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PubMed1992

Secretory granule autoantigen in insulin-dependent diabetes mellitus is related to 62 kDa heat-shock protein (hsp60).

Recent studies in NOD mice suggest that cellular and humoral responses against beta cell protein(s) cross-reactive with mycobacterial heat-shock protein, hsp60, are implicated in the development of autoimmune diabetes. However, this putative, hsp60-related autoantigen has not yet been identified nor have the preceding events triggering the autoimmunity against it. Our recent studies show that antibodies to the mammalian hsp60 bind specifically to the 62 kDa protein located to insulin secretory granules and mitochondria of pancreatic beta cells of healthy mice [1]. In islets of prediabetic NOD mice affected by insulitis, the cellular distribution of this hsp60-related antigen was found to be altered. In the present report, we have examined whether this endogenous hsp60-related protein of secretory granules serves as an autoantigen in type I diabetes. The results of Western blot analysis indicate that diabetic mice sera show reactivity to a 62 kDa islet cell antigen. The NOD mice sera that were positive in detection of the 62 kDa islet cell antigen were also able to recognize the recombinant human hsp60. Immunogold electron microscopy revealed that diabetic NOD mouse sera, cross-reactive to human recombinant hsp60, recognize the antigen located in secretory granules of beta cells. Double-immunogold labelling demonstrated that antigens recognized by both diabetic NOD mice sera and monoclonal hsp60 antibodies co-localized in the same secretory granules of beta cells. Preincubation of islet cell sections with one type of antibody blocks subsequent binding of the other, indicating that epitopes recognized by both antisera on these proteins are shared. Moreover, preadsorption of diabetic sera with the recombinant human hsp60 abolished labelling of secretory granules. These results indicate that the hsp60-related protein of beta cell secretory granules is an autoantigen in type I diabetes in NOD mice.

Animals↗
PubMed1992

Characterization and epitope mapping of human monoclonal antibodies to PDC-E2, the immunodominant autoantigen of primary biliary cirrhosis.

Further to define the epitopes of PDC-E2, the major autoantigen in primary biliary cirrhosis (PBC), we have developed and characterized five human monoclonal antibodies. These antibodies were derived by fusing a regional hepatic lymph node from a patient with PBC with the mouse human heterohybrid cell line F3B6. Previous studies of epitope mapping of PDC-E2 have relied on whole sera and have suggested that the immunodominant epitope lies within the inner lipoyl domain of the molecule. However, selective absorption studies using whole sera and a series of overlapping recombinant peptides of PDC-E2 have suggested that the epitope may also include a large conformational component. Moreover, several laboratories have suggested that autoantibodies against the 2-oxo acids dehydrogenase autoantigens are cross-reactive. The five monoclonal antibodies generated included three IgG2a and two IgM antibodies and were studied for antigen specificity using recombinant PDC-E2, recombinant BCKD-E2, histone, dsDNA, IgG (Fc), collagen and a recombinant irrelevant liver specific control, the F alloantigen. The antibodies were also used to probe blots of human, bovine, mouse and rat mitochondria. Finally, fine specificity was studied by selective ELISA and absorption against overlapping expressing fragments of PDC-E2. All five monoclonals, but none of the other mitochondrial autoantigens were specific for PDC-E2. In fact, although affinity purified antibodies to PDC-E2 from patients with PBC cross-reacted with protein X, the human monoclonals did not, suggesting that protein X contains an epitope distinct from that found on PDC-E2. Additionally, all three IgG2 monoclonals recognized distinct epitopes within the inner lipoyl domain of PDC-E2.

Animals↗
PubMed2005

Apoptotic modifications affect the autoreactivity of the U1 snRNP autoantigen.

