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PubMed1998

Immunological cross-reactivity to multiple autoantigens in patients with liver kidney microsomal type 1 autoimmune hepatitis.

We describe two patients with liver kidney microsomal antibody type 1 (LKM1)-positive autoimmune hepatitis (AIH) with associated endocrinopathies. The first patient had insulin-dependent diabetes (IDDM), and the second patient had Addison's disease and hypoparathyroidism, and is also positive for islet cell antibodies, without overt diabetes. To account for the existence of multiple endocrinopathy in these patients, we investigated whether there is sequence similarity between the target of LKM1 antibodies, cytochrome P4502D6 (CYP2D6), and other human proteins, and if so, whether this structural similarity produces a detectable cross-reactive immune response. Our database search identified two proteins, carboxypeptidase H, an autoantigen in insulin-dependent diabetes, and 21-hydroxylase, the major autoantigen in Addison's disease, that share sequence similarity to the second major LKM1 epitope on CYP2D6. We tested the reactivity of sera from these patients to the homologous regions of the three autoantigens using an enzyme-linked immunosorbent assay (ELISA). The cut-off for positivity was established by testing sera from 22 healthy children. To determine the significance of reactivity to the peptide homologues of the three autoantigens, we investigated 16 additional patients with LKM1 AIH and 20 children with chronic hepatitis B virus infection as pathological controls. We found that reactivity to the second major epitope of CYP2D6 is significantly associated with reactivity to the homologous regions of carboxypeptidase H (CPH) and 21-hydroxylase (21-OHase) in patients with LKM1 AIH, and that this simultaneous recognition is cross-reactive. We suggest that a cross-reactive immune response between homologous autoantigens may contribute to the development of multiple endocrinopathies in LKM1 AIH.

Amino Acid Sequence↗
PubMed1994

Characterization of adrenal autoantigens recognized by sera from patients with autoimmune polyglandular syndrome (APS) type I.

Steroidogenic enzymes P450scc, P450c17 and P450c21 have recently been shown to be the main autoantigens recognized by sera from patients with autoimmune polyglandular syndrome (APS type I) with or without Addison's disease. We have studied the interrelationships of autoantigens revealed with APS type I sera in the adrenal and in placenta by immunodiffusion and immunoblotting, and correlated the findings to reactivities towards the above steroidogenic enzymes. We studied 50 patients with APS type I, 36 of whom also had Addison's disease, three patients with isolated (adult type) Addison's disease, seven healthy relatives of the patients with APS type I, 18 patients with insulin-dependent diabetes mellitus, 17 patients with autoimmune liver disease and 26 healthy controls. Immunodiffusion revealed two precipitating autoantigens in adrenal gland, and one of these was also found in placenta. In immunoblotting, five major adrenal antigens with molecular sizes of 55 kDa, 48 kDa, 43 kDa, 39 kDa and 19 kDa were seen. Reactivity to the 55 kDa, 39 kDa or 19 kDa represents the occurrence of antibodies to P450c17 or to its components as revealed by comparative studies with mouse antibodies to recombinant P450c17. These three bands in immunoblot as well as precipitating antibodies were observed exclusively in APS type I patients who had or developed Addison's disease. The 48 kDa antigen was found also in placenta and is probably P450scc, judged by the high correlation of P450scc antibodies with immunodiffusion and immunoblotting results using placental homogenate. There was no association between reactivity to the 43 kDa band and other immune parameters studied. The results thus indicate that P450scc and P450c17 enzymes are the precipitating adrenal autoantigens recognized by sera from APS type I patients. However, according to immunoblot results there could be some yet unidentified adrenal autoantigens to which APS type I patients could develop antibodies.

Addison Disease↗
PubMed1992

Expression of the 64 kDa/glutamic acid decarboxylase rat islet cell autoantigen is influenced by the rate of insulin secretion.

