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PubMed1975

Studies on sperm antigenicity. 2. In vivo and in vitro cellular reactivity in guinea pigs sensitized to homologous and heterologous spermatozoal autoantigens.

In vitro delayed type hypersensitivity was demonstrated with peritoneal exudate cells from guinea pigs of the Rockefeller and Hartley strains, immunized with different preparations of the guinea pig male reproductive tract (RMT) emulsified in complete Freund's adjuvant-H37Ra. The RMT preparations were purified guinea pig spermatozoal autoantigens S, P, and T; whole guinea pig spermatozoa, and extract from epididymal tissue. The cellular sensitivity in vivo was demonstrated by injecting the proper antigen into the skin of the tested animals and in vitro by the macrophage inhibition technique. Peritoneal exudate cells from guinea pigs sensitized with whole guinea pig spermatozoa cells were inhibited in vitro by the specific antigen, epididymal extract, and autoantigen-T. Autoantigen-S was found to be a weak immunogen. However, the migration of peritoneal exudate cells from guinea pigs sensitized with large amounts of antigen-S was inhibited by whole spermatozoa in vitro. This cross-reactivity revealed the possibility that the immunogenicity of purified autoantigen-S might be connected to its molecular size. According to the immunizing dose of the antigens, testicular lesions of either the aspermatogenic or orchitis type were found in the testes of sensitized guinea pigs. Lesions in the testes of the guinea pigs were not detectable by cross-immunization with heterologous human or rat spermatozoa, although some degree of in vitro cross-reactivity was detected by skin test studies.

Animals↗
PubMed1992

Molecular biology of nuclear autoantigens.

This article provides a historical overview of the application of molecular and immunologic techniques to the analysis of autoantigenic structure and function, as well as to autoantibody recognition of protein and nucleic acid autoantigens. Examples presented here illustrate the role of autoantibodies as tools in the elucidation of the autoimmune components of cellular ribonucleoproteins. In turn, the subsequent molecular dissection of autoantigenic ribonucleoproteins has advanced understanding of autoantibody specificities. The nature of autoantibodies reactive with various proteins and nucleic acids will be the subject of the following articles in this issue. Taken together, these studies of antibody-antigen interactions that arise during the autoimmune response have revealed novel mechanisms of molecular recognition within the RNP autoantigens. These findings are of general importance for understanding basic cellular processes and have contributed to our knowledge of the underlying mechanisms of immunoregulatory abnormalities that arise in autoimmune diseases.

Autoantibodies↗
PubMed2006

[Establishment of a mouse model of primary biliary cirrhosis by AMA M2 autoantigen injection].

OBJECTIVES: To establish a primary biliary cirrhosis (PBC) model by AMAM2 autoantigen injection into C57BL/6 mice. METHODS: Mice of the model group were immunized intraperitonealy with 200 microl of purified recombinant AMAM2 autoantigen in complete Freund's adjuvant (CFA). Mice immunized with bovine serum albumin and CFA in the same way were used as negative controls. Sixty-six weeks later, mice were sacrificed and their sera were collected. Sera samples were assayed for AMAM2 autoantibody, alkaline phosphatase (ALP), ALT and total bilirubin (TBil). Their liver, stomach, muscle and kidney tissues were sectioned and stained using HE to observe the pathological changes. RESULTS: Antibodies to AMAM2 autoantigen were readily induced in the model group. The mice in the model group had no significant changes in the level of serum ALT and TBil but had an obvious increase of ALP (P<0.05). The stomach, muscle and kidney tissues showed no evident damage while the livers had obvious pathological changes, including bile duct degeneration or proliferation, and mononuclear cell infiltration. CONCLUSION: The AMAM2 autoantigen-induced PBC animal model was successfully established in C57BL/6 mice in our experiment and its characteristic biochemical and pathology are quite similar to that in the early stage of human PBC. This model may provide a useful experimental approach for further study of the pathogenesis and clinical treatment of human PBC.

