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PubMed1996

RNA recognition by autoantigens and autoantibodies.

The La, Ro, Sm and RNP autoantigens have been intensely studied over the past decade since cDNAs encoding autoantigens have been available. Most of these autoantigens are closely associated with RNA in RNP particles and molecular studies have provided insights into their modes of recognition and binding to RNA. For example, a common RNA Recognition Motif (RRM) was found to be a critical component of the RNA-binding domain of these autoantigens and the three dimensional structure of the RRM has been solved. As described in other articles in this series, the presence of La, Ro, Sm and RNP autoantibodies correlates with disease subsets, such as Sjogren's syndrome, systemic lupus erythematous and other connective tissue diseases. Immunological analysis of sera from autoimmune patients using recombinant autoantigens has revealed that multiple epitopes reside along the proteins and these represent both continuous and discontinuous (conformational) autotopes. Findings to date support a model of autoantibody induction which involves the direct presentation of proteinaceous autoantigens to the immune system. Circumstantial evidence has suggested that immunological crossreactivity between systemic autoantigens and structural components of infectious agents may play an initial role in the autoimmune response to certain antigens. However, the etiology of autoimmune diseases is probably multifactoral with genetic and other immune features acting on the organismal level. In addition, RNA molecules themselves can be autoantigens with higher order structural conformations which are recognized by RNP-type autoantibodies. Immune crossreactivity and/or direct presentation may generate autoantibodies reactive with conformational RNA epitopes. If crossreactivity with components of cellular or infectious agents give rise to RNA epitopes, they may represent structural or functional mimetics of the primary epitopes that actually drive the response. These ideas are discussed with respect to the role of mimetic processes in molecular recognition during autoimmunity.

Animals↗

PubMed2004

Autoantigen complementarity: a new theory implicating complementary proteins as initiators of autoimmune disease.

Autoimmune diseases affect approximately 1 in 21 persons in the United States. Treatment often requires long-term cytotoxic therapy. How and why these deleterious diseases occur is unclear. A serendipitous finding in our laboratory using serum from patients with autoimmune vasculitis led us to develop the theory of autoantigen complementarity, a novel concept that may elucidate the etiological and pathogenetic mechanisms underlying autoimmune disease in general. The theory proposes that the inciting immunogen that elicits a cascade of immunological events is not the self-antigen (the autoantigen) or its mimic but rather a protein that is complementary in surface structure to the autoantigen; that is, a protein homologous or identical to the amino acid sequence of translated antisense RNA from the noncoding strand of the autoantigen gene. The cascade begins when this complementary protein initiates the production of antibodies that in turn elicit an anti-antibody or anti-idiotypic response. These anti-idiotypic antibodies can now react with the autoantigen. Strikingly, homology search of complementary proteins yields microbial and fungal proteins, thus indicating that invading micro-organisms can deliver the inciting immunogen. Curiously, approximately 50% of our patients transcribe the complementary protein's antisense RNA. If it transpires that these aberrant RNAs are translated, the complementary protein would be produced by the individual. Here we review published research investigating complementary proteins, anti-idiotypic immune responses, and antisense transcripts, all of which support complementary proteins as initiators of autoimmune disease. In addition, we provide possible microbial and/or fungal organisms that may incite some of the most studied autoimmune diseases. Lastly, we propose mechanisms by which cell-mediated autoimmunity can be triggered by autoantigen complementarity. Based on our data and the contributions of the researchers described in this review, identification of proteins complementary to autoantigens is likely to be informative in most autoimmune diseases. This vein of study is in the early phases; however, we expect "autoantigen complementarity" is an underlying mechanism in many autoimmune diseases.

Animals↗

PubMed2002

Autoantigen microarrays for multiplex characterization of autoantibody responses.

We constructed miniaturized autoantigen arrays to perform large-scale multiplex characterization of autoantibody responses directed against structurally diverse autoantigens, using submicroliter quantities of clinical samples. Autoantigen microarrays were produced by attaching hundreds of proteins, peptides and other biomolecules to the surface of derivatized glass slides using a robotic arrayer. Arrays were incubated with patient serum, and spectrally resolvable fluorescent labels were used to detect autoantibody binding to specific autoantigens on the array. We describe and characterize arrays containing the major autoantigens in eight distinct human autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. This represents the first report of application of such technology to multiple human disease sera, and will enable validated detection of antibodies recognizing autoantigens including proteins, peptides, enzyme complexes, ribonucleoprotein complexes, DNA and post-translationally modified antigens. Autoantigen microarrays represent a powerful tool to study the specificity and pathogenesis of autoantibody responses, and to identify and define relevant autoantigens in human autoimmune diseases.