This study examined the relationship between insulin secretion and expression of the 64 kDa/glutamic acid decarboxylase autoantigen in pancreatic islets. Islets isolated from Wistar rats were cultured for 3 days under different conditions: in 5.5 mmol/l glucose with or without alpha-ketoisocaproic acid or glipizide and in 28 mmol/l glucose with or without diazoxide. The 64 kDa/glutamic acid decarboxylase autoantigen was precipitated from lysates of [35S]-methionine-labelled islets with sera from patients with Type 1 (insulin-dependent) diabetes mellitus and identified by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and fluorography. In parallel, insulin contents of the islets and the media were determined as well as the rates of glucose-stimulated (pro)insulin biosynthesis. alpha-Ketoisocaproic acid and glipizide were found to stimulate the expression of the 64 kDa/glutamic acid decarboxylase autoantigen and also the rate of insulin secretion. Diazoxide on the other hand reduced the rate of the 64 kDa/glutamic acid decarboxylase autoantigen synthesis in parallel with an inhibition of glucose-stimulated insulin release. Under most of the conditions employed, (pro)insulin biosynthesis was not affected. The correlation found between the rate of insulin release and expression of the 64 kDa/glutamic acid decarboxylase autoantigen might provide an explanation for the earlier observed relationship between the functional demands on the Beta cells and their rate of destruction which may result in diabetes.

Animals↗
PubMed1991

Localization of post-vasectomy sperm autoantigens in the Lewis rat.

Major rat sperm autoantigens of 86, 63, 43, 28 and 20 kDa are recognized by post-vasectomy and hyperimmunization antisera from the Lewis rat (Handley et al., Biol. Reprod. 39 (1988) 1239-1250). In the present study, affinity purified monospecific isoantibodies to each autoantigen were produced by elution from antigens which had been separated by SDS-PAGE and transferred to nitrocellulose. Western blot analysis confirmed a singular specificity for the 63, 28 and 20 kDa antisera and demonstrated some cross reactivity between the 86 kDa and the 43 kDa antisera. The polyclonal antiserum from which the monospecific antisera were produced stained the entire spermatozoon, while monospecific antibodies bound only to the sperm tail, staining the proximal portion (43 and 28 kDa), a distal domain (63 kDa), or the entire tail (86 kDa). Immunohistochemically stained sections of normal rat testes revealed that the 63, 43 and 28 kDa autoantigens were synchronously expressed in the cytoplasm of spermatids in the apical portions of seminiferous tubules during stages II-VIII in the cycle of the seminiferous epithelium. The 86 kDa autoantigen showed little or no staining in testis sections, implying that this autoantigen appeared on mature sperm following spermiation. These and other data suggest that a highly polymeric structure, possibly within the outer dense fibers of the tail, is a dominant sperm autoimmunogen following vasectomy of the Lewis rat.

Animals↗
PubMed2004

The clinical value of intracellular autoantigens B-cell epitopes in systemic rheumatic diseases.

A hallmark of autoimmune diseases is the production of autoantibodies against intracellular autoantigens. Although their pathogenetic and their etiologic relationship are not fully understood, these autoantibodies are important tools for establishing the diagnosis, classification and prognosis of autoimmune diseases. Systemic rheumatic diseases are among the most complex disorders because their clinical presentation and constellation of findings are in part reflected by the wide spectrum of autoantibodies found in the sera of patients suffering from these disorders. These autoantibodies usually target large complexes consisting of protein antigens noncovalently associated with (ribo)-nucleic acid(s), like the spliceosome or Ro/La-RNPs. In this review, we first address the main characteristics and the clinical value of several autoantibodies, with respect to their diagnostic sensitivity and specificity. Subsequently, we provide a brief overview of the antigenic determinant types that have been identified on the corresponding autoantigens. The antibody targets of autontigens include primary, secondary, tertiary and quarternary structure epitopes, as well as cryptotopes, neoepitopes and mimotopes. We next focus on antigenic structures corresponding to B-cell epitopes with high disease specificity and sensitivity for all the major autoantigens in systemic autoimmunity including the Ro/La and U1 ribonucleoprotein complexes and the Ku70/80, ribosomal P, DNA topoisomerase I, filaggrin, Jo-1 and PM/SCl-100 autoantigens. These epitopes, defined at the peptide level, can be chemically synthesized and engineered for the development of new inexpensive and easier to perform assays and the improvement of the methods for autoantibody detection. Specific examples of newly developed assays that incorporate (i) epitopes with high disease specificity and sensitivity, (ii) modified epitopes, (iii) conformational epitopes and (iv) complementary epitopes are discussed in detail. Finally, we examine the potential of combining these synthetic epitopes for future development of multiplex diagnostic tests based on miniaturized autoantigen arrays.

Autoantigens↗
PubMed2006

Model of stimulation-responsive splicing and strategies in identification of immunogenic isoforms of tumor antigens and autoantigens.

