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ID PMID Title PublicationDate abstract
9112225 Clinical and immunological aspects of autoantibodies to RA33/hnRNP-A/B proteins--a link be 1996 Heterogeneous nuclear ribonucleoprotein (hnRNP) complexes are major constituents of the spliceosome. They are composed of approximately 30 different proteins which can bind to nascent pre-mRNA. Among these, the hnRNP-A/B proteins form a subgroup of highly related proteins consisting of two adjacent RNA binding domains (RBD) within the N-terminal parts, whereas the C-terminal halves contain almost 50% glycine residues. These proteins, in particular A2/RA33, are targeted by autoantibodies from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD). In SLE anti-hnRNP antibodies frequently occur together with antibodies to U1 small nuclear RNP (U1-snRNP) and Sm, other proteins of the spliceosome. Preliminary epitope mapping studies have revealed major antibody binding sites in the RNA binding regions for all three diseases. Nevertheless, there is some indication of disease specific epitope recognition. Studies in animal models have demonstrated anti-RA33/hnRNP-A/B antibodies in lupus-prone mouse strains. Thus, autoantibodies to the spliceosomal hnRNP-A/B proteins are a common feature of RA, SLE, and MCTD. However, these diseases differ in their reactivities to other spliceosomal proteins, especially anti-U1 snRNP and Sm. Therefore, anti-RA33/hnRNP-A/B autoantibodies are not only valuable diagnostic markers but may also allow additional insights into the pathogenesis of rheumatic autoimmune diseases.
1611714 Autoantibodies to major and minor nuclear lamins are not restricted to autoimmune diseases 1992 May Autoantibodies to lamins, the major polypeptide components of the nuclear lamina, have been reported in selected sera from patients with autoimmune diseases, including anti-lamin B in systemic lupus erythematosus (SLE) and anti-lamins AC in autoimmune chronic active hepatitis (CAH). We have studied the frequency, specificity, and isotypy of autoantibodies to major and minor lamins by immunoblotting on purified rat liver lamins in 190 sera from normal controls (n = 62), rheumatic disease controls (n = 42), and autoimmune disease patients (n = 86). The frequency of anti-lamin in normal controls was 85.5%, and ranged from 77 to 100% in the other groups. Anti-lamin frequency was not related to age, sex, or disease duration. Reactivity with lamin A or with minor lamins only was observed with 7 various sera and 2 normal sera, respectively. Between groups, the proportions of reactive sera were not different for lamins AC (18-47%) and for lamin B (22-36%). In particular, anti-lamin B and anti-lamins AC were not more common in SLE or CAH than in normal sera. The most frequent lamin specificity of SLE sera was anti-lamins ABC. Anti-lamin isotypes were IgG and/or IgM. Titers of IgM antibodies were not higher in any group. However, IgG anti-lamin titers were higher in CAH than in normal, ankylosing spondylitis, or SLE sera. The highest end point titers (greater than or equal to 1:3200) were observed with CAH, SLE, and rheumatoid arthritis (RA) sera with IgG anti-lamins AC, B, or ABC, or with IgM anti-lamins ABC. None of these SLE and RA patients had evidence of liver disease. Reactivity with minor lamins was more frequent in CAH. We conclude that anti-lamin autoantibodies are present in sera from most individuals and that the highest titers are found in sera from patients with autoimmune diseases.
1593578 Cognitive impairment in patients with systemic lupus erythematosus. 1992 Apr Seventy unselected patients with systemic lupus erythematosus (SLE) were studied to determine the prevalence of cognitive impairment and the association with other clinical variables. Twenty-five patients with rheumatoid arthritis (RA) and 23 healthy subjects were used as controls. All patients were evaluated with a battery of standardized neuropsychological tests to determine ability in 8 areas of cognitive function. Clinically overt neuropsychiatric (NP) SLE, cumulative disease manifestations and concurrent medications were documented. In patients with SLE, generalized disease activity was expressed using the SLE disease activity index. Cognitive impairment was identified in 15/70 (21%) patients with SLE, 1/25 (4%) patients with RA and in 1/23 (4%) healthy subjects (p = 0.042). The prevalence was higher in patients with active NP-SLE at the time of assessment (2/5, 40%) compared to patients with inactive NP-SLE (2/10, 20%) but was also increased in those patients who had never had known clinical NP-SLE (11/55, 20%). A history of serositis (p = 0.015), active SLE (p = 0.064) and corticosteroid use (p = 0.027) at the time of assessment were more common in patients with cognitive impairment. The results suggest that cognitive impairment is increased in patients with SLE. It may occur independently of clinically overt NP-SLE and is more common in patients with active disease who are receiving corticosteroids.