Animals↗

PubMed2000

Mechanisms of neonatal tolerance induced in an animal model for primary Sjögren's syndrome by intravenous administration of autoantigen.

Neonatal exposure to autoantigen is believed to induce effective antigen-specific T-cell tolerance in experimental models of autoimmunity. We have identified 120 kDa alpha-fodrin autoantigen in an animal model for primary Sjögren's syndrome (SS), that has been determined as a candidate autoantigen in both an animal model and the patients with primary SS. We demonstrate here that neonatal injection of autoantigen induce relevant tolerance when treated with intravenous (i.v.) administration within 24 h after birth, but not with i.v. injection after the thymectomy or with intraperitoneal injection. Autoantigen-specific T-cell response was significantly reduced in mice induced neonatal tolerance, and the activation markers of splenic CD4+ T cells were down-regulated in mice treated with neonatal administration. Because we detected that neonatal i.v. injection of autoantigen prevented Th1 response, it is possible that the autoantigen administration within 24 h after birth induce regulatory T cells that had a protective effect against Th1-mediated autoimmune diseases. These results indicate that the prevention of the spontaneous anti-120 kDa alpha-fodrin response in vivo, by tolerization of the autoantigen-reactive T cells, blocked the development of autoimmune lesions in an animal model for primary SS.

Animals↗

PubMed2001

Systemic sclerosis (scleroderma): specific autoantigen genes are selectively overexpressed in scleroderma fibroblasts.

The pathogenesis of systemic sclerosis (SSc) involves complex interactions between activated fibroblasts eventually leading to fibrosis, and impaired immune tolerance characterized by a variety of circulating SSc-specific autoantibodies. The expression of autoantigens in fibroblasts, a key target tissue in SSc, may play an important role in this process. To obtain a global view of this process, we examined gene expression profiles of SSc dermal fibroblasts using cDNA microarrays. The results show that dermal fibroblasts from SSc patients obtained from either affected or unaffected skin displayed a characteristic pattern of increased SSc autoantigen gene expression compared with that from normal controls. In particular, fibrillarin (p = 0.028), centromeric protein B (p = 0.01), centromeric autoantigen P27 (p = 0.042), and RNA polymerase II (220 kDa; p = 0.02) were significantly overexpressed in SSc fibroblasts. Quantitative RT-PCR confirmed overexpression of these autoantigens and also revealed increased levels of DNA topoisomerase I transcripts in SSc fibroblasts compared with normal control fibroblasts (p = 0.0318). The polymyositis/scleroderma autoantigen gene was overexpressed in some SSc patients (p = 0.09). To examine the specificity of these overexpressed autoantigen genes for SSc and its tissue specificity for fibroblasts, cDNA microarrays of dermal fibroblasts from patients with eosinophilic fasciitis and scleromyxedema were studied as well as PBMC and muscle biopsies from SSc patients. None of these tissues showed significant alterations in gene expression of SSc-specific autoantigens. Therefore, SSc-associated autoantigen genes are selectively overexpressed in SSc dermal fibroblasts, a major tissue involved in disease pathogenesis.

Autoantigens↗

PubMed1992

Refined definition of the 56K and other autoantigens in the 50-60 kDa region.

Alteration of the acrylamide:bisacrylamide ratio in the SDS-polyacrylamide gel used for Western blotting strongly improved the unambiguous detection of antibodies against 50-60 kDa autoantigens present in autoimmune patient sera. The relative migration of Ro52, the 56K autoantigen and calreticulin increased with reduced acrylamide:bisacrylamide ratios in contrast to that of Ro60, La and Jo-1. These analyses indicated that these six autoantigens correspond to six distinct polypeptides. Further analyses using recombinant calreticulin showed that (i) the 56K autoantigen is neither identical nor related to calreticulin and (ii) calreticulin is not a Ro autoantigen. A series of experiments designed to better characterize the 56K autoantigen showed that (i) the antigen is not detectable in fixed cells, presumably due to masking of the epitopes; (ii) about equal amounts of the antigen were recovered in nuclear and cytoplasmic cell fractions after enucleation of the cells; (iii) the 56K autoantigen is not stably associated with either RNA or other proteins.

Animals↗

PubMed1999

Post-obstruction rat sperm autoantigens identified by two-dimensional gel electrophoresis and western blotting.

