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PubMed1990

Cell surface expression of the 70-kD component of Ku, a DNA-binding nuclear autoantigen.

The Ku complex, a heterodimer of 86- and 70-kD proteins, is a nuclear DNA-binding autoantigen. However, hydrophobicity analysis of the deduced amino acid sequence of the 70-kD protein had strongly suggested that this might also be a membrane protein. In the present study, using antibodies to synthetic peptides and a polyclonal antiserum to the purified protein, we show that the 70-kD protein of the Ku complex is present in isolated plasma membranes of human cells. By indirect immunofluorescence microscopy and fluorescein-activated cell sorting, we demonstrate that this autoantigen is exposed on the cell surface. In addition, we have identified several domains of the protein that are exposed. Our study provides one of the first demonstrations of a eukaryotic, nuclear DNA-binding protein that is also on the cell membrane. Moreover, our results might help explain how autoantibodies to the Ku autoantigen could target cells for an autoimmune attack.

Amino Acid Sequence↗
PubMed1997

Autoantigen Ku and its role in multiple cellular processes.

Ku is a DNA binding protein composed of 70 and 80 kDa subunits which was discovered as autoantigen in a patient with scleroderma-polymyositis overlap syndrome. Ku can bind to the end of DNA and also to some internal sequences. Ku-autoantigen acts as a potential transcription factor for several RNA polymerase II genes and RNA polymerase I gene. Ku is also associated with DNA-dependent protein kinase and involved in V(D)J recombination and DNA break repair mechanisms. Ku may be involved in replication, helicase activity and cell signaling. Therefore, Ku-autoantigen is a very important cellular factor which plays important role in the multiple cellular processes.

Animals↗
PubMed1998

Vesicular autoantigens of type 1 diabetes.

Type 1 diabetes, also referred to as insulin-dependent diabetes mellitus (IDDM), is an autoimmune disorder resulting from the destruction of pancreatic beta-cells and insulin deficiency. In the last 10 years significant progress has been made in this field, primarily because of the identification of predisposing genes, the extensive investigation of animal models, and the characterization of major autoantigens. This review draws attention to how the study of beta-cell autoantigens may contribute insight into the pathogenesis of IDDM and provides an update on the cell biology of glutamic acid decarboxylase (GAD) and islet cell autoantigen 512, two major targets of autoimmunity in Type 1 diabetes on which I have focused my efforts. For reasons of space I have mostly considered here studies on GAD which have been published since 1994.

Amino Acid Sequence↗
PubMed1998

Chronic parvovirus B19 infection induces the production of anti-virus antibodies with autoantigen binding properties.

Human parvovirus B19 infection in adults shows some clinical features similar to those found in autoimmune connective tissue diseases. To better clarify the relationship between viral infection and autoimmunity, we have evaluated the ability of anti-parvovirus antibodies to specifically recognize autoantigens in ten patients with chronic symmetric arthritis resembling rheumatoid arthritis or with recurrent episodes of arthritis and cutaneous manifestations and persistence of specific IgM antibodies against B19 parvovirus. We synthetized a 24-amino acid immunodominant peptide corresponding to a part of the virus protein 1 and virus protein 2 overlapping region. The peptide has been used to test patients' sera at different time points with an enzyme-linked immunosorbent assay (ELISA) and to purify anti-virus antibodies by affinity chromatography on a peptide-Sepharose column. Eluted immunoglobulins recognized the B19 peptide in both direct and competitive ELISA. Affinity-purified anti-parvovirus antibodies were then tested on a panel of autoantigens including human keratin, collagen type II, thyreoglobulin, single-strand (ss)DNA, cardiolipin and ribonucleoprotein antigen Sm. Eluted antibodies specifically recognized keratin, collagen type II, ssDNA and cardiolipin. Autoantibody activity was not detected in the immunoglobulin fraction after complete removal of anti-peptide antibodies and in antibodies eluted from normal donors. Epstein-Barr virus-transformed cell clones obtained from two subjects produced antibodies which simultaneously recognize the viral peptide and several autoantigens. To further confirm the role of the virus in inducing an autoantibody response, eight BALB/c mice were immunized with the viral peptide coupled to a carrier protein. Autoantibody activity against keratin, collagen II, cardiolipin and ssDNA was detected in six of the eight mice which developed a strong anti-virus response. Together, these data indicate that B19 parvovirus may be linked to the induction of an autoimmune response.