Animals↗
PubMed1991

Pancreatic beta cells express two autoantigenic forms of glutamic acid decarboxylase, a 65-kDa hydrophilic form and a 64-kDa amphiphilic form which can be both membrane-bound and soluble.

The 64-kDa pancreatic beta-cell autoantigen, which is a target of autoantibodies associated with early as well as progressive stages of beta-cell destruction, resulting in insulin-dependent diabetes (IDDM) in humans, has been identified as the gamma-aminobutyric acid-synthesizing enzyme glutamic acid decarboxylase. We have identified two autoantigenic forms of this protein in rat pancreatic beta-cells, a Mr 65,000 (GAD65) hydrophilic and soluble form of pI 6.9-7.1 and a Mr 64,000 (GAD64) component of pI 6.7. GAD64 is more abundant than GAD65 and has three distinct forms with regard to cellular compartment and hydrophobicity. A major portion of GAD64 is hydrophobic and firmly membrane-anchored and can only be released from membrane fractions by detergent. A second portion is hydrophobic but soluble or of a low membrane avidity, and a third minor portion is soluble and hydrophilic. All the GAD64 forms have identical pI and mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Results of pulse-chase labeling with [35S]methionine are consistent with GAD64 being synthesized as a soluble protein that is processed into a firmly membrane-anchored form in a process which involves increases in hydrophobicity but no detectable changes in size or charge. All the GAD64 forms can be resolved into two isoforms, alpha and beta, which differ by approximately 1 kDa in mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis but are identical with regard to all other parameters analyzed in this study. GAD65 has a shorter half-life than the GAD64 forms, remains hydrophilic and soluble, and does not resolve into isomers. Comparative analysis of the brain and beta-cell forms of GAD show that GAD65 and GAD64 in pancreatic beta-cells correspond to the larger and smaller forms of GAD in brain, respectively. The expression of different forms and the flexibility in subcellular localization of the GAD autoantigen in beta-cells may have implications for both its function and autoantigenicity.

Animals↗
PubMed1989

[Characteristics of lymphocyte autoantigens].

Specificity of autoantibodies against lymphocyte antigens was assayed in sera of patients with autoimmune hematologic diseases, leukemias, secondary immunodeficiencies as well as in sera of persons seropositive to antibodies against retroviruses HTLV-I and HTLV-III. Autoantigens of the lysates of stimulated peripheral blood lymphocytes and Hut-102 cells were characterized with the aid of immune blotting and radioimmunoprecipitation. No differences were found in autoantigen spectra identified by sera from patients belonging to different groups. Autoantigens 75 cd, 60 cd, 50 cd and 12 cd occurring in both cell types were demonstrable at a greater frequency. Some of the sera also demonstrated the total antigens 34 cd and 29 cd. The role of autoantigens in the pathology development is discussed.

Autoantibodies↗
PubMed1986

H-2 restricted regulation by soluble autoantigens of the tick-borne encephalitis virus-induced autoreactive T-effector and T-suppressor lymphocytes in mice.

Soluble autoantigens (mouse red blood cells lysed by sonication) blocked in vitro the antigen-recognizing receptors of tick-borne encephalitis (TBE) virus-induced autoreactive T-lymphocytes (ARTL), effectors of the local graft-versus-host reaction (GVHR) in a syngeneic system and prevented the development of GVHR in vivo. Antigen-recognizing receptors were also found on T-suppressors (Ts) that became activated during experimental tick-borne encephalitis in mice and inhibited the activity of ARTL. The interaction between these receptors and autoantigens in vitro resulted in a loss of the ability of Ts to inhibit in vivo the ARTL-mediated GVHR. A similar result was obtained with ARTL and Ts activated in mice infected with Langat, dengue type 2 (D2) and yellow fever (strain 17D) viruses. The block of the antigen-recognizing receptors of T-cells was reversible, and not associated with lymphokine production or effector death. The block of the antigen-recognizing receptors in vitro and the loss of the corresponding T-cell function in vivo occurred provided that the donors of soluble erythrocyte antigens (SEA) and of the lymphocytes had at least one common major histocompatibility complex (MHC) haplotype. Injection SEA from donors whose H-2 complex haplotypes were identical to those of TBE-infected recipients prevented in the latter the formation of ARTL or Ts. The autoantigens inhibiting the ARTL and Ts activities seemed to be products of the MHC genes. The role of soluble H-2 autoantigens in preventing virus-induced autoimmune reaction and maintaining a state of natural immunological tolerance is discussed.