Although antisperm autoantibody responses to obstruction of the male reproductive system have been documented, information on the nature of the cognate sperm autoantigens has been limited. In the present study, the patterns of sperm autoantigens recognized by sera from rats after obstruction of the vas deferens or epididymis were studied by high resolution two-dimensional (2-D) gel electrophoresis and western blotting. Comparisons of patterns of autoantigens stained on 2-D western blots of sera from prepubertal vasectomy, prepubertal epididymal ligation and adult vasectomy groups revealed both similarities and differences. Sera from sham-operated animals showed no detectable reaction or much lighter staining of a small number of spots. Visualization of sperm autoantigens on 2-D western blots supported the hypothesis that there is a relatively small set of sperm proteins that can be regarded as dominant post-obstruction sperm autoantigens because they are recognized by multiple post-obstruction sera. The 2-D analysis revealed previously undetected distinctions in the autoantigens recognized after adult and prepubertal vasectomy, as well as variations with the site of obstruction. These differences in the response may be due in part to changes in antigens of spermatozoa in different parts of the tract and at different ages, as well as variations in exposure of sperm cell proteins to the immune system resulting from the sites of spermatic granulomas. Preparative 2-D gels and western blotting with post-obstruction sera are now being used to identify specific sperm autoantigens by microsequencing of selected proteins.

Animals↗

PubMed2004

Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF.

Peripheral autoantigen binding B cells are poorly competitive with naive B cells for survival and undergo rapid cell death. However, in monoclonal Ig-transgenic mice lacking competitor B cells, autoantigen binding B cells can survive for extended periods. The basis for competitive elimination of autoantigen binding B cells has been unknown. Here we demonstrate that autoantigen binding B cells have increased dependence on BAFF for survival. In monoclonal Ig-transgenic mice, each autoantigen binding B cell receives elevated amounts of BAFF, exhibiting increased levels of NFkappaB p52 and of the prosurvival kinase Pim2. When placed in a diverse B cell compartment, BAFF receptor engagement and signaling are reduced and the autoantigen binding cells are unable to protect themselves from Bim and possibly other death-promoting factors induced by chronic BCR signaling. These findings indicate that under conditions where BAFF levels are elevated, autoantigen-engaged cells will be rescued from rapid competitive elimination, predisposing to the development of autoimmune disease.

Adoptive Transfer↗

PubMed1993

Primary structure and characterization of an androgen-stimulated autoantigen purified from mouse seminal-vesicle secretion.

A protein extract of mouse seminal-vesicle secretion was used to immunize mature mice (Balb/c) of both sexes. Results of Western-blot analyses for these secretory proteins indicated that only one minor protein component could be recognized by the autoantisera prepared from either autoimmunization of male mice or isoimmunization of female mice. The autoantigen was purified from seminal-vesicle secretion. The purified autoantigen retained the ability to induce autoantibody formation. The autoantigen has glycoprotein characteristics: the majority of the carbohydrate is N-linked and the remainder is O-linked. Rabbit antibodies to the autoantigen were used to isolate the corresponding cDNA from a mouse seminal-vesicle cDNA library. The primary structure deduced from the cDNA sequence was confirmed by direct amino acid sequence determination. The results indicate that the core protein consists of 131 amino acid residues. Analysis of the primary structure indicates that the autoantigen has two potential acceptor sites for the N-linked carbohydrate at Asn-12 and Asn-122, three potential phosphorylation sites for casein kinase II at Thr-55, Ser-68 and Thr-76, and three potential phosphorylation sites for protein kinase C at Thr-28, Thr-40 and Thr-124. The core protein and the carbohydrate portion together have a molecular mass of 19 kDa. Results from Western- and Northern-blot analyses for various tissues indicate that the seminal vesicle is the sole organ producing this autoantigen. Expression of this autoantigen gene was stimulated by testosterone.

Amino Acid Sequence↗

PubMed1991

Clarification of the identity of the major M2 autoantigen in primary biliary cirrhosis.