Adolescent↗
PubMed2000

SR proteins are autoantigens in patients with systemic lupus erythematosus. Importance of phosphoepitopes.

OBJECTIVE: To determine whether members of the highly phosphorylated SR protein family are autoantigens and, if so, to determine the frequency and molecular basis of antigen recognition. METHODS: Native human SR proteins were purified to homogeneity from HeLa cells, and an enzyme-linked immunosorbent assay (ELISA) was developed. Further studies employed immunoblotting of both phosphorylated and dephosphorylated SR proteins. RESULTS: Anti-SR protein reactivity was frequently detected in the sera of patients with systemic lupus erythematosus (SLE). Sera from 52% of the SLE patients in a group of patients with a variety of autoimmune and other disorders (n = 137) and from 50% of the SLE patients in a separate group (n = 102) were positive in an ELISA. In contrast, sera from patients with other disorders, such as rheumatoid arthritis and primary antiphospholipid syndrome, reacted infrequently. Reactivity with double-stranded DNA (dsDNA), used in the diagnosis of SLE, did not correlate with SR protein reactivity. Anti-SR autoantisera did not bind highly charged unphosphorylated peptides related to the SR domain, which is rich in arginine and phosphoserine residues. Surprisingly, many of the epitopes were influenced by the presence or absence of SR protein phosphorylation. In immunoblots, some patient sera lost reactivity upon SR protein dephosphorylation, while others significantly gained reactivity. CONCLUSION: We have identified a novel set of autoantigens in SLE, the SR protein family of non-small nuclear RNP pre-messenger RNA splicing factors. Anti-SR autoantibodies are distinct from those which bind dsDNA. The identification of this new set of autoantigens and the observation that the auto-epitope(s) involves posttranslational modification offer new possibilities for understanding autoimmunity and its development.

Antibodies, Antinuclear↗
PubMed2001

The DNA mismatch repair enzyme PMS1 is a myositis-specific autoantigen.

OBJECTIVE: The specificity of the autoantibody response in different autoimmune diseases makes autoantibodies useful for diagnostic purposes. It also focuses attention on tissue- and event-specific circumstances that may select unique molecules for an autoimmune response in specific diseases. Defining additional phenotype-specific autoantibodies may identify such circumstances. This study was undertaken to investigate the disease specificity of PMS1, an autoantigen previously identified in some sera from patients with myositis. METHODS: We used immunoprecipitation analysis to determine the frequency of autoantibodies to PMS1 in sera from patients with myositis, systemic lupus erythematosus, or scleroderma and from healthy controls. Additional antigens recognized by PMS1-positive sera were further characterized in terms of their susceptibility to cleavage by apoptotic proteases. RESULTS: PMS1, a DNA mismatch repair enzyme, was identified as a myositis-specific autoantigen. Autoantibodies to PMS1 were found in 4 of 53 patients with autoimmune myositis (7.5%), but in no sera from 94 patients with other systemic autoimmune diseases (P = 0.016). Additional mismatch repair enzymes (PMS2, MLH1) were targeted, apparently independently. Sera recognizing PMS1 also recognized several other proteins involved in DNA repair and remodeling, including poly(ADP-ribose) polymerase, DNA-dependent protein kinase, and Mi-2. All of these autoantigens were efficiently cleaved by granzyme B, generating unique fragments not observed during other forms of cell death. CONCLUSION: PMS1 autoantibodies are myositis specific. The striking correlation between an immune response to a group of granzyme B substrates (functioning in DNA repair and remodeling) and the myositis phenotype strongly implies that tissue- and event-specific biochemical events play a role in selecting these molecules for an autoimmune response. Understanding the role of granzyme B cleavage in this response is an important priority.