We recently proposed a novel model of stimulation-responsive splicing for the selection of autoantigens and self-tumor antigens. Our model theorizes that the significantly higher rates of alternative splicing of autoantigen and self-tumor antigen transcripts that occur in response to stimuli could induce extra-thymic expression of untolerized antigen epitopes for elicitation of autoimmune and anti-tumor responses. To facilitate the identification of immunogenic isoforms of antigens, we have developed strategies using improved SEREX in conjunction with database-mining and immunogenic isoform mapping. Identification of immunogenic isoforms of autoantigens and self-tumor antigens is very important for the development of novel therapeutics and diagnostic tools for autoimmune diseases and tumors, such as: (1) autoantigen isoform microarrays for disease diagnosis and prognosis; (2) autoantigen isoform-specific tolerizing vaccines and splicing-redirection therapies, as well as (3) immunogenic antigen isoform-specific immunotherapy for tumors.

Alternative Splicing↗
PubMed2004

Increased noncanonical splicing of autoantigen transcripts provides the structural basis for expression of untolerized epitopes.

BACKGROUND: Alternative splicing is important for increasing the complexity of the human proteome from a limited genome. Previous studies have shown that for some autoantigens, there is differential immunogenicity among alternatively spliced isoforms. OBJECTIVES: Herein, we tested the hypothesis that alternative splicing is a common feature for transcripts of autologous proteins that are autoantigens. The corollary hypothesis tested was that nonautoantigen transcripts have a lower frequency of alternative splicing. METHODS: The extent of alternative splicing within 45 randomly selected self-proteins associated with autoimmune diseases was compared with 9554 randomly selected proteins in the human genome by using bioinformatics analyses. Isoform-specific regions that resulted from alternative splicing were studied for their potential to be epitopes for antibodies or T-cell receptors. RESULTS: Alternative splicing occurred in 100% of the autoantigen transcripts. This was significantly higher than the approximately 42% rate of alternative splicing observed in the 9554 randomly selected human gene transcripts ( P < .001). Within the isoform-specific regions of the autoantigens, 92% and 88% encoded MHC class I and class II-restricted T-cell antigen epitopes, respectively, and 70% encoded antibody binding domains. Furthermore, 80% of the autoantigen transcripts underwent noncanonical alternative splicing, which is also significantly higher than the less than 1% rate in randomly selected gene transcripts ( P < .001). CONCLUSION: These studies suggest that noncanonical alternative splicing may be an important mechanism for the generation of untolerized epitopes that may lead to autoimmunity. Furthermore, the product of a transcript that does not undergo alternative splicing is unlikely to be a target antigen in autoimmunity.

Alternative Splicing↗
PubMed2006

Identification of alpha-enolase as an autoantigen associated with severe asthma.

BACKGROUND: Approximately 5% to 10% of patients with asthma have severe disease that is not effectively controlled by typical therapies. The existence of an autoantigen associated with severe asthma has been previously reported. OBJECTIVE: We attempted to identify the autoantigen. METHODS: Severe asthma was defined as patients having at least 1 severe asthmatic exacerbation requiring an emergency department visit or admission in the last year despite continuous typical therapies. Autoantibodies to airway epithelial cells (A549) were examined in sera from patients with severe asthma by immunoblot analysis. RESULTS: IgG autoantibodies to the 52-kd airway epithelial cell antigen were detected in sera from 32 of 78 patients with severe asthma (41%), 9 of 83 patients with mild-to-moderate asthma (11%), and 2 of 58 healthy controls (3%; P < .001). The 52-kd autoantigen was identified as alpha-enolase by mass spectrometry analysis and confirmed by using recombinant human alpha-enolase protein. The detection of IgG autoantibodies to alpha-enolase was the most significant indicator for distinguishing severe asthma from mild-to-moderate asthma, even after adjusting for the effects of other clinical variables, including age, sex, atopy, and FEV(1) (adjusted odds ratio, 5.2; 95% CI, 2.1-12.9; P < .001). CONCLUSION: The alpha-enolase was identified as an autoantigen associated with severe asthma. Further studies are needed to determine the significance of this autoantigen in severe asthma. CLINICAL IMPLICATIONS: IgG autoantibodies to alpha-enolase could be a biological marker for severe asthma.

Adult↗
PubMed2003

Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis.