A hallmark of systemic autoimmune diseases is the presence of high titers of serum autoantibodies targeting a diversity of autoantigens. Most components of the U1 snRNP complex are autoantigenic in systemic lupus erythematosus (SLE) and SLE overlap syndrome, which is also called mixed connective tissue disease (MCTD). It is hypothesized that posttranslational modifications, in particular cell death-associated modifications, play an important role in breaking tolerance to self-antigens. Recently, it became clear that the U1 snRNP particle, more specifically its U1-70K protein component, displays a new epitope during apoptosis. This review intends to give an overview of the modifications that occur on the U1 snRNP autoantigens, especially those arising during cell death, to summarize recent data describing autoantibody reactivities with apoptosis-specific epitopes on the U1 snRNP complex, and to provide some insight into the mechanisms that might underlie the immune response to self-antigens.

Animals↗
PubMed2005

Identification of tear lipocalin as a novel autoantigen target in Sjögren's syndrome.

Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and tissue damage mainly confined to the salivary and lacrimal glands, resulting in dryness of mouth and eyes. Since different epithelial cells of exocrine and non-exocrine tissues are primarily affected, an autoimmune reaction against antigens commonly expressed in epithelial cells is believed to play a pathogenic role. To identify novel autoantigen targets associated with the systemic involvement in SS, we screened a random peptide library with pooled IgG immunoglobulins derived from patients with primary SS. Among the identified peptides, one was recognized by the majority of patients' sera, but not by sera of normal donors and of patients with other autoimmune diseases. The peptide showed homology with an Epstein-Barr Virus (EBV) derived protein and with tear lipocalin, a protein highly expressed in tears and saliva, and with alpha-fodrin, a cytoskeleton protein considered an important autoantigen target in SS. Anti-peptide antibodies affinity purified from patients' sera recognize the viral protein, tear lipocalin and alpha-fodrin. Our findings suggest that EBV infection may be linked to the pathogenesis of SS and that tear lipocalin can be considered a novel and yet unidentified autoantigen in SS.

Antigens, Viral↗
PubMed2006

Mesangial autoantigens in IgA nephropathy: matrix synthesis and localization.

Primary IgA nephropathy, a chronic nephritis with variable prognosis, is characterized by mesangial immunoglobulin A, frequently with codeposition of other immunoglobulin isotypes and complement components accompanying matrix expansion typically preceding glomerular scarring. Glomerular immunoglobulin G, when present, is localized to the mesangial periphery found variably in repeat biopsies. IgG anti-mesangial cell autoantibodies (IgG-MESCA) in sera of patients with IgA nephropathy, specific by F(ab')(2) binding to 48- and 55-kD autoantigen(s) could account for these deposits, but their in vivo localization, and the functional role in promoting scarring is unknown. A specific monoclonal antibody raised previously to these human mesangial cell autoantigen fractions, in this study localized to similar glomerular sites, reinforcing the view that immunoglobulin G deposition in vivo is a result of antibody-autoantigen binding. The propensity for immunoglobulin G more than other isotypes to enhance inflammation prompted study of its functional role in vitro. Using cultured human mesangial cells in a complement-free tritiated glycosaminoglycan synthesis single outcome assay, purified IgG fractions from patient sera increased matrix production in a dose-dependent manner compared with controls. At a constant total IgG concentration, matrix synthesis was proportional to the titre of IgG-MESCA. Autoreactive IgG stimulated matrix synthesis when compared with controls or IgA fractions. These findings are consistent with IgG-MESCA autoantibodies enhancing mesangial matrix synthesis in vitro, which suggests that in IgA nephropathy, similar prosclerotic autoimmune mechanisms might operate. Recombinant TGFbeta(1) also induced matrix synthesis, raising the possibility that both autoimmune mechanisms and those TGFbeta(1)-dependent are functional or inter-related. The pathogenesis of glomerular scarring and loss in IgA nephropathy may include, in part, these mechanisms.

Antibodies, Monoclonal↗
PubMed2004

Altered structure of autoantigens during apoptosis.

The clustering and concentration of autoantigens at the surface of apoptotic cells, in combination with the striking tolerance-inducing function of apoptotic cells, have focused attention on abnormalities in apoptotic cell execution and clearance as potential susceptibility and initiating factors in systemic autoimmunity. Structural changes that occur during cell death may influence the immunogenicity of self antigens. This article discusses the modifications that autoantigens undergo during cell death, identifies certain proimmune forms of apoptotic death in which autoantigen structure is frequently modified, and reviews the mechanisms through which such structural changes might lead to initiation of an autoimmune response.