1. In primary biliary cirrhosis, the major M2 autoantigen, reacting with antimitochondrial antibodies in sera from greater than 90% of patients, has been identified as the E2 component of the pyruvate dehydrogenase complex. However, two recent reports suggest that alternative polypeptides may be major autoantigens. 2. The evidence that a 75 kDa subunit of complex I of the respiratory chain is a major autoantigen (Frostell, Mendel-Hartvig, Nelson, Totterman, Bjorkland & Ragan, Scand. J. Immunol. 1988; 28, 157-65) is refuted. The findings of Frostell et al. can be explained by contamination of complex I with the pyruvate dehydrogenase complex, evidence for which is presented here. 3. Inspection of the partial amino acid sequence of an unidentified mitochondrial autoantigen (Muno, Kominami, Ishii, Usui, Saituku, Sakakibara & Namihisa, Hepatology 1990; 11, 16-23) shows that it is the E1 beta-subunit of the pyruvate dehydrogenase complex, previously identified as a major autoantigen, and not a 'new' alternative major autoantigen. 4. These findings substantiate previous work showing that the mitochondrial M2 autoantigens identified so far in primary biliary cirrhosis are all polypeptide components of the pyruvate dehydrogenase complex or the other related 2-oxo acid dehydrogenase complexes.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMed2005

An HIV-1 tat-autoantigen fusion protein suppresses insulitis in NOD mice.

To assess the immunomodulatory activity of the HIV Tat transduction peptide for enhancement of suppression of Type 1 autoimmune diabetes, the 11 amino acid HIV-1 Tat transduction peptide was genetically linked to the major islet autoantigens proinsulin (INS) and glutamic acid decarboxylase (GAD). The Tat-autoantigen fusion proteins were synthesized in Escherichia coli and characterized by acrylamide gel separation and immunoblot analysis. Histological examination of pancreatic islets isolated from juvenile NOD mice inoculated orally with the Tat-autoantigen conjugates revealed a significant reduction in islet inflammation (insulitis) in comparison with islets from unimmunized mice. Increased serum IgG1 antibody isotype titers detected in Tat-autoantigen inoculated mice suggest that the transduction peptide-autoantigen fusion proteins stimulate Th2 lymphocyte mediated bystander suppression. The reduction of islet insulitis observed in Tat-autoantigen inoculated mice suggests that the adjuvant effect of the Tat transduction peptide resides in Tat enhanced delivery of linked autoantigens through enterocytes to lymphocytes in the gut-associated lymphoid tissues.

Animals↗

PubMed2006

Bacterial and plant enterotoxin B subunit-autoantigen fusion proteins suppress diabetes insulitis.

Several bacterial and plant enterotoxin B subunit-islet autoantigen fusion proteins were compared for their ability to serve as islet autoantigen carriers and adjuvants for reduction of pancreatic islet inflammation associated with type 1 diabetes. The cholera toxin B subunit (CTB), the heat-labile toxin B subunit from enterotoxigenic Escherichia coli (LTB), the Shigella toxin B subunit (STB), and the plant toxin ricin B subunit (RTB) were genetically linked to the islet autoantigens proinsulin (INS) and glutamic acid decarboxylase (GAD). The adjuvant-autoantigen gene fusions were transferred to a bacterial expression vector and the corresponding fusion proteins synthesized in E. coli. The purified adjuvant-autoantigen proteins were fed to 5-wk-old nonobese diabetic (NOD) mice once a week for 4 wk. Histological examination of pancreatic islets isolated from inoculated mice showed significant levels of insulitis reduction in comparison with uninoculated mice. The ratio of serum anti-INS and anti-GAD IgG2c to IgG1 antibody isotype titers increased in all ligand-autoantigen inoculated animal groups, suggesting an increase in effector Th2 lymphocytes in B subunit-mediated insulitis suppression. The results of these experiments indicate that bacterial and plant enterotoxin B subunit ligand-autoantigens enhance insulitis reduction in NOD mice. This research prompts further exploration of a multiadjuvant/autoantigen co-delivery strategy that may facilitate type 1 diabetes prevention and suppression in animals and humans.

Animals↗

PubMed1987

Experimental allergic orchitis in mice: IV. Preliminary characterization of the major murine testis specific aspermatogenic autoantigen(s).

