support for a genetic modulation of Treg frequency is provided and the role Tregs play in the loss of tolerance in PBC is illustrated.
Journal ArticleDOI
Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells.
Hiroto Kita,Zhe-Xiong Lian,Judy Van de Water,Xiao-Song He,Shuji Matsumura,Marshall M. Kaplan,Velimir A. Luketic,Ross L. Coppel,Aftab A. Ansari,M. Eric Gershwin +9 more
TL;DR: Using peripheral blood mononuclear cells from PBC, an HLA-A2–restricted CTL epitope of the E2 component of pyruvate dehydrogenase (PDC-E2) is identified, the immunodominant mitochondrial autoantigen, which for the first time defines a unique role for autoantibodies in the pathogenesis of an autoimmune disease.
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