Animals↗
PubMed1988

Autoreactive B cells in normal humans. Autoantibody production upon lymphocyte stimulation with autoantigen-xenoantigen conjugates.

Mononuclear cells (MNC) from the blood of healthy individuals cannot be stimulated in vitro with the soluble autoantigen thyroglobulin (Tg). However, when Tg or pepsin fragments of Tg were coupled with a carrier protein, tetanus toxoid (TT), MNC from four healthy TT vaccinated individuals responded to the carrier-autoantigen conjugates by generating anti-Tg antibody forming cells (AFC), as shown in a spot enzyme-linked immunosorbent assay. Generation of anti-TT and anti-Tg AFC after stimulation with the conjugates required the donors to be boostered with TT. The autoantibodies were exclusively of the IgM class, in contrast to the carrier-specific anti-TT antibodies, which were predominantly of the IgG isotype. Activation of normal B cells to anti-Tg production was dependent on the presence of T cells in the cultures and required physical linkage of carrier and autoantigen: no anti-Tg AFC could be detected when MNC were stimulated with uncoupled combinations of Tg and TT. The autoreactive and the carrier-reactive B cells exhibited almost identical conjugate dose-response profiles, which suggest that they responded in a similar way to regulatory signals. These findings indicate that normal blood B cells are competent to respond to the autoantigen Tg in conjunction with signals originating from xeno-antigen-stimulated T cells.

Antibodies, Bacterial↗
PubMed1977

Human and guinea-pig cross-reacting spermatozoa autoantigens and autoantibodies.

Cross-reactivity between human and guinea-pig spermatozoa autoanigens has been studied in two systems: (1) guinea-pig anti-autoantigens S, P and T immune sera reacting on human spermatozoa and (2) activity of human anti-sperm sera on guinea-pig spermatozoa. These assays, as well as the results of cross-absorptions in the two systems, revealed a close antigenic relationship between the two species of spermatozoa concerning the guinea-pig autoantigen S. However, there were some differences in its localization and serological manifestations in both species. The guinea-pig autoantigen T bore a more distant, though definite, relationship with human spermatozoa. No clear evidence of cross-reactivity between the two species was found for autoantigen P. At variance with autoimmune (or isoimmune) human antibodies, 'natural' human antibodies active on guinea-pig spermatozoa were absorbed by guinea-pig spleen cells.

Animals↗
PubMed1983

Absence of allotypic variation in the autoantigen for thyroid stimulating autoantibodies.

The question of whether autoimmune reactions result from abnormality of the autoantigen or of the autoantibody is fundamental. When reaction of the thyroid stimulating autoantibodies (TSaab) of Graves' disease with their autoantigen is measured in the mouse bioassay which has a very sensitive dose-response curve this provides a favourable system for detecting any influence of allotypic variation in the autoantigen on the affinity of the corresponding autoantibodies. Seven high potency long acting thyroid stimulator (LATS) sera were tested for degree of neutralization by soluble extracts from nine thyroids, using the mouse bioassay to measure changes in LATS activity. The thyroid extracts differed in neutralizing potency and the LATS sera differed in susceptibility to neutralization, but these variations were consistent enough to enable ranking and there were no significant exceptions from especially strong or weak reactions between any individual thyroid extract and any individual LATS serum. Even autologous reactants had no greater or lesser affinity than homologous ones. Five LATS protector (LATSP) sera, tested against six thyroid extracts, including their own, again showed no evidence of allotypic variation in the autoantigen, nor did 55 LATSP sera tested with one of four thyroid extracts. Altogether we have looked at over 200 individual reactions between soluble thyroid antigen and thyroid stimulating autoantibody (LATS and LATSP). We have not found a single significant instance of any exceptionally strong or weak affinities, even with autologous antigen. The findings are in accord with Burnet's theory that autoimmune reactions are due to the emergence of forbidden clones of lymphocytes, reactive with normal self antigens.