Apoptosis↗
PubMed1998

The gastric H+,K+-ATPase is a major autoantigen in chronic Helicobacter pylori gastritis with body mucosa atrophy.

BACKGROUND & AIMS: A subgroup of Helicobacter pylori-infected patients develops autoantibodies to gastric parietal cell canaliculi. The aim of this study was to define the unknown autoantigen. METHODS: We screened 72 H. pylori-infected patients, 5 patients with autoimmune gastritis, and 36 healthy controls for immunoglobulin G autoantibodies to canaliculi by immunohistochemistry. The antigen specificity was determined by immunoprecipitation of the murine gastric H+,K+-adenosine triphosphatase (H+,K+-ATPase) expressed in oocytes and by immunoblotting on human gastric membranes from the body mucosa. RESULTS: Autoantibodies specific for the conformational peptides of the H+,K+-ATPase were detected in 3% (1/36) of controls, in all patients with autoimmune gastritis (5/5), in 25% (18/72) of H. pylori-infected patients, and in 47% (15/32) of the infected patients with anticanalicular autoantibodies. No other major autoantigen was identified. Atrophy in the gastric body mucosa was found in 60% (9/15) of infected patients with both anticanalicular and anti-H+,K+-ATPase antibodies, but only in 13% (5/37) of infected patients lacking both autoantibodies (P < 0.01). CONCLUSIONS: The gastric H+,K+-ATPase is a major autoantigen in H. pylori-associated antigastric autoimmunity. Thus, anti-H+,K+-ATPase autoantibodies, which are closely linked to classical autoimmune gastritis, are also significant indicators for body mucosa atrophy in chronic H. pylori gastritis.

Adult↗
PubMed2000

Autoantibodies and autoantigens in chronic immune thrombocytopenic purpura.

Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disorder in which antiplatelet autoantibodies bind to antigens on the surface of platelets, resulting in their destruction. The newer antigen-specific (phase III) assays can detect platelet-associated and plasma autoantibodies in approximately 75% and 50% of patients, respectively. Antiplatelet autoantibodies bind to both platelets and megakaryocytes and preliminary evidence suggests that they not only cause platelet destruction but can also decrease platelet production either by interfering with megakaryocyte proliferation/maturation or by causing intramedullary platelet destruction. Autoantibodies are capable of activating complement and causing platelet phagocytosis both in vitro and in vivo. Many platelet-associated and plasma autoantibodies from ITP patients are light chain-restricted, which suggests a clonal origin. Approximately 75% of platelet autoantigens are localized to either the platelet glycoprotein (GP) IIb/IIIa or Ib/IX complex. Inhibition of the binding of autoantibodies from several ITP patients by either another ITP autoantibody or by a monoclonal anti-GPIIb/IIIa antibody suggests that the antigenic repertoire in chronic ITP may be limited. Most autoantigens on GPIIb/IIIa appear to be conformational since they are dependent on the presence of divalent cations. A variety of new investigative techniques have localized a few autoantigens to specific regions of the cytoplasmic or extracellular regions of both GPIIb/IIIa and GPIb/IX.

Antigens, Human Platelet↗
PubMed2003

Recombinant autoantigens for diagnosis and therapy of autoimmune diseases.

The characteristic of autoimmune diseases resides in the existence of T- and B-cell autoreactivity when directed against self-proteins. Thus autoantibodies are considered to be of diagnostic relevance. The advent of recombinant protein expression technology has made it possible to produce economically high-quality autoantigens for use in immunoassays for detecting autoantibodies in patients' sera. The intention of this short review is to give the reader a brief description of autoantigen production methodologies with their advantages, disadvantages and the limitations of these techniques in the diagnostics of autoimmune diseases. Further possible usage of recombinant autoantigens as tools in investigation and therapy of autoimmune diseases is discussed.

Autoantigens↗
PubMed2003

Antinuclear antibodies recognize cellular autoantigens driven by apoptosis.