Adult↗
PubMed2002

Recognition of Granzyme B-generated autoantigen fragments in scleroderma patients with ischemic digital loss.

OBJECTIVE: To examine whether autoantibodies recognizing granzyme B (GB)-cleaved autoantigens are associated with ischemic digital loss (IDL) in limited systemic sclerosis (SSc). METHODS: Fifteen of 19 patients with limited SSc and IDL were matched by age, sex, race, and duration of disease to controls with limited SSc but without IDL. The sera were used to immunoblot HeLa cell lysates and chromosome preparations that had been incubated in vitro in the absence or presence of GB. Anticentromere antibodies (ACAs) were assayed by immunofluorescence and immunoprecipitation of in vitro-translated centromere proteins (CENP-B and CENP-C). Immunoprecipitation of GB-cleaved CENPs was also performed. RESULTS: GB-cleaved autoantigens were immunoblotted by 16 of 19 IDL sera (84.2%) compared with 6 of 15 non-IDL sera (40.0%) (odds ratio 8.0, 95% confidence interval 1.6-40.0). This association persisted after adjustment for ACA status. Furthermore, the presence of antibodies to centromere proteins as well as to GB-cleaved antigens was highly specific for IDL, occurring in 12 of 19 IDL patients (63.2%) and in none of 15 controls (P < 0.0001). An identical 60-kd GB-generated fragment was recognized by 5 of 16 IDL sera (31.3%) and was demonstrated to arise through GB-mediated cleavage of CENP-C. GB-cleaved CENP-C fragments were recognized preferentially over the intact CENP-C molecule by antibodies from patients with IDL. CONCLUSION: The striking recognition of GB-generated autoantigen fragments by sera from patients with limited SSc and IDL constitutes the first in vivo evidence that antibodies against GB-generated centromeric peptide fragments identify a distinct clinical subset.

Autoantibodies↗
PubMed2006

Organ specific autoantigens and the autoreactiveT cell repertoire: the case of myelin oligodendrocyte glycoprotein.

There is strong evidence that immunological self tolerance critically relies on the elimination of potentially autoaggressive T lymphocyte clones from the emerging immune repertoire during intrathymic T cell differentiation. These 'forbidden' T cells are deleted as a result of a confrontation with their specific self antigen as presented on medullary stroma cells. But this purging mechanism is remarkably leaky, allowing numerous autoreactive T cells to join the healthy immune repertoire. A paper in this issue of the European Journal of Immunology studies the effect of organ-specific autoantigen expression on the cognate T cell repertoire. Myelin oligodendrocyte glycoprotein (MOG), a putative autoantigen in human multiple sclerosis, is used as a model self antigen. T cell receptor profiles in wild-type mice were compared with those in MOG-knock-out mice. Surprisingly, significant differences were not found suggesting that, in this particular case, autoantigen expression does not affect the autoreactive T cell repertoire.

Animals↗
PubMed2006

T-cell epitopes of the La/SSB autoantigen: prediction based on the homology modeling of HLA-DQ2/DQ7 with the insulin-B peptide/HLA-DQ8 complex.

T-cell epitopes are important components of the inappropriate response of the immune system to self-proteins in autoimmune diseases. In this study, the candidate T-cell epitopes of the La/SSB autoantigen, the main target of the autoimmune response in patients with Sjogren's Syndrome (SS), and Systemic Lupus Erythematosus (SLE) were predicted using as a template the HLA-DQ2 and DQ7 molecules, which are genetically linked to patients with SS and SLE. Modeling of DQ2 and DQ7 was based on the crystal structure of HLA-DQ8, an HLA molecule of high risk factor of type I diabetes, which is also an autoimmune disease. The quality and reliability of the modeled DQ2 and DQ7 was confirmed by the Ramachandran plot and the TINKER molecular modeling software. Common and/or similar candidate T-cell epitopes, obtained by comparing three different approaches the Taylor's sequence pattern, the TEPITOPE quantitative matrices, and the MULTIPRED artificial neural network, were subjected to homology modeling with the crystal structure of the insulin-B peptide complexed with HLA-DQ8, and the best superposed candidate epitopes were placed into the modeled HLA-DQ2 and DQ7 binding grooves to perform energy minimization calculations. Six T-cell epitopes were predicted for HLA-DQ7 and nine for HLA-DQ2 covering parts of the amino-terminal and the central regions of the La/SSB autoantigen. Residues corresponding to the P1, P4, and P9 pockets of the HLA-DQ2 and DQ7 binding grooves experience very low SASA because they are less exposed to the microenvironment of the groove. The proposed T-cell epitopes complexed with HLA-DQ2/DQ7 were further evaluated for their binding efficiency according to their potential interaction energy, binding affinity, and IC50 values. Our approach constitutes the ground work for a rapid and reliable experimentation concerning the T-cell epitope mapping of autoantigens, and could lead to the development of T-cell inhibitors as immunotherapeutics in autoimmune diseases.