9024938 Vesnarinone is a selective inhibitor of macrophage TNF(alpha) release. 1996 Jun Vesnarinone is an experimental drug that has been used successfully in the treatment of congestive heart failure patients. In this report we investigate the effect of vesnarinone on the cytokine secretory products of mononuclear phagocytes. In a concentration-dependent manner, the drug inhibits the endotoxin(LPS)-stimulated release of tumor necrosis factor (TNF) alpha and suppresses interleukin(IL)-6 release, but does not affect the release of IL-1 alpha, IL-10 and leukemia inhibitory factor (LIF) by mouse peritoneal macrophages. Using competitive polymerase chain reaction (PCR) analyses, we find that vesnarinone significantly reduces TNF(alpha), but not IL-10 mRNA. In addition to LPS, the drug inhibits TNF(alpha) release induced by several other stimuli. The inhibitory effect of the drug on the TNF(alpha) biosynthesis can be observed in differentiated human monocytes, in macrophage cell lines, and in synovial adherent cells from rheumatoid arthritis patients. Although the precise mode of action of vesnarinone in the signal transduction pathway leading to the selective inhibition of TNF(alpha) is not known, the drug might be useful in the treatment of diseases involving that cytokine.
8769502 Evolution of idiopathic pleural effusion: a prospective, long-term follow-up study. 1996 Jun The management of idiopathic pleural effusion remains controversial. Because the long-term evolution of this entity is not well known, two different approaches, aggressive and conservative, have been proposed. We conducted a 10-year study of the evolution of idiopathic pleural effusion. METHODS: Between 1984 and 1994, we prospectively studied 40 consecutive patients (30 men and 10 women; mean [+/- SD] age, 53.8 +/- 19.4 years) with exudative pleural effusion undiagnosed after exhaustive evaluation. The pleural fluid adenosine deaminase level was below 43 IU/L in all; periodic chest radiographs and clinical evaluation were carried out in all patients for a mean of 62 months (range, 36 to 108 months). Further diagnostic procedures were performed whenever the effusion recurred or when indicated by the clinical picture. RESULTS: Effusions resolved in a mean time of 5.6 months (range, 7 days to 48 months). Five patients (12.5%) had one or more relapses of their pleural effusion, and in a further 5 (12.5%), the effusion persisted unchanged for more than 1 month. In 32 cases (80%), no potential cause of the effusion was detected. The diagnoses in the remaining eight cases were asbestos pleural effusion in three, pulmonary adenocarcinoma in one, mesothelioma in one, congestive heart failure in one, liver cirrhosis in one, and rheumatoid arthritis in one. Tuberculosis was not detected in any of the cases, although 19 patients initially had positive tuberculin tests. CONCLUSIONS: Most idiopathic pleural effusions follow a benign course. Our results support conservative treatment of patients with idiopathic pleural effusion. Antituberculous treatment does not appear to he warranted, regardless of tuberculin test results, if the pleural fluid adenosine deaminase level is not elevated.