Active experimental allergic orchitis (EAO), characterized by inflammation of the testes (autoimmune orchitis), aspermatogenesis, epididymitis and vasitis was induced in mice using a panel of tissue antigens as immunogens. Immunization with allogeneic murine tissue homogenates emulsified in complete Freund's adjuvant (CFA) accompanied by the injection of pertussigen revealed that only adult murine testicular and epididymal homogenates are capable of eliciting murine EAO. All other tissue antigens studied including prepubertal mouse and epididymal homogenates failed to elicit significant disease. Immunization with xenogeneic testicular antigens also failed to elicit significant disease indicating that the major murine aspermatogenic autoantigen(s) is also highly species specific. Sensitization with allogeneic mouse testicular homogenates (MTH) from different disease resistant strains was for the most part no less potent in inducing significant disease than was immunization with mouse testicular homogenates from disease susceptible strains. However, testicular homogenates from NZB/B1NJUnm and MRL/MpJ-/+Unm mice were significantly less potent at inducing autoimmune epididymitis as compared to other strains, indicating possible interstrain differences in the immunogenicity of the aspermatogenic autoantigen(s) relevant to eliciting epididymitis. Attempts at solubilization and purification of the major murine aspermatogenic autoantigen(s) utilizing techniques employed for the purification of aspermatogenic autoantigens such as AP3 from guinea pig (GP) testes were unsuccessful. Additional extraction procedures resulted in solubilization of the relevant autoantigen(s) only after reduction in the presence of 6 M guanidine hydrochloride. These data suggest that: (1) there may be a much more limited number of aspermatogenic autoantigens in murine testes as compared to GP testes; (2) the disease inducing determinant(s) may be expressed as either a sequential antigenic determinant(s) or as an antigenic determinant(s) in the carbohydrate portion of a glycoprotein or glycopeptide; and (3) the disease inducing autoantigen(s) may be present in situ in a highly insoluble form requiring active processing within the target organ in order to generate soluble antigen capable of being seen by immune reactants.

Animals↗

PubMed2003

Giantin is the major Golgi autoantigen in human anti-Golgi complex sera.

Anti-Golgi complex antibodies (AGAs) are primarily associated with systemic lupus erythematosus and Sjögren's syndrome. Here we report on the immunoreactivity of AGAs against five Golgi autoantigens (giantin, golgin-245, golgin-160, golgin-95/GM130, and golgin-97) and provide data from epitope mapping on the most common Golgi autoantigen, namely giantin. A total of 80 human sera containing AGAs, as defined by indirect immunofluorescence on HEp-2 cells, were analyzed by ELISA using recombinant autoantigens and immunoprecipitation. The proportion of AGA sera that reacted with the five Golgi autoantigens was correlated with the molecular mass of the Golgi antigens. Autoantibodies to giantin, the largest Golgi autoantigen, were the predominant AGAs, being found in 50% of the AGA sera. Epitope mapping of giantin was performed using six recombinant fragments spanning the entire protein. Antigiantin-positive sera with low titer autoantibodies recognized epitopes in the carboxyl-terminal fragments that are proximal to the Golgi membrane, whereas higher titer sera exhibited strong reactivity to amino-terminal and central domains that are likely to extend from the Golgi membrane into the cytoplasm. Our working hypothesis is that aberrantly expressed Golgi complex autoantigens may be released into the immune system when cells undergo lysis. By virtue of a carboxyl-terminal transmembrane domain, giantin is likely to be more stably associated with the cytoplasmic face of the Golgi complex than are other golgins, which are peripheral proteins. The stable association of giantin with the putative released Golgi complex may contribute to its preferential autoantigenicity.

Autoantibodies↗

PubMed1993

p70 lupus autoantigen binds the enhancer of the T-cell receptor beta-chain gene.

The p70 (Ku) autoantigen has been described as a nonhistone nuclear protein recognized by antibodies from lupus patients. In our studies on the regulation of T-cell receptor (TCR) beta-chain gene expression we have identified the p70 lupus autoantigen as a DNA-binding protein that binds the enhancer of the TCR beta-chain gene. This enhancer is essential for expression of the TCR beta gene. The core TCR beta enhancer contains the E3 motif, which we show here is essential for enhancer activity. The protection of the E3 motif in T cells and the marked reduction in enhancer activity when the E3 motif is mutated underline its physiological importance in regulating beta enhancer activity. The p70 lupus autoantigen gene was identified by screening T-cell lambda gt11 libraries with an E3 probe. The gene encodes a protein which binds the E3 motif in a sequence-specific manner. The identification of a 70-kDa protein as a major E3-binding protein by UV crosslinking is consistent with the conclusion that the p70 lupus autoantigen binds the beta enhancer. Finally, we have shown that T-cell nuclear proteins which bind the E3 motif bear p70 (Ku) lupus autoantigenic determinants. Together these data suggest that the p70 autoantigen binds a critical motif in the beta enhancer and probably regulates TCR beta gene expression.

Animals↗

PubMed2001

IgA cross-reactivity between a nuclear autoantigen and wheat proteins suggests molecular mimicry as a possible pathomechanism in celiac disease.