OBJECTIVE: Present study addresses the issue whether cellular antigens recognised by antinuclear autoantibodies are driven by apoptosis. MATERIALS AND METHODS: HEp-2 cells were committed to apoptosis by camptothecin; DNA fragmentation and FasL and Bax expression monitored apoptosis. Autoantigens were probed by indirect immunofluorescence and Western blot with autoantibodies or monoclonals against: DNA, Ro60, La, U1-RNP, CENP-B, DNA Topoisomerase I, Jo-1 and NuMA. A comparison of antinuclear antibody reactivity between living and apoptotic cells was performed by ELISA. RESULTS: Apoptotic changes such as chromatin fragmentation, blebs and apoptotic bodies were induced with 20 mM camptothecin. Autoantigens were better detected in apoptotic cells. U1-RNP, Jo1, DNA-Topoisomerase I, CENP-B and NuMA exhibited fragmentation and redistribution as a consequence of apoptosis; in contrast, Ro60 and La ribonucleoproteins did not show proteolysis. Additionally the ELISA titers of antinuclear antibodies were higher in apoptotic cells than in normal cells. CONCLUSION: Apoptosis induces molecular changes in different autoantigens, this modification increases the antigen-driven response of autoantibodies such as anti-RNP, anti-DNA Topoisomerase I, anti-CENP-B and anti-Jo1. Apoptotic changes would contribute to break down the tolerance in autoimmune connective tissue disease.

Antibodies, Antinuclear↗
PubMed2003

Advances in B-cell epitope analysis of autoantigens in connective tissue diseases.

The characterization of autoantibody specificities in rheumatic diseases is important in both diagnostic and basic research areas. Identification of the epitopes recognized by autoantibodies and their clinical and biological significance is not a trivial task. Epitopes may range in complexity from simple linear sequences of amino acids to complex quaternary structures. In addition to this structural complexity the frequency with which an autoantigen and its epitopes are recognized in a patient population may be useful in diagnosis, defining disease subgroups, and may offer information on disease prognosis. In this review recent advances in the epitope mapping of autoantigens in connective tissue diseases are discussed, with particular emphasis placed on the methodologies used to identify epitopes and the classification of the structural features of epitopes. To illustrate the identification of epitope structure, clinically relevant autoantigens, including CENP-A, PM/Scl-100, fibrillarin, filaggrin, Ro-52, and dsDNA, are discussed as examples of each type of epitope.

Amino Acid Sequence↗
PubMed1998

Localization of autoepitopes on the PCM-1 autoantigen using scleroderma sera with autoantibodies against the centrosome.

Characterization of epitope domains of autoantigens is important for deducing the cellular functions of autoantigens and may be important for understanding the autoimmune response. In the reported studies, epitope analysis of the centrosome autoantigen PCM-1 was performed. For these investigations, portion of the PCM-1 cDNA were subcloned into the pMAL expression plasmid, fusion proteins were induced, and aliquots of the extracts were probed by immunoblot analysis using two human autoimmune anticentrosome autoantisera. Immunoblotting identified three individual autoepitopes of 26-40 amino acid residues, amino acids 506-545, 1434-1465, and 1661-1686, within the PCM-1 protein. ELISA assays using non-denatured proteins did not identity any additional autoepitopes in the remainder of the PCM-1 molecule. To analyze the identified autoepitopes further, synthetic peptides were generated that covered each of the three autoepitopes and the synthetic peptides then were probed using the scleroderma sera. Peptides that covered the antigenic regions from amino acids 506-545 and 1434-1465 failed to react with the anticentrosome autoantisera suggesting that overall protein conformation may be important for the formation of those two autoepitopes. Peptides derived from the sequence of the third autoepitope were recognized by autoantibodies present in the anticentrosome autoantisera allowing the identification of the tripeptide KDC as the autoepitope in this region of the PCM-1 molecule. These studies lay the foundation for future investigations of the autoimmune response in scleroderma patients that are producing anticentrosome autoantibodies and should allow an investigation of the cellular role of the PCM-1 protein.