7594527 Inhibition of expression of cyclin A in human B cells by an immunosuppressant mizoribine. 1995 Dec 1 Mizoribine has been used to prevent rejection of organ allografts in humans and in animal models. Recent clinical trials have demonstrated its efficacy in rheumatoid arthritis and lupus nephritis, in which abnormalities of B cell functions are also involved. We therefore examined the effects of mizoribine on the in vitro function of human B cells. IgM production was induced from highly purified B cells obtained from healthy donors by stimulation with Staphylococcus aureus Cowan I (SA) plus IL-2. Mizoribine suppressed the production of IgM at its pharmacologically attainable concentrations (1 to 3 micrograms/ml) in a dose-dependent manner. Mizoribine had to be present within the first 96 h after the initiation of cultures to exert its suppressive effects on B cell responses. Cell cycle analysis disclosed that mizoribine significantly decreased the numbers of B cells in S + G2 + M phases. Mizoribine did not decrease GTP levels in SA-stimulated B cells, whereas mizoribine led to a decrease in GTP levels in activated T cells, which was reversed by addition of GMP. Consistently, the suppressive effects of mizoribine on the IgM production of SA-stimulated B cells was not reversed by the addition of GMP as much as 40 microM, which overcame the inhibitory effects of mizoribine on the proliferation of anti-CD3-stimulated T cells. Although mizoribine did not suppress the expression of CD25 and cdc2 kinase, mizoribine markedly suppressed the expression of cyclin A in SA-activated B cells. These results indicate that mizoribine directly suppresses the function of human B cells without interfering with the initial phase of activation. Moreover, the data demonstrate that mizoribine interferes with the cell cycle progression of activated B cells by suppressing the expression of cyclin A by a mechanism distinct from guanine ribonucleotide depletion.
7544246 Autoantibodies to malondialdehyde-modified epitope in connective tissue diseases and vascu 1995 Aug Malondialdehyde (MDA), a peroxidative end-product released during polyunsaturated fatty acid degradation, reacts strongly with lysine residues of cellular proteins. MDA-modified proteins become immunogenic and may elicit specific autoantibody formation. We hypothesized that systemic diseases in which inflammatory events occur, could be an interesting model for studying oxidative stress. A few studies have suggested that MDA-modified proteins may exist in systemic diseases, and that autoantibodies to MDA-modified structures might reflect this oxidative process. Autoantibodies to MDA-modified epitope(s) were therefore assayed in sera of patients with systemic lupus erythematosus (SLE, n = 29), scleroderma (SCL, n = 11), giant cell arteritis (GCA, n = 11), periarteritis nodosa (PAN, n = 10), rheumatoid arthritis (RA, n = 9), and healthy subjects (HS, n = 32). Significantly increased anti-MDA-modified epitope(s) autoantibodies were found in patients with SLE and also in other systemic diseases such as PAN and SCL. Autoantibodies to MDA-modified epitope(s) were predominantly of IgM isotype, with low levels of IgG and no IgA activity. In SLE, anti-MDA-modified epitope(s) autoantibody titres correlated strongly with systemic lupus activity measure (SLAM, r = 0.702, P = 0.0001), anti-nuclear antigen autoantibodies (ANA, r = 0.4, P = 0.029), IgG anti-cardiolipin (r = 0.558, P = 0.03) and the steroid drug regimen (r = 0.52, P = 0.004). Autoantibodies to MDA-modified epitope(s) may reflect oxidative modifications occurring in systemic diseases, and might be useful as clinical markers of SLE activity if further investigated.
7743549 The importance of DR4Dw4 beta chain residues 70, 71, and 86 in peptide binding and T cell 1995 May The expression of specific alleles of the human HLA-DR locus is associated with increased risk for the development of rheumatoid arthritis. Examination of the amino acid sequence of the DR beta chain has revealed that risk for RA correlates with a cluster of polymorphic residues located between positions 67 and 86, and in particular with the identity of residues 70, 71, and 86. To examine the contributions of these HLA-DR polymorphic residues to antigen-specific T cell responses, the DRB1*0401 gene was subjected to site-directed mutagenesis and forms possessing alanine in place of the naturally occurring amino acid at positions 70, 71, 86, and 70/71 were generated. The mutated genes were coexpressed with the DRA gene in Chinese hamster ovary cells and the transfectants were tested as stimulator cells for a panel of three human influenza virus hemagglutinin-specific T cell clones. Additionally, soluble forms of the mutant DR molecules were examined for their ability to bind peptide. All of the mutants had a modest loss of affinity for the peptide relative to the wild type, but there were no significant differences in peptide binding ability among the substituted molecules. In contrast to the relatively uniform influence on peptide binding, the impact of these mutations on T cell stimulation was heterogeneous. Specifically, these studies indicate that residue 71 plays a critical role in T cell stimulation either through direct contact with the T cell receptor or by changing the orientation or conformation of the peptide-MHC complex. Replacement of residue 71 with alanine abrogated stimulation of all of the T cell clones. Two of three clones were affected by changes at residue 70 while none lost recognition when amino acid 86 was converted from Val to Ala. These data emphasize that subtle alterations in structure can have a profound impact on T cell recognition.