Animals↗
PubMed1994

HLA restriction and TCR usage of T lymphocytes specific for a novel candidate autoantigen, X2 MBP, in multiple sclerosis.

Previous investigations of the major 18.5-kDa isoform of myelin basic protein (MBP) as a target autoantigen in multiple sclerosis (MS) have failed to identify an epitope uniformly recognized with higher frequency in MS patients compared with controls. Because remyelination has been observed in MS plaques, we were prompted to investigate T cells specific for myelin protein isoforms with up-regulated expression during remyelination. We have recently described such T cells that recognize the exon 2-encoded region of MBP (X2 MBP), a sequence included in the 21.5- and 20.2-kDa isoforms of MBP. These cells were shown to be CD4+, HLA class II restricted, and cytolytic. In members of one multiplex MS family, X2 MBP-specific T lymphocytes were as prevalent as T cells specific for immunodominant regions within the major 18.5-kDa isoform of MBP. The present study characterizes X2 MBP-specific T cell responses in additional multiplex MS family members as well as in heterogeneous (non-familial) MS patients and in healthy controls. The frequencies of X2 MBP-specific T cells in each of the affected family members from two of three MS families were significantly increased as compared with both the heterogeneous MS group and the healthy control group. Also, X2 MBP-specific T cell lines from affected family members were primarily restricted to molecules encoded by the DR2/DQw1 allele. Although TCR usage was generally heterogeneous, there was evidence of intraindividual sequence identity. These data suggest that: 1) Myelin proteins with up-regulated expression during the course of disease should be considered as candidate autoantigens in MS. 2) The functional basis for the association of DR2/DQw1 inheritance with MS susceptibility may be related to presentation of autoantigens by this allele. 3) TCR therapy will need to be individually tailored to target the most prevalent autoantigen-specific response.

Adult↗
PubMed1994

Viral induction of the human autoantigen calreticulin.

Specific but ubiquitous cytoplasmic proteins are the targets of autoantibodies such as anti-Ro/SS-A, anti-La/SS-B, and anti-calreticulin. These antibodies may be pathogenic in systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). Tissue localization of the pathogenic process could be best explained by an abnormal expression of these cytoplasmic proteins. Several factors could likely displace the host proteins to the cell surface. This study was designed to use cytomegalovirus (CMV) infected human fibroblasts (MRC-5) as a model, to test whether a viral infection would induce the expression of the human autoantigen(s). Expression of Ro/SS-A, calreticulin, and MHC class I antigens, both in the cytoplasm and on the cell surface, was examined by a fixed cell ELISA, immunofluorescence, and immunoblotting. Infection of fibroblasts with CMV was found to increase the cell surface expression of calreticulin (p = 0.0314), but not the 60KD Ro/SS-A. Cytoplasmic expression of both the autoantigens tested increased following CMV infection. Enhanced expression of class I MHC was detected on the cell surface in response to the virus infection. The expression of the autoantigens and MHC class I polypeptides, as well as the virally induced elevated mitotic rate, diminished after 24 h of infection. Viral infection was found to alter the distribution of host cell proteins, including autoantigens. Cell surface expression of calreticulin could provide a target for circulating autoantibody and contribute to the autoimmune process.

Amino Acid Sequence↗
PubMed1996

[Functional analysis of an autoantigen reactive B cell clone derived from MRL/MP-lpr/lpr mice].