BACKGROUND & AIMS: The mechanism for development of primary biliary cirrhosis (PBC) remains enigmatic, but molecular mimicry has been implicated because of well-known cross-reactivity of human mitochondrial autoantigens and equivalent bacterial antigens. Virtually all patients with PBC have antimitochondrial autoantibodies (AMA), but, interestingly, approximately 50% also manifest antinuclear antibodies (ANA). METHODS: To determine whether generation of ANA are due to molecular mimicry of mitochondrial peptides, we established 6 T-cell clones selected by a peptide corresponding to the E2 subunit of mitochondrial pyruvate dehydrogenase complex and analyzed for reactivity to mimicry peptides derived from mitochondrial and nuclear autoantigens, including control sequences. RESULTS: For mitochondrial autoantigens, 1 peptide from the E2 subunit of the pyruvate dehydrogenase complex, 1 peptide from the E2 subunit of the oxo-glutarate dehydrogenase complex, 1 peptide from the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex, and 1 peptide from the E3-binding protein cross-reacted with these T-cell clones. For the nuclear autoantigens, 5 peptides from gp210 and 1 from Sp100 cross-reacted with these clones. Furthermore, 1 of 3 T-cell clones selected by recombinant gp210 protein reacted with a mimicry peptide corresponding to amino acids 188-201 of gp210, indicating that this part of the protein is a naturally processed immunodominant T-cell epitope. CONCLUSIONS: These results demonstrate molecular mimicry between mitochondrial and nuclear autoantigens in PBC and that a mimicry peptide may become an immunodominant T-cell epitope. These data have significance not only for PBC but also for the production of ANA in other disease processes.

Amino Acid Sequence↗
PubMed1999

Analysis of T cell receptors specific for U1-70kD small nuclear ribonucleoprotein autoantigen: the alpha chain complementarity determining region three is highly conserved among connective tissue disease patients.

The U1-70kD autoantigen is a major target of B cell responses in patients with connective tissue diseases (CTD). T cell responses are important in the pathogenesis of CTD, however little is known about autoantigen-specific T cells in these diseases. We have recently proven that U1-70kD-reactive human T cells exist. To further characterize these autoreactive T cells, U1-70kD-reactive T cell clones have been generated from patients with CTD using either a recombinant fusion protein or synthetic peptides spanning the U1-70kD polypeptide. T cell receptors (TCR) isolated from the U1-70kD-reactive T cell clones were sequenced and the third complementarity-determining region (CDR3) compared to determine if a common motif was present. mAb blocking of antigen-induced proliferation was done to determine the HLA restriction element used in recognition of the U1-70kD autoantigen by T cells. The results presented here indicate that TCRAV CDR3 usage is highly restricted among U1-70kD autoantigen-specific human T cells clones derived from CTD patients with distinctive structural features. Furthermore, the recognition of the U1-70kD autoantigen occurs in the context of HLA-DR.

Amino Acid Sequence↗
PubMed1997

Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance.

Oral administration of protein can induce antigen-specific immune hyporesponsiveness. However, the utility of oral tolerance to autoantigens in the treatment of autoimmune diseases may be limited when candidate autoantigens cannot be produced by conventional systems in quantities sufficient for clinical studies. Plants may be ideally suited for this purpose, as they can synthesize, glycosylate and assemble mammalian proteins to provide huge quantities of relatively low cost soluble proteins. Furthermore, edible transgenic plants could provide a simple and direct method of autoantigen delivery for oral tolerance. Therefore, the aim of this study was to determine whether a transgenic plant expression system was capable of synthesizing the diabetes-associated autoantigen, glutamic acid decarboxylase (GAD) in an immunogenic form and whether the oral administration of an autoantigen expressed by a plant could directly induce protective immune responses in a mouse model of diabetes. We show that a GAD-expressing transgenic plant, given as a dietary supplement, inhibits the development of diabetes in the non-obese diabetic (NOD) mouse.

Agrobacterium tumefaciens↗
PubMed2001

Melanocyte-associated T cell epitopes can function as autoantigens for transfer of alopecia areata to human scalp explants on Prkdc(scid) mice.

Alopecia areata is a tissue restricted autoimmune condition affecting the hair follicle, resulting in hair loss. The goal of this study was to test the hypothesis that the autoantigen of alopecia areata is melanocyte associated. Potential autoantigens were tested in the human scalp explant/Prkd(scid) CB-17 mouse transfer system. Scalp T cells from lesional (bald) alopecia areata scalp were cultured with antigen-presenting cells, and antigen, along with interleukin-2. The T cells were then injected into autologous lesional scalp grafts on SCID mice, and hair regrowth was measured. Hair follicle homogenate was used as an autoantigen control. T cells cultured with melanoma homogenate induced statistically significant reduction in hair growth (p <0.01 by ANOVA). HLA-A2-restricted melanocyte peptide epitopes were then tested with lesional scalp T cells from HLA-A2-positive alopecia areata patients. Melanocyte-peptide-activated T cells significantly reduced the number of hairs regrowing in two experiments with six patients (p <0.001 by ANOVA). Injected scalp grafts showed histologic and immunochemical changes of alopecia areata. The most consistent peptide autoantigens were the Gp100-derived G9-209 and G9-280 peptides, as well as MART-1 (27-35). Melanocyte peptide epitopes can function as autoantigens for alopecia areata. Multiple peptides were recognized, suggesting epitope spreading.