7557499 Persistent grossly elevated erythrocyte sedimentation rate in elderly people: one year fol 1995 The significance of a very elevated erythrocyte sedimentation rate (ESR) in elderly patients is debated. In a retrospective study, we searched the records of a laboratory providing the sole service to a health district for ESR measurement and identified all non-surgical and non-psychiatric patients over the age of 65 who had had an ESR above 50 mm/h. Diagnoses and mortality in a 1-year follow-up were determined from case notes. Four hundred and nine subjects (median age 75; range 65-99) were identified and data on 401 of these (155 male, 246 female; median ESR 80 mm/h, range 50-148) were adequate for 1 year follow-up. Forty-eight percent had a persistently raised ESR (two values > 50 mm/h separated by at least 14 days; group 1); 39% had a single ESR measurement only (group 2), and 13% had a transiently raised ESR (group 3). The commonest diagnosis in group 1 patients was rheumatological disease (51.8%), followed by infection (31.9%) and non-haematological malignancy (11%). Infection was the commonest diagnosis in groups 2 (47.4%) and 3 (43.7%), followed by non-haematological malignancy (19.9%) in group 2 and rheumatological disease (20.4%) in group 3. In only 1 in 20 cases was no diagnosis apparent at 1 year. The standardised mortality ratio (SMR) of the combined groups 1 and 2 (482; CI: 421-544) was strikingly raised, and even more so if patients with rheumatoid arthritis were excluded (542; CI 458-625). Where there were sufficient numbers of deaths to make SMR estimations valid, a gradient of mortality against the level of the ESR could be observed.(ABSTRACT TRUNCATED AT 250 WORDS)
7520755 Inhibition of receptor binding by high-affinity RNA ligands to vascular endothelial growth 1994 Aug 30 The proliferation of new blood vessels (angiogenesis) is a process that accompanies many pathological conditions including rheumatoid arthritis and solid tumor growth. Among angiogenic cytokines that have been identified to date, vascular endothelial growth factor (VEGF) is one of the most potent. We used SELEX [systematic evolution of ligands by exponential enrichment; Tuerk, C., & Gold, L. (1990) Science 249, 505-510] to identify RNA ligands that bind to VEGF in a specific manner with affinities in the low nanomolar range. Ligands were selected from a starting pool of about 10(14) RNA molecules containing 30 randomized positions. Isolates from the affinity-enriched pool were grouped into six distinct families on the basis of primary and secondary structure similarities. Minimal sequence information required for high-affinity binding to VEGF is contained in 29-36-nucleotide motifs. Binding of truncated (minimal) high-affinity ligands to VEGF is competitive with that of other truncated ligands and heparin. Furthermore, truncated ligands from the six ligand families inhibit binding of [125I]VEGF to its cell-surface receptors. Oligonucleotide ligands described here represent an initial set of lead compounds in our ongoing effort toward the development of potent and specific VEGF antagonists.