Amino Acid Sequence↗
PubMed1995

Evaluation of recombinant Ro/SSA, La/SSB, Sm, and U1 RNP autoantigens in clinical diagnosis.

This study comprises an analysis of the diagnostic usefulness of Ro/SSA, La/SSB, Sm and U1 RNP autoantigens obtained by DNA recombinant technology. We studied the presence of these autoantibodies in 33 patients with systemic lupus erythematosus (SLE) and 30 normal individuals by enzyme-linked immunosorbent assay (ELISA) using recombinant autoantigens and by Western immunoblot with these same antigens obtained from natural sources (rabbit thymus and human spleen). The strength of agreement between results found with these two techniques was moderate in the case of anti-Ro/SSA (kappa = 0.474, P < 0.001) and anti-U1 RNP (kappa = 0.566. P < 0.001) antibodies and almost perfect in the case of anti-La/SSB (kappa = 0871, P < 0.001) and anti-Sm (kappa = 0.833, P < 0.001). Furthermore, analysis of the disagreement between the two techniques evidenced a measurement bias for anti-Ro/SSA and anti-U1 RNP antibodies (Mc NEMAR'S statistic 13 and 11, respectively) whose direction, though difficult to define in the absence of a gold standard for such determinations, could be accounted for by the ELISA technique's greater tendency to produce positive results. Our conclusion is that the diagnostic usefulness of recombinant La/SSB and Sm autoantigens has been satisfactorily proven, whereas the case of the Ro/SSA and U1 RNP systems should be subject to further in-depth study of the autoepitopes recognised and the possible modifications which the latter might undergo as a result of their obtension from procariotic sources.

Autoantigens↗
PubMed2003

Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans.

Molecular mimicry is one of the mechanisms by which enterovirus infections have been postulated to have a role in the pathogenesis of type 1 diabetes. Immunogenic epitopes in enterovirus capsid protein VP1 and procapsid protein VP0 have sequence similarities with diabetes-associated epitopes in tyrosine phosphatase IA-2/IAR and heat shock protein 60. In the present study, documented enterovirus infection was shown to induce humoral responses, that in 7% and 1% of patients cross-reacted with the known diabetes-associated epitopes in tyrosine phosphatase IAR and heat shock protein 60, respectively. In contrast, none of the children vaccinated against poliomyelitis had antibodies to the diabetes-associated epitope of tyrosine phosphatases IA-2/IAR. The antibody response studied in serum samples from six patients with coxsackievirus A9 infection was mainly targeted to capsid protein VP1. Coxsackievirus A9 infection induced antibodies cross-reacted with one epitope in heat shock protein 60, but not with epitopes derived from other autoantigens. Most diabetic children had high levels of antibodies to both coxsackievirus and poliovirus derived VP1 peptides but the pattern of reactivity did not differ from that seen in healthy children. The reactivity of linear epitopes derived from autoantigens was low in general and associated with the presence of multiple autoantibodies in the patients. Some linear auto-epitopes derived from tyrosine phosphatase IA-2, glutamic acid decarboxylase 65, preproinsulin, and heat shock protein 60 were recognized by sera from diabetic patients, but not by sera from healthy children. In conclusion, enteroviruses may induce immune responses that react with islet cell autoantigens, which is a concern when a putative inactivated enterovirus vaccine is considered.