Adult↗
PubMed2003

CD4+ CD25+ T cells responding to serologically defined autoantigens suppress antitumor immune responses.

A variety of tumor-derived antigens have been defined by IgG antibodies in tumor bearers' sera with serological identification of antigens by recombinant expression cloning (SEREX), a serological expression cloning method. The majority of these antigens show no structural abnormality and seem to be wild-type autoantigens. Coimmunization with DNA encoding these autoantigens and tumor-specific cytotoxic T lymphocytes epitopes heightened CD8+ T cell responses and increased resistance to tumor challenge in a CD4+ T cell-dependent manner. In contrast, immunization with these SEREX-defined autoantigens alone leads to heightened susceptibility to tumor challenge. This suppressive effect of immunization is mediated by CD4+ CD25+ T cells. In mice immunized with one of the SEREX-defined autoantigens, Dna J-like 2, the number of alpha-GalCer/CD1d tetramer+ CD3+ T cells [representing natural killer T (NKT) cells] was reduced in the pulmonary compartment, whereas no evident change in the number of other T cell subsets was observed. Experiments with Jalpha281-/- mice lacking most NKT cells indicate that NKT cells are primarily responsible for metastasis suppression and that their activity is inhibited by immunization with Dna J-like 2. We propose that SEREX identifies a pool of autoantigens that maintains and regulates immunological homeostasis via CD4+ CD25+ regulatory T cells.

Adoptive Transfer↗
PubMed1999

Localization of the human 64kD autoantigen D1 to myofibrils in a subset of extraocular muscle fibers.

PURPOSE: To evaluate the tissue-specific expression pattern of the 64kD human autoantigen D1, a tropomodulin-related protein that may be involved in thyroid-associated ophthalmopathy. METHODS: Recombinant 64kD human autoantigen D1 was generated in a bacterial expression system and used to immunize rabbits. Specific antibodies were affinity-purified and used for Western blots on normal and hyperthyroid rat and rabbit tissue, and immunofluorescence localization on cryosections of rat tissue. RESULTS: Anti-64kD human autoantigen D1 antibodies recognize specifically a approximately 70kD polypeptide in western blots of extraocular muscle, sternothyroid muscle, and smooth muscle. Immunofluorescence staining demonstrates that the 64kD human autoantigen D1 localizes to myofibrils in slow fibers from rat extraocular and sternothyroid muscle. The level of this protein is not altered in extraocular muscles from hyperthyroid rabbits. CONCLUSIONS: The 64kD human autoantigen D1 is expressed in slow fibers of extraocular and sternothyroid muscles as a component of myofibrils, and is not upregulated in conditions of hyperthyroidism.

Actins↗
PubMed1999

Cleavage by granzyme B is strongly predictive of autoantigen status: implications for initiation of autoimmunity.

Systemic autoimmune diseases are a genetically complex, heterogeneous group of disorders in which the immune system targets a diverse but highly specific group of intracellular autoantigens. The molecules targeted are not unified by common structure, function, or distribution in control cells but become clustered and concentrated in surface blebs when cells undergo apoptosis. We show here that the majority of autoantigens targeted across the spectrum of human systemic autoimmune diseases are efficiently cleaved by granzyme B in vitro and during cytotoxic lymphocyte granule-induced death, generating unique fragments not observed during any other form of apoptosis. These molecules are not cleaved by caspase-8, although this protease has a very similar specificity to granzyme B. The granzyme B cleavage sites in autoantigens contain amino acids in the P(2) and P(3) positions that are preferred by granzyme B but are not tolerated by caspase-8. In contrast to autoantigens, nonautoantigens are either not cleaved by granzyme B or are cleaved to generate fragments identical to those formed in other forms of apoptosis. The striking ability of granzyme B to generate unique fragments is therefore an exclusive property of autoantigens and unifies the majority of molecules targeted in this spectrum of diseases. These results focus attention on the role of the cytotoxic lymphocyte granule-induced death pathway in the initiation and propagation of systemic autoimmunity.