9098429 Tap gene associations in UK caucasoids. 1994 Jun The authors determined the allele frequencies of the TAP1 and TAP2 transporter genes in a healthy UK Caucasoid population by ARMS-PCR. TAP1A was the most frequent TAP1 allele by far, being present in 76% of subjects. TAP1 alleles could not be assigned in 24% of subjects, since the combinations TAP1A/1b and TAP1C/1D cannot be separated. TAP2A was the most frequent TAP2 alleles (75% of subjects) followed by TAP2B (43%), TAP2C (11%), TAP2D (8%) and TAP2E (6%). The authors also identified an individual with a previously undescribed TAP2 allele, TAP2H (isoleucine at amino acid [aa] 379, alanine at aa 565, alanine at aa 665). It was not possible to assign unequivocally TAP2 alleles in 15 individuals (9%) as TAP2A/D and TAP2C/E cannot be distinguished from each other. To address this problem a separate study of families of rheumatoid arthritis (RA) patients selected for this ambiguity were studied. In all five informative families, TAP2A/2D was confirmed as the combination present. In the population studied no evidence was found for linkage disequilibrium between TAP1 and TAP2 or between the TAP genes and HLA-DP. There was no evidence for extensive linkage disequilibrium between the TAP genes and HLA-DQR, although TAP2B was associated with DRI (delta = 0.056, corrected P < 0.01) and TAP2D with DR4 (delta = 0.018). In the RA families studied, TAP2D was found on DRB1*0401-bearing haplotypes.
8069529 Soluble Fc epsilon RII/CD23 in patients with autoimmune diseases and Epstein-Barr virus-re 1994 Feb The low-affinity Fc receptor for IgE (Fc epsilon RII/CD23) and its soluble form (sCD23, IgE-binding factor) have multiple functions, and enhanced levels of these are associated with various immunological diseases. We established two sensitive ELISA systems using enzyme-conjugated mAb and biotinylated mAb. The detection limits of the ELISA systems were 0.03 and 1.0 ng/ml, which showed good correlation in the range 1.0-10 ng/ml. In the ELISA system using enzyme-conjugated mAb, the average sCD23 concentration in 303 normal healthy volunteers was 1.4 +/- 0.3 ng/ml. In the ELISA system using biotinylated mAb, sCD23 levels in normal healthy volunteers showed almost the same values. In patients with autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, progressive systemic sclerosis, and mixed connective tissue disease, the sCD23 levels were significantly higher than those in normal individuals. Furthermore, in Epstein-Barr virus-related disorders after liver transplantation with immunosuppression, plasma levels of sCD23 rapidly increased to more than 12 ng/ml when clinical symptoms were evident. In addition, the sCD23 values remained high, although elevated GOT levels gradually decreased to standard values and EBV hepatitis improved. These data suggest that sCD23 levels are a sensitive marker of autoimmune diseases and EBV-related disorders in addition to allergic disorders. The ELISA system for sCD23 may be an additional diagnostic tool in estimating the clinical courses of these diseases.
8308768 A comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcuta 1993 Nov OBJECTIVE: To compare the relative bioavailability of low dose methotrexate (MTX) administered as tablet, oral solution, and subcutaneous (sc) injection to that of intramuscular (im) injection in patients with rheumatoid arthritis (RA). METHODS: Twelve patients meeting the American College of Rheumatology criteria for RA had serial blood MTX concentration samples drawn over a 24-h period after receiving their normal weekly MTX dose. Relative bioavailability (F) of the tablet and oral solution formulations was determined by comparison of the area under the time-versus-serum-concentration curves (AUC) for the 2 different oral formulations as a percentage of the AUC for im injection. Also, relative bioavailability of the sc formulation was compared to im in 6 of the patients. RESULTS: Mean F for the oral tablet was 0.85, while that for the oral solution was 0.87. Both oral formulations showed a statistically significant difference in mean F when compared to im (tablet vs im, p = 0.002, oral solution vs im, p = 0.009). No statistically significant difference, however, was found in mean relative bioavailability between tablet and solution (p = 0.744). The mean F for sc was 0.97; no statistically significant difference existed between the mean F values for the sc and im routes of administration (p = 0.657). CONCLUSIONS: Our data suggest the oral solution may be substituted for tablet dosing and sc injection substituted for im. Thus, a variety of different dosing methodologies may be considered providing the most appropriate route in each patient, given issues of compliance, medication cost, and preference.