Adolescent↗
PubMed2006

Proteomic analysis of the autoantibody response following immunization with a single autoantigen.

In most autoimmune diseases, the autoantibody response is directed against several antigens of the target organ whose identification is crucial for understanding the physiopathological process. Thus, technologies allowing a characterization of the whole autoantibody pattern of both human and experimental autoimmune diseases are required. Here we have used immunoproteomic analysis of human epidermal extracts to characterize the diversity of the anti-desmosome antibody response induced in normal mice immunized with desmoglein 1, the major autoantigen of pemphigus foliaceus, an autoimmune blistering skin disease. In particular, this analysis enables us to characterize the binding properties of anti-desmosome mAbs derived from these mice and to show that the autoantibody response induced upon immunization with a single autoantigen targets different epidermal autoantigens with a pattern similar to that observed in certain variety of human pemphigus.

Amino Acid Sequence↗
PubMed1997

Purification and crystallisation of the autoantigen thyroid peroxidase from human Graves' thyroid tissue.

Milligram quantities of the human membrane autoantigen thyroid peroxidase (TPO) have been purified to a high degree of homogeneity by a combination of detergent solubilisation, monoclonal antibody affinity, and ion exchange chromatography, from pooled Graves' disease thyroid glands. The purified TPO of greater than 90% purity was enzymatically active as judged by its ability to oxidise guaiacol. Crystals of TPO have been grown from solutions of the protein solubilised in sodium deoxycholate, in the presence of ammonium sulphate. The crystals exhibited birefringence under polarised light, indicative of molecular order. Crystallisation of this large, membrane autoantigen represents the first step in delineating the complete three-dimensional structure of a human autoantigen involved in destructive thyroiditis.

Autoantigens↗
PubMed2001

Identification of a novel autoantigen UACA in patients with panuveitis.

To identify the target autoantigens in Vogt-Koyanagi-Harada disease, we made use of an immunoscreening of a bovine uveal cDNA expression library with serum samples obtained from patients with Vogt-Koyanagi-Harada disease. We identified a novel bovine antigen and homologous human autoantigen and designated it as UACA (uveal autoantigen with coiled coil domains and ankyrin repeats). mRNA of human UACA is expressed most abundantly in skeletal muscles and in various human tissues, including choroid, retina, and epidermal melanocytes. IgG autoantibodies were quantitated in an ELISA, using recombinant C-terminal 18.0% fragment of human UACA. The prevalence of IgG anti-UACA autoantibodies in patients with panuveitis (Vogt-Koyanagi-Harada disease, Behçet's disease, sarcoidosis) was significantly higher than that in healthy controls (19.6-28.1% vs 0%, P < 0.05) indicating that autoimmunity directed against UACA is a common phenomenon in these diseases.

Adolescent↗
PubMed2000

Autoantigen-responsive T cell clones demonstrate unfocused TCR cross-reactivity toward multiple related ligands: implications for autoimmunity.

It has been suggested that the cross-reaction of a single T cell receptor with multiple different peptide ligands is a mechanism for maintaining a diverse yet compact immune repertoire. In the context of autoimmune disease it is important to understand how this property is balanced against the maintenance of self-tolerance. Specifically, whether the cross-reactivity inherent in the immune system is focused or unfocused will have important consequences for the development of autoimmune disease. If cross-reactivity is "focused," then in an immune response to a foreign antigen all T cell receptors that recognize the foreign antigen will cross-react with a specific autoantigenic peptide. However, if cross-reactivity is "unfocused," an immune response to a foreign antigen will result in the activation of a small number of self-reactive cells within a larger pool of cells specific for the foreign antigen. We have tested whether cross-reactivity is focused or unfocused by generating a panel of T cell clones that respond to two closely related ligands. W144 is an autoantigenic peptide of myelin proteolipid protein, PLP 139-151 (HSLGKWLGHPDKF), and Q144 is an altered peptide of PLP 139-151 bearing a glutamine for tryptophan substitution at position 144. The Q144-responsive clones have a broad degree of cross-reactivity with other position 144 substituted peptides. We find that despite their characteristic responses to Q144 and W144, the patterns of responses of these clones to other structurally related ligands are random, demonstrating that cross-reactivity is unfocused in the absence of selection. Maintaining a diverse range of cross-reactive interactions may limit nonspecific responses to autoantigens.

