Molecular mimicry and autoantigens in connective tissue diseases

Horsfall, Angela C.

doi:10.1007/bf00464701

Cited by 33 publications

(25 citation statements)

References 26 publications

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“…Conversely, studies of the protein antigens targeted by the autoantibodies may help to explain the disease process itself. They have revealed so called "viral footprints," sequences shared by these protein antigens and viral proteins (40,41). A large body of evidence is accumulating that implicates infection by microorganisms (viruses, mycoplasma, and bacteria) as inciting events for autoimmune disease in persons with a certain HLA-mediated predisposition for autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Rare scleroderma autoantibodies to the U11 small nuclear ribonucleoprotein and to the trimethylguanosine cap of U small nuclear RNAs.

Gilliam

Steitz

1993

Proc. Natl. Acad. Sci. U.S.A.

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We have identified a scleroderma serum (Ru) with a previously undescribed specificity to protein components of the Ull smafl nuclear ribonucleoprotein particle (snRNP), a low-abundance member of the Sm class of U RNPs. The Ull RNP can be specifically immunoprecipitated from sonicated HeLa cells with Ru serum. In nuclear extracts, a fraction of the Ull particle is found complexed to the U12 RNP, an even lower abundance Sm snRNP. In glycerol gradient fractions, Ru serum identifies a 65-kDa protein that cosediments with the U11-U12 complex and is shifted upon targeted degradation of the U12 RNA. The 65-kDa protein therefore appears to be a component of the U11-U12 snRNP complex, whereas another Ru-reactive (140 kDa) protein may be associated with the free Ull RNP. The Ru serum also contains autoantibodies directed against the trimethylguanosine cap of U RNAs. This rare specificity has been described previously in only three other scleroderma patients.Scleroderma patients have in their sera autoantibodies to various cellular proteins (1). Included are nuclear antigens such as SCL-70/topoisomerase I and the kinetochore of centromeres (ACA) and nucleolar proteins such as RNA polymerase I, the nucleolar organizer (NOR-90/hUBF), and fibrillarin, a protein associated with small nucleolar RNAs. These autoantibodies are specific for scieroderma and are helpful for diagnosis and prediction of disease progression in individual patients. Antibodies to proteins associated with the uridine-rich small nuclear RNAs (U RNAs) are found in the sera of patients with systemic lupus erythematosus (2). Anti-Sm autoantibodies immunoprecipitate all the abundant U RNAs (105-1O6 copies per mammalian cell) except U3. Thus the Ul, U2, U5, and the U4-U6 small nuclear ribonucleoprotein particles (snRNPs), which are involved in the splicing of pre-mRNA (3, 4), are primary targets. There also exist several low-abundance Sm snRNPs (5). All Sm RNAs except U6 have a unique 5' 2,2,7-trimethylguanosine (TMG) cap, which in the case of Ul and U2 aids in targeting these snRNAs to the nucleus after assembly with the Sm proteins in the cytoplasm (6). Autoantibodies specific for certain Sm snRNPs have been reported in various autoimmune disorders (7-11).We describe here two rare autoantibodies from the serum of a patient (Ru) with diffuse systemic sclerosis. MATERIALS AND METHODSAntibodies. Serum samples from the patient Ru were obtained in 1991 when she was admitted to Yale/New Haven Hospital for routine monthly extracorporeal photopheresis treatments. The patient was a 40-year-old white woman with diffuse systemic sclerosis since 1985. Her symptoms began with Raynaud phenomenon, followed by rapid progression of sclerosis of the skin of the face, trunk, and extremities in 1986. Mild restrictive lung disease and esophageal dysmotility were documented at that time. She was admitted to the Yale Scleroderma Photopheresis Protocol in 1989 and experienced some resolution of the cutaneous sclerosis, with regression to involvement of only the face and ...

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Section: Discussionmentioning

confidence: 99%

Rare scleroderma autoantibodies to the U11 small nuclear ribonucleoprotein and to the trimethylguanosine cap of U small nuclear RNAs.

Gilliam

Steitz

1993

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies (11,12) have shown that mAb C355.1 produces an unusual luminal staining pattern on biliary epithelium unlike the conventional mitochondrial cytoplasmic staining pattern seen with other mAbs specific to PDC-E2. This prompted Suggested examples of molecular mimicry include U1-snRNP, Ml matrix protein of influenza B viruses, Sm antigen, EpsteinBarr virus nuclear antigen 1, La protein and the M6 protein of Streptococcus pyrogenes (27). However, the demonstration of sequence homology or induction of crossreactive antibodies only suggests an association, but does not prove an etiological relationship between the molecular mimics and the clinical disease.…”

Section: Discussionmentioning

confidence: 99%

“…Unexplained (35) based on the assumption that the lipoyl domain is also an epitope for T cells. They noted the similarity in sequence between the HLA-DRa molecule and the lipoic acid binding site and hypothesized this as a possible triggering factor in disease by as yet unknown mechanisms (27).…”

Section: Discussionmentioning

confidence: 99%

Random phage mimotopes recognized by monoclonal antibodies against the pyruvate dehydrogenase complex-E2 (PDC-E2).