MRL/MP-lpr/lpr (MRL/lpr) mice are known to provide a good model for the study on the pathogenesis of systemic lupus erythematosus with massive involvement of abnormal T lymphocytes in the spleen and lymphonodes. However, a direct role of B cells of MRL/lpr mice in autoimmune responses is not clear until this time. In the present study, to investigate the characteristic of B cells of the mice, we tried to establish a B cell clone after hybridization between splenic B cells of these mice and 2.52 M, a HAT selective medium sensitive mutant B cell line in the presence of polyethylene glycol and dimethyl sulfoxide and examined its response to autoantigens. MRL27.4, a subclone of a resulting hybridoma, expressed IgM, B220, IKk, ICAM-1, and LEA-1 on the cell membrane as well as CD5 molecules by analysis with flow microfluorometory (FMF). Also, MRL27.4 was shown to exhibit rosette formation against blood cells treated with bromelain (Br-RBC) at a frequency of more than 95%, and to express DNA-receptor (DNA-R) on its surface by FMF analysis with biotin-labeled ssDNA. In contrast, the parental 2.52 M did not form rosettes with Br-RBC and the expression of DNA-R on the cell membrane of 2.52 M was significantly less compared with that of MRL27.4. Interestingly, MRL27.4 produced a high titer of IgM-anti-ssDNA antibodies and IL-6 after treatment with the purified RBC membrane or immobilized DNA. On the other hand, the parental 2.52 M neither produce IgM-anti-ssDNA antibodies nor IL-6 under the same conditions. The results suggest that MRL27.4 is an autoantigen reactive B cell clone derived from MRL/lpr mice and its surface DNA-R, by itself, function to autoantigens. In this process, there might be an autocrine network mediated by IL-6. In conclusion, MRL27.4 provides a good model for the study on the direct function of B cells of MRL/lpr mice during abnormal immune responses to autoantigens.

Animals↗
PubMed1988

Autoantibodies to mitochondria in systemic sclerosis. Frequency and characterization using recombinant cloned autoantigen.

Mitochondrial autoantibodies, a hallmark of primary biliary cirrhosis (PBC), have been widely described for many years in patients with systemic sclerosis, and there have been several reports of the concurrence of systemic sclerosis and PBC. However, there is very little information with respect to the significance of these autoantibodies or any definitive evidence that the antigens involved represent the mitochondrial autoantigens (M2 complex) described in PBC. We have cloned and sequenced a rat complementary DNA which encodes for all the epitopes recognized by autoantibodies to the major, or 70-kd, mitochondrial autoantigen in patients with PBC. Using this recombinant fused autoantigen, as well as by immunoblotting with human placental mitochondria, we tested for antimitochondrial antibody specificity in sera from 250 patients with systemic sclerosis. Nineteen sera (7.6%), including those from patients with CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) and diffuse scleroderma, had reactivity with human placental mitochondria proteins by immunoblot testing. All 19 sera reacted with the M2 complex. All sera that reacted with the 70-kd protein likewise reacted with the recombinant cloned autoantigen. The predominant autoantibody isotype to the 70-kd protein was IgG3. Interestingly, the 70-kd protein is 11% proline, an amino acid which is frequently preceded by hydrophobic amino acids.

Antibody Specificity↗
PubMed2003

Proinsulin-a pathogenic autoantigen in type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterised by immunity to pancreatic beta-cell autoantigens, associated with beta-cell destruction leading to insulin deficiency and hyperglycaemia. The rigorous definition of an autoimmune disease requires evidence that an autoantigen elicits pathological immune responses. Using criteria for the pathogenicity of an autoantigen, we examine the evidence for proinsulin as an autoantigen in T1D. We conclude that proinsulin satisfies these criteria. As a corollary, proinsulin is a potential immunotherapeutic tool for the prevention of T1D.

Amino Acid Sequence↗
PubMed1996

Epitope mapping of the Ro/SSA60KD autoantigen reveals disease-specific antibody-binding profiles.