Amino Acid Sequence↗
PubMed1994

The immunoreactive region in a novel autoantigen contains a nuclear localization sequence.

Antibodies in the serum of patients with autoimmune diseases have been used to identify human autoantigens. Because autoantibodies often recognize active sites within corresponding protein antigens, autoantibodies have facilitated the functional characterization of these polypeptides. In the present study, serum from a patient with Sjögren's syndrome was used to identify a novel autoantigen which was designated Ge-1. Using the patient's serum, a 4.8-kb cDNA encoding Ge-1 was identified. Fragments of the cDNA were ligated into prokaryotic expression vectors, expressed in Escherichia coli, and used to produce recombinant Ge-1 fusion proteins. Fusion proteins containing different portions of Ge-1 were used to identify a 58 amino acid immunoreactive region within the protein. This immunoreactive region contained the protein's putative nuclear localization sequence (NLS). To demonstrate that the immunoreactive region was capable of functioning as a NLS, a eukaryotic expression plasmid was constructed to encode the immunoreactive region fused to the cytoplasmic protein, chicken muscle pyruvate kinase. After transfection of this plasmid into COS-1 cells, the fusion protein was detected in the nucleus. The presence of the NLS motif within the immunoreactive region of Ge-1 and other nuclear autoantigens suggests that the NLS may be a target of human autoantibodies.

Amino Acid Sequence↗
PubMed2000

Human autoantibodies to a novel Golgi protein golgin-67: high similarity with golgin-95/gm 130 autoantigen.

Autoantibodies to subcellular organelles have been described in patients with various systemic rheumatic diseases and our laboratories have been focused on studies of the Golgi complex as the autoimmune target. We have previously isolated and described four of the five known Golgi autoantigens reported to date. During the characterization of Golgi autoantigen golgin-95/gm130, another human cDNA that shared a significant degree of similarity in both nucleotide and amino acid sequences was identified. Analysis of cDNAs from different libraries suggested that this is a distinct gene encoding a protein of 67 kDa which has four regions with sequence identity to gm130, ranging between 42 and 60%. In this report, we describe the complete cDNA encoding a closely related Golgi protein provisionally named golgin-67. Among a group of 84 human anti-Golgi sera, five (6%) were shown to recognize golgin-67. Anti-golgin-67 human sera and affinity purified rabbit antibody to the recombinant protein gave predominant Golgi staining. Golgin-67 is thus the smallest member of a growing family of Golgi autoantigens rich in alpha-helical coiled-coil domain. The current hypothesis for the generation of autoimmune antibody to the Golgi complex is discussed.

Amino Acid Sequence↗
PubMed2000

The identification of endothelial cell autoantigens.

The identity of many endothelial cell autoantigens remains unclear. This study has used human monoclonal anti-endothelial cell autoantibodies isolated from patients with SLE to identify endothelial autoantigens. Thirteen antibodies reactive with endothelial cell membrane preparations were isolated and cloned, one of which has previously been demonstrated to be pro-inflammatory. Western blotting demonstrates that these antibodies recognize a variety of proteins in endothelial cell membrane preparations. Further characterization of five antibodies by cDNA library screening, immunofluorescence and Western blotting proves that two of these antibodies recognized the cytoskeletal proteins tubulin and vimentin. A further antibody identified a clone derived from human collagenase, an identification supported by Western blotting. The multiple clones selected by other antibodies are not compatible with the molecular weight of the antigen recognized in Western blotting studies. This study has clearly identified two endothelial cell autoantigens present in membrane preparations and provides strong evidence as to the identity of a third.

Antibodies, Monoclonal↗