Autoantibodies↗
PubMed1999

Centrosome proteins: a major class of autoantigens in scleroderma.

Autoantibodies to intracellular antigens are a hallmark of autoimmune diseases, although their role in disease pathogenesis is unclear. Centrosomes are organelles involved in the organization of the mitotic spindle and they are targets of autoantibodies in systemic sclerosis (SSc). We used recombinant centrosome autoantigens, centrosome-specific antibodies, and immunoassays to demonstrate that a significant proportion of SSc patients exhibited centrosome reactivity. Two centrosome proteins cloned in our laboratory were used to screen 129 SSc sera by Western blotting. The same sera were screened by immunofluorescence using centrosome-specific antibodies to distinguish centrosomes from nuclear speckles commonly stained by SSc sera. Using these criteria, 42.6% of SSc patients were autoreactive to centrosomes, a larger percentage than reacted with all other known SSc autoantigens. Most centrosome-positive sera reacted with both centrosome proteins and half were negative for other routinely assayed SSc autoantibodies. By these criteria, we have identified a novel class of SSc autoreactivity. Only a small percentage of normal individuals and patients with other connective tissue diseases had centrosome reactivity. These results demonstrate that centrosome autoantibodies are a major component of autoreactivity in SSc and thus have potential in disease diagnosis. Centrosome autoantigens may be useful in studying the development of autoantibodies and chronic inflammation in SSc and perhaps other autoimmune diseases.

Antigens↗
PubMed1993

Molecular characteristics of the Goodpasture autoantigen.

Goodpasture syndrome is an autoimmune disease causing rapidly progressive glomerulonephritis and pulmonary hemorrhage. The clinical manifestations are caused by autoantibodies that bind to a constituent, termed the Goodpasture autoantigen, of alveolar and glomerular basement membranes. Searches for the identity of this constituent have recently culminated in the discovery of two new chains (alpha 3 and alpha 4) of type IV collagen and the identification of the alpha 3 chain as the Goodpasture autoantigen. The gene, COL4A3, encoding this autoantigen was recently cloned and localized to the q35-37 region of chromosome 2. The major protomeric form of the alpha 3 chain is a homotrimer. The alpha 3-protomers associate through NC1-to-NC1 interactions mainly with each other to form a suprastructure, although some associate with protomers containing the alpha 1(IV) and alpha 2(IV) chains. The alpha 3-protomers also form suprastructures involving triple helical interactions of three or more protomers. The Goodpasture epitope is localized to the carboxylterminal region of the alpha 3(IV) chain, encompassing the last 36 residues of the chain, as the primary interaction site, and its structure is discontinuous.

Amino Acid Sequence↗
PubMed2002

Targeting autoantigen-specific T cells and suppression of autoimmune encephalomyelitis with receptor-modified T lymphocytes.

We demonstrate here the feasibility of antigen-specifically redirecting T cells against autoreactive T lymphocytes and thereby treating a model autoimmune disease. We created and transgenically expressed on T cells a heterodimeric chimeric receptor that genetically links an autoantigenic peptide, its restricting MHC, and the signal transduction domain of the T-cell receptor (TCR) zeta-chain. Engagement of the chimeric receptor by the TCR of autoreactive T cells activated the receptor-modified T cells in vitro and in vivo, inducing proliferation and cytolysis. Adoptively transferred receptor-modified T cells prevented and treated a model autoimmune disease, experimental allergic encephalomyelitis (EAE), even after epitope spreading had diversified the autoantigenic response. Treatment reduced disease severity and increased survival of affected animals, and was durable for >75 days. The receptor-modified cells acted both by strongly attenuating T-cell response to autoantigen as well as by shifting the residual response from an immunopathologic Th1 to a protective Th2 format.

Animals↗
PubMed1997

Identification of tissue transglutaminase as the autoantigen of celiac disease.