Cha

Leung

Water

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Dihydrolipoamide acetyltransferase, the E2 component ofthe pyruvate dehydrogenase complex (PDC-E2), is the autoantigen most. commonly recognized by autoantibodies in primary biliary cirrhosis (PBC). We identified a peptide mimotope(s) of PDC-E2 by screening a phage-epitope library expressing random dodecapeptides in the pIll coat protein of fd phage using C355.1, a murine monoclonal antibody (mAb)that recognizes a conformation-dependent epitope in the inner lipoyl domain of PDC-E2 and uniquely stains the apical region of bile duct epithelium (BDE) only in patients with PBC. Eight different sequences were identified in 36 phage clones. WMSYPDRTLRTS was present in 29 clones; WESYPFRVGTSL, APKTYVSVSGMV, LTYVSL-QGRQGH, LDYVPLKHRHRH, AALWGVKVRHVS, KVLN-RIMAGVRH and GNVALVSSRVNA were singly represented. Three common amino acid motifs (W-SYP, TWS, and VRH) were shared among all peptide sequences. Competitive inhibition of the immunohistochemical staining of PBC BDE was performed by incubating the peptides WMSYPDRTLRTS, WESYPDRTLRTS, APKTWSVSGMV, and AALWGVKV-RHVS with either C355.1 or a second PDC-E2-specific mAb, C150.1. Both mAbs were originally generated to PDC-E2 but map to distinct regions of PDC-E2. Two of the peptides, although selected by reaction with C355.1, strongly inhibited the staining of BDE by C150.1, whereas the peptide APK-TYVSVSGMV consistently inhibited the staining of C355.1 on biliary duct epithelium more strongly than the typical mitochondrial staining of hepatocytes. Rabbit sera raised against the peptide WMSYPDRTLRTS stained BDE of livers and isolated bile duct epithelial cells of PBC patients more intensively than controls. The rabbit sera stained all size ducts in normals, but only small/medium-sized ductules in PBC livers.These studies provide evidence that the antigen present in BDE is a molecular mimic of PDC-E2, and not PDC-E2 itself.

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“…For example, patients with systemic lupus erythematosus (SLE) or SLE-overlap syndromes often have high serum titers of autoantibodies directed to a variety of self antigens. Several mechanisms have been proposed for the induction of autoantibodies such as a polyclonal B cell activation [l], molecular mimicry [2], or a failure to anergize or induce apoptosis of self-reactive B cells [3].…”

Section: Introductionmentioning

confidence: 99%

Characterization of human variable domain antibody fragments against the U1 RNA‐associated A protein, selected from a synthetic and a patient‐derived combinatorial V gene library

et al. 1996

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This is the first study describing recombinant human antibody fragments directed to the U1 RNA-associated A protein (U1A). Three anti-U1A antibody fragments (Fab) were isolated from a semi-synthetic human Fab library and one anti-U1A single-chain variable fragment (scFv) was isolated from a library which was derived from the IgG-positive splenic lymphocytes of an autoimmune patient. Competition studies with autoantibodies against the U1 small nuclear ribonucleoprotein (snRNP) particle from patients with systemic lupus erythematosus (SLE) and SLE-overlap syndromes revealed that U1A binding of these antibody fragments can be inhibited by about 40% of the patient sera. All antibody fragments recognized the native U1 snRNP in immunoprecipitation assays. Two of three Fab clones as well as the scFv clone derived from the repertoire of an autoimmune patient use the same heavy chain germ-line gene DP-65. Epitope mapping revealed that these three clones appear to recognize an identical epitope domain present on the C-terminal RNP motif of the U1A protein. The DP-65 heavy chain gene is used in less than 1% of the B cells in healthy individuals, while three out of four anti-U1A antibody fragments use this gene. This points to a restricted VH gene usage in the case of U1A, suggesting that the DP-65 heavy chain has a natural shape complementarity to the U1A protein.

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Molecular mimicry and autoantigens in connective tissue diseases

Cited by 33 publications

References 26 publications

Rare scleroderma autoantibodies to the U11 small nuclear ribonucleoprotein and to the trimethylguanosine cap of U small nuclear RNAs.

Rare scleroderma autoantibodies to the U11 small nuclear ribonucleoprotein and to the trimethylguanosine cap of U small nuclear RNAs.

Random phage mimotopes recognized by monoclonal antibodies against the pyruvate dehydrogenase complex-E2 (PDC-E2).

Characterization of human variable domain antibody fragments against the U1 RNA‐associated A protein, selected from a synthetic and a patient‐derived combinatorial V gene library

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