Celiac disease patients display IgA antibody reactivity to wheat as well as to human proteins. We used serum IgA from celiac patients and, for control purposes, from patients with Crohn's disease, ulcerative colitis and from healthy individuals to identify celiac disease-specific IgA autoantigens in nitrocellulose-blotted extracts from various human cell types (epithelial, endothelial, intestinal cells, fibroblasts). The pattern, recognition intensity and time course of IgA autoreactivity was monitored using serial serum samples obtained from celiac children before and under gluten-free diet. By immunoblot inhibition and subcellular (cytosolic, nuclear) cell fractionation we identified a 55 kDa nuclear autoantigen expressed in intestinal, endothelial cells and in fibroblasts which was recognized by IgA antibodies of approximately half of the celiac disease patients and cross-reacted with wheat proteins. IgA reactivity to the 55 kDa autoantigen disappeared during gluten-free diet and was inhibited after pre-absorption of sera with wheat proteins but not with tissue transglutaminase, previously reported as the unique celiac disease-specific autoantigen. In conclusion, we defined a novel 55 kDa celiac disease-specific nuclear IgA autoantigen which shares epitopes with wheat proteins and which is different from tissue transglutaminase and calreticulin. Although the newly defined autoantigen was recognized much less frequently than tissue transglutaminase, our data suggest molecular mimicry between wheat and human proteins as a possible pathomechanism for the induction and/or maintenance of mucosal tissue damage in celiac disease.

Adolescent↗

PubMed2001

Novel fragments of the Sjögren's syndrome autoantigens alpha-fodrin and type 3 muscarinic acetylcholine receptor generated during cytotoxic lymphocyte granule-induced cell death.

OBJECTIVE: To determine whether the Sjögren's syndrome autoantigens alpha-fodrin and the type 3 muscarinic acetylcholine receptor (M3R) are cleaved during cytotoxic lymphocyte granule-induced death, to yield novel fragments. METHODS: Primary salivary gland epithelial cells, human salivary gland cells, and HeLa cells were incubated with granule contents. The susceptibility to cleavage and the generation of novel fragments of Sjögren's syndrome autoantigens in this form of apoptosis was assessed by immunoblotting. Cleavage of M3R was further characterized by assays performed on the M3R molecule generated by in vitro translation. RESULTS: This study demonstrated that alpha-fodrin was uniquely cleaved during cytotoxic lymphocyte granule-induced cell death, generating a 155-kd fragment distinct from those generated by caspase 3 in other forms of apoptosis. The study also demonstrates that M3R (which is restricted in expression to the peripheral autonomic organs) was efficiently cleaved by granzyme B (but not by caspases) at several sites, both in vitro and in intact cells. This is the first description of cleavage of a transmembrane autoantigen by granzyme B. CONCLUSION: The observation that both ubiquitously expressed autoantigens (e.g., alpha-fodrin, La, and nuclear mitotic apparatus protein) and tissue-restricted autoantigens (e.g., M3R) targeted in Sjögren's syndrome are specifically cleaved by granzyme B, generating unique fragments, strongly suggests that a common biochemical event (novel autoantigen cleavage during granule-induced epithelial cell death) is responsible for selecting this apparently unconnected group of molecules for a high-titer autoantibody response. The data focus attention on the role of cytotoxic lymphocytes in the initiation and propagation of Sjögren's syndrome.

Animals↗

PubMed1997

The transcriptional activator Sp1, a novel autoantigen.

OBJECTIVE: To identify one nuclear autoantigenic protein within a complex of DNA binding proteins that bind to GC-rich sequences in Epstein-Barr virus and cellular DNA, and to describe the clinical characteristics of patients whose sera contained autoantibodies to this novel autoantigen. METHODS: Antibodies to autoantigen Sp1 were initially measured by an electrophoretic mobility shift assay to detect DNA binding proteins. Nuclear extracts and purified Sp1 protein were used in these assays. Recognition of the autoantigen by autoimmune sera was confirmed by immunoprecipitation and immunoblotting. RESULTS: The autoantigen was identified as Sp1. Anti-Sp1 was detected in sera from 8 (3%) of 230 patients. These sera contained antinuclear antibodies, but lacked antibodies to double-stranded DNA or to several extractable nuclear antigens. The patients whose sera contained antibodies to Sp1 were white women with fatigue, arthritis, Raynaud's phenomenon, malar rash, and photosensitivity. CONCLUSION: Sp1 is the first described example of an RNA polymerase II transcription activator as an autoantigen. The presence of Sp1 autoantibodies is associated with undifferentiated connective tissue disease.

Adult↗