Celiac disease is characterized by small intestinal damage with loss of absorptive villi and hyperplasia of the crypts, typically leading to malabsorption. In addition to nutrient deficiencies, prolonged celiac disease is associated with an increased risk for malignancy, especially intestinal T-cell lymphoma. Celiac disease is precipitated by ingestion of the protein gliadin, a component of wheat gluten, and usually resolves on its withdrawal. Gliadin initiates mucosal damage which involves an immunological process in individuals with a genetic predisposition. However, the mechanism responsible for the small intestinal damage characteristic of celiac disease is still under debate. Small intestinal biopsy with the demonstration of a flat mucosa which is reversed on a gluten-free diet is considered the main approach for diagnosis of classical celiac disease. In addition, IgA antibodies against gliadin and endomysium, a structure of the smooth muscle connective tissue, are valuable tools for the detection of patients with celiac disease and for therapy control. Incidence rates of childhood celiac disease range from 1:300 in Western Ireland to 1:4700 in other European countries, and subclinical cases detected by serological screening revealed prevalences of 3.3 and 4 per 1000 in Italy and the USA, respectively. IgA antibodies to endomysium are particularly specific indicators of celiac disease, suggesting that this structure contains one or more target autoantigens that play a role in the pathogenesis of the disease. However, the identification of the endomysial autoantigen(s) has remained elusive. We identified tissue transglutaminase as the unknown endomysial autoantigen. Interestingly, gliadin is a preferred substrate for this enzyme, giving rise to novel antigenic epitopes.

Animals↗
PubMed2003

Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3.

It remains unclear how and why autoimmunity occurs. Here we show evidence for a previously unrecognized and possibly general mechanism of autoimmunity. This new finding was discovered serendipitously using material from patients with inflammatory vascular disease caused by antineutrophil cytoplasmic autoantibodies (ANCA) with specificity for proteinase-3 (PR-3). Such patients harbor not only antibodies to the autoantigen (PR-3), but also antibodies to a peptide translated from the antisense DNA strand of PR-3 (complementary PR-3, cPR-3) or to a mimic of this peptide. Immunization of mice with the middle region of cPR-3 resulted in production of antibodies not only to cPR-3, but also to the immunogen's sense peptide counterpart, PR-3. Both human and mouse antibodies to PR-3 and cPR-3 bound to each other, indicating idiotypic relationships. These findings indicate that autoimmunity can be initiated through an immune response against a peptide that is antisense or complementary to the autoantigen, which then induces anti-idiotypic antibodies (autoantibodies) that cross-react with the autoantigen.

Amino Acid Sequence↗
PubMed2006

LEDGF/DFS70, a major autoantigen of atopic dermatitis, is a component of keratohyalin granules.

Lens epithelium-derived growth factor/dense fine speckles 70 kDa protein (LEDGF/DFS70) is a transcriptional cofactor, a transcriptional activator, survival factor, and HIV-1 transporter. It is also a major autoantigen in patients with atopic dermatitis (AD), because autoantibodies to this protein are found in approximately 30% of AD patients. To better understand the role of autoantibodies and autoantigens in the pathogenesis of AD, we examined the distribution of LEDGF/DFS70 in the epidermis of normal human skin by light and electron microscopic immunocytochemistry. Increased amounts of LEDGF/DFS70 were located in the nuclei of cells in the basal layer, whereas the cytoplasm of cells in the granular layer stained for LEDGF/DFS70 by light microscopy. Using immunoelectron microscopy, we observed the accumulation of LEDGF/DFS70 in keratohyalin granules (KGs) in the cytoplasm of cells in the granular layer. In addition, Ig heavy chain-binding protein/glucose-regulated protein, 78-kDa (Bip/GRP78), a stress sensing protein in the endoplasmic reticulum, colocalized with LEDGF/DFS70 in the KGs. These results suggest that LEDGF/DFS70 is predominantly located in the nucleus of the basal epidermal cells and translocates into the cytoplasm during differentiation. Once in the cytoplasm, LEDGF/DFS70 accumulates in the KGs in the granular layer. Finally, LEDGF/DFS70, a "nuclear" autoantigen in AD, may play a functional role in the KGs.

Adaptor Proteins, Signal Transducing↗