Apoptosis↗
PubMed2005

Experimental autoimmune encephalomyelitis in mice expressing the autoantigen MBP 1-10 covalently bound to the MHC class II molecule I-Au.

Most autoantigens implicated in multiple sclerosis (MS) are expressed not only in the central nervous system (CNS) but also in the thymus and the periphery. Nevertheless, these autoantigens might induce a strong autoimmune response leading to severe destruction within the CNS. To investigate the influence of a dominantly presented autoantigen on experimental autoimmune encephalomyelitis (EAE), we generated transgenic mice expressing the autoantigenic peptide MBP 1-10 covalently bound to the MHC class II molecule I-Au. These mice were crossed either with B10.PL or with TCR-transgenic Tg4 mice, specific for the transgenic peptide-MHC combination. In double transgenic mice we found strong thymic deletion and residual peripheral T cells were refractory to antigen stimulation in vitro. Residual peripheral CD4+ T cells expressed activation markers and a high proportion was CD25 positive. Transfer of both CD25-negative and CD25-positive CD4+ T cells from double transgenic animals into B10.PL mice strongly inhibited the progression of EAE. Despite this thorough tolerance induction, some double transgenic mice developed severe signs of EAE after an extended period of time. Our data show that in the circumstances where autoantigenic priming persists, and where the number of antigen-specific T cells is high enough, autoimmunity may prevail over very potent tolerance-inducing mechanisms.

Animals↗
PubMed1982

Immunochemical analysis of guinea pig sperm autoantigens.

Autoantibodies raised in guinea pigs (GP) by hyperimmunization with epididymal sperm recognize antigens present on the plasma membrane of intact sperm and antigens associated with acrosome-reacted sperm. Plasma membrane autoantigens were characterized by SDS-PAGE analysis of immune precipitates from detergent extracts of radiolabeled epididymal sperm. Three major protein bands with approximate molecular weights (MW) of 69,000, 62,000 and 40,000 daltons were exhibited. Galactose oxidase and periodate oxidation followed by tritiation revealed two major plasma membrane glycoprotein autoantigens with MWs of 35,000 and 32,000 daltons and one sialoglycoprotein of 34,000 daltons. Antigenic molecules of similar MW were also detected by autoantisera to guinea pig testicular homogenates. Immune precipitates of radiolabeled detergent extracts of acrosome-reacted sperm analyzed by SDS-PAGE exhibited two major carbohydrate-containing peaks, one with a MW of approximately 42,000 daltons and one of 6,000 daltons. Since the 6,000 dalton peak was immunoprecipitated from the organic phase of both chloroform:methanol 2:1 and n-butanol extracts, the antigen may be a glycolipid. The possible existence of glycolipid autoantigen in GP sperm was further supported by the reaction in a solid phase radioimmunoassay of autoantibodies to GP sperm with glycolipid extracts from GP testis. This study demonstrates the presence of multiple autoantigenic specificities in the sperm-plasma membrane, acrosome-reacted sperm and testis of guinea pigs. It also demonstrates for the first time glycolipid autoantigens in testis and sperm.

Acrosome↗
PubMed2002

Autoantigens and Sjögren syndrome.

PURPOSE: To review recent experimental evidence on the involvement of autoantigens and autoantibodies in the pathogenesis of organ-specific autoimmunity in Sjögren syndrome (SS). METHODS: Among candidate autoantigens in SS, we investigated the role of alpha-fodrin in the lacrimal gland using a mouse model and a lacrimal gland cell line established in p53 knockout mice. We also tried to identify a novel organ-specific autoantigen by screening the human salivary gland cell line (HSG) against sera from SS patients. The specificity and sensitivity of this autoantigen to SS patient sera, its cellular localization, and the gene encoding the protein were analyzed. RESULTS: In addition to the previously identified 120-kd alpha-fodrin in the salivary gland, a shorter fragment was detected, indicating that there may be a distinct apoptosis-related protease that cleaves alpha-fodrin in the lacrimal gland. A novel salivary gland-specific autoantibody was detected in 50.9% of sera from SS patients. The antigen recognized by this antibody may be a 45-kd nucleus protein not recognized in its native form. CONCLUSION: The precise roles of autoantigens in organ-specific autoimmunity are still unclear, although accumulated evidence suggests that they may be associated with disease progression. Further studies of alpha-fodrin and the 45-kd antigen may contribute to the understanding of the pathogenesis of SS and may provide a new strategy for organ-specific therapy, such as vaccination with analogue peptides.

Animals↗