Anti-Ro60KD autoantibodies are commonly found in sera from patients with primary Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE). In order to identify the epitopes of this autoantigen, 22-mer, synthetic peptides overlapping by eight residues, and covering the entire sequence of the Ro60KD autoantigen were prepared. Three groups of sera were evaluated according to their autoantibody specificites. The first group consisted of monospecific anti Ro60KD sera from four patients with SLE and one with SS, the second one was composed of anti-Ro60KD+anti-La(SSB)-positive sera from four patients with SS and the third group included three normal sera and one anti Ro52KD serum. It was found that sera from SLE patients interact with a common antigenic site spanning the sequence TKYKQRNGWSHKDLLRSHLKP (169-190) of the Ro60KD protein. On the other hand, sera from SS patients recognise the ELYKEKALSVETEKLLKYLEAV (211-232) region of this autoantigen. Determination of the minimal required peptide length for optimal antibody recognition showed that the defined epitopes can be shortened to the NGWSHKDLLR (175-184) and KALSVETEKLLKYLEAV (216-232) sequences respectively. Inhibition experiments using the Ro60KD antigen and soluble peptides corresponding to the 175-184 and 216-232 segments further confirmed the specific antibody binding. These results, although only a small number of sera were used, indicate that the Ro60KD autoantigen, which is not characterized by disease specificity, contains two discrete epitopes specifically recognized from SLE and SS patient sera. Finally, the sequence similarity of the NGWSHKDLLR (175-184) epitope with some of the HLA haplotypes, associated with anti-Ro response, deserves to be noted.

Amino Acid Sequence↗
PubMed1979

Ultrastructural localization of guinea pig spermatozoal autoantigens on germinal cells by immunoperoxidase techniques.

Three guinea pig spermatozoal autoantigens S, P and T, each one able to induce autoimmune aspermatogenic orchiepididymitis and autoantibodies, were ultrastructurally localized in male germinal cells by immunoperoxidase techniques. Both living and prefixed sectioned cell preparations were treated and examined. Fab antibody fragments were used to study intracellular antigens (whole antibodies were inefficient). Water-soluble S and P autoantigens were found in acrosomal structures in the same sites: proacrosomal and acrosomal granules of the young spermatids, on the head caps of spermatids and acrosomal cap of spermatozoa, along the inner and outer acrosomal membranes and in the outer zone of the acrosomal matrix of the same cells. S was never found in the inner zone of spermatid or spermatozoa acrosomes, while P was present in this inner zone, but only of young spermatids. Water-insoluble T autoantigen was found on the plasmalemma and outer acrosomal membranes of spermatids and spermatozoa, inside the spermatid cytoplasm and, sometimes, on the inner acrosomal membrane of young spermatids. The specificity of the immunological localization for each antigen was confirmed by testing with specific antisera following absorption with homologous and heterologous antigens. No other testicular cell type (including Sertoli cells per se) was found to bear S, P or T autoantigens. When use was made of autoimmune sera obtained through autologous whole spermatozoa, the observed staining was an additive combination of what was observed when using the preceding three immune sera, anti-S, anti-P and anti-T.

Animals↗
PubMed2004

Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease.

Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver characterized by hypergammaglobulinemia, characteristic autoantibodies, association with HLA DR3 or DR4 and a favorable response to immunosuppressive treatment. The etiology is unknown. The detection of non-organ and liver-related autoantibodies remains the hallmark for the diagnosis of the disease in the absence of viral, metabolic, genetic, and toxic etiology of chronic hepatitis or hepatic injury. The current classification of AIH and the several autoantibodies/target-autoantigens found in this disease are reported. Current aspects on the significance of these markers in the differential diagnosis and the study of pathogenesis of AIH are also stated. AIH is subdivided into two major types; AIH type 1 (AIH-1) and type 2 (AIH-2). AIH-1 is characterized by the detection of smooth muscle autoantibodies (SMA) and/or antinuclear antibodies (ANA). Determination of antineutrophil cytoplasmic autoantibodies (ANCA), antibodies against the asialoglycoprotein receptor (anti-ASGP-R) and antibodies against to soluble liver antigens or liver-pancreas (anti-SLA/LP) may be useful for the identification of patients who are seronegative for ANA/SMA. AIH-2 is characterized by the presence of specific autoantibodies against liver and kidney microsomal antigens (anti-LKM type 1 or infrequently anti-LKM type 3) and/or autoantibodies against liver cytosol 1 antigen (anti-LC1). Anti-LKM-1 and anti-LKM-3 autoantibodies are also detected in some patients with chronic hepatitis C (HCV) and chronic hepatitis D (HDV). Cytochrome P450 2D6 (CYP2D6) has been documented as the major target-autoantigen of anti-LKM-1 autoantibodies in both AIH-2 and HCV infection. Recent convincing data demonstrated the expression of CYP2D6 on the surface of hepatocytes suggesting a pathogenetic role of anti-LKM-1 autoantibodies for the liver damage. Family 1 of UDP-glycuronosyltransferases has been identified as the target-autoantigen of anti-LKM-3. For these reasons the distinction between AIH and chronic viral hepatitis (especially of HCV) is of particular importance. Recently, the molecular target of anti-SLA/LP and anti-LC1 autoantibodies were identified as a 50 kDa UGA-suppressor tRNA-associated protein and a liver specific enzyme, the formiminotransferase cyclodeaminase, respectively. Anti-ASGP-R and anti-LC1 autoantibodies appear to correlate closely with disease severity and response to treatment suggesting a pathogenetic role of these autoantibodies for the hepatocellular injury. In general however, autoantibodies should not be used to monitor treatment, predict AIH activity or outcome. Finally, the current aspects on a specific form of AIH that may develop in some patients with a rare genetic syndrome, the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) are also given. Autoantibodies against liver microsomes (anti-LM) are the specific autoantibodies detected in AIH as a disease component of APECED but also in cases of dihydralazine-induced hepatitis. Cytochrome P450 1A2 has been identified as the target-autoantigen of anti-LM autoantibodies in both APECED-related AIH and dihydralazine-induced hepatitis. The latter may indicate that similar autoimmune pathogenetic mechanisms can lead to liver injury in susceptible individuals irrespective of the primary defect. Characterization of the autoantigen-autoantibody repertoire continues to be an attractive and important tool to get access to the correct diagnosis and to gain insight into the as yet unresolved mystery of how hepatic tolerance is given up and AIH ensues.

Journal Article↗
PubMed1997

Down-regulation of Ku autoantigen, DNA-dependent protein kinase, and poly(ADP-ribose) polymerase during cellular senescence.

During aging and cellular senescence mutations accumulate in genomic and mitochondrial DNA. Ku autoantigens, DNA-dependent protein kinase, and poly (ADP-ribose) polymerase have an essential role in DNA damage recognition. Our purpose was to find out whether cellular senescence of fibroblasts affects the protein components that recognize DNA damage and induce the repair process. We compared presenescent and replicatively senescent human WI-38 fibroblasts with each other and with SV-40 immortalized and serum-deficient quiescent WI-38 cells. Our results showed that replicative senescence significantly decreased the nuclear level of both p70 and p86 components of Ku autoantigen. SV-40 immortalization and cellular quiescence did not affect the level of the p86 component but slightly increased that of p70. Both replicative senescence and cellular quiescence decreased the activity of DNA-dependent protein kinase in WI-38 fibroblasts. On the other hand, SV-40 immortalization increased the activity of DNA-dependent protein kinase. The protein level of poly(ADP-ribose) polymerase (PARP) was strongly decreased in replicatively senescent fibroblasts. Quiescence of early-passage fibroblasts also slightly reduced the protein level of PARP. Apoptosis was not observed in replicatively senescent fibroblasts. Our results show that replicative senescence and to some extent cellular quiescence down-regulate the recognition system of DNA damage involving Ku autoantigens, DNA-dependent protein kinase, and PARP and hence could enhance the accumulation of DNA damage during aging.

Amino Acid Sequence↗