8402323 The effects of liposome-encapsulated and free clodronate on the growth of macrophage-like 1993 Aug Clodronate (dichloromethylene bisphosphonate) inhibits the activity of osteoclasts, thereby preventing bone resorption in disorders characterized by excessive bone loss. Intravenously injected clodronate encapsulated in liposomes is also known to inactivate phagocytic cells in spleen and liver in vivo. The macrophage suppressive effect of clodronate is of interest in autoimmune diseases, like rheumatoid arthritis, in which phagocytic cells are involved in inflammatory processes, but knowledge of the interaction of clodronate with phagocytic cells is scarce. We have studied the uptake of clodronate, both free and encapsulated in negatively charged liposomes, by the macrophage-like cell line RAW 264 and by other types of cell lines. The uptake was assessed by a growth inhibition assay. The liposome-encapsulated clodronate was 50 and 350 times more potent than free drug for RAW 264 and CV1-P, respectively. Cell lines with a lower endocytotic capacity were insensitive to liposome-mediated delivery of the drug. The action of free clodronate seemed to be extracellular in all cell lines studied. Calcium and/or iron have been suggested to be involved in the intracellular uptake and action of clodronate in phagocytic cells. We found that the uptake of free clodronate by RAW 264 cells was indeed mediated by calcium and iron, while the uptake of liposomal drugs was only slightly affected by calcium. The increased intracellular calcium concentration in macrophages did not significantly affect the growth-inhibitory properties of clodronate, whereas iron loading of the cells partially restored the cell growth. The data do not support the role of calcium chelation as a mechanism of action of clodronate, but suggest that intracellular iron is, at least partially involved.
8456633 Doxycycline protects serum alpha-1-antitrypsin from human neutrophil collagenase. 1993 Interstitial collagenases, members of the matrix metalloproteinase family, are key initiators of collagen destruction during various disorders such as rheumatoid arthritis. Recently interstitial collagenases were found to efficiently degrade an additional non-collagenous substrate, the serum alpha-1-antitrypsin (AAT also called alpha-1-proteinase inhibitor or serpin). Serpins are major endogenous inhibitors of serine proteinases, particularly neutrophil elastase. Of relevance to neutrophil-mediated collagen degradation, the tetracycline family of antibiotics are now known to inhibit inhibit mammalian collagenases by a mechanism unrelated to their antimicrobial activity. This study identifies an additional mechanism by which tetracyclines may retard tissue breakdown during inflammatory diseases. Doxycycline, added to the reaction mixture as in concentrations as low as 10 microM, which correspond to levels of the drug readily achieved in vivo, produced detectable inhibition of serpinase activity of neutrophil collagenase, although levels of 50-100 microM or greater were required to reduce AAT degradation more than 75%. The concentration of doxycycline to inhibit 50% (IC50 of serpinase activity) of AAT degradation by neutrophil collagenase was found to approximate 20 microM, a value similar to the IC50 for doxycycline required to inhibit collagen degradation by neutrophil collagenase. Doxycycline was also found to inhibit at cell level neutrophil-mediated degradation of AAT. The protection of bodies' AAT-shield from serpinolytic activity of collagenase would result in inhibition of serine proteinases such as neutrophil elastase. Tetracyclines may thus protect matrix constituents from a wider spectrum of neutral proteases than previously recognized, not just from the matrix metalloproteinases collagenase and gelatinase.
28769176 EFFICACY OF SUCRALFATE IN PREVENTING GASTROINTESTINAL SIDE EFFECTS OF NSAIDs. 1994 Apr To find out the efficacy of sucralfate in preventing gastrointestinal side effects of non-steroidal anti-inflammatory drugs (NSAIDs) a prospective, randomised single blind study was conducted from 1989 to 1992. Patients with osteoarthritis, rheumatoid arthritis and other long standing painful conditions, who were expected to receive NSAIDs for over three months, were recruited into the study. All medicines were discontinued for a period of 10-15 days prior to initial endoscopic assessment. NSAID therapy was started and the patients were randomised to receive either placebo (group A) or sucralfate (group B) in addition. Patient were reassessed clinically every week and an endoscopic examination was repeated after 6-8 weeks of follow-up. A total of 176 patients were studied in group A (n=91) and group B (n=85). At the end of 8 weeks gastrointestinal symptoms were present in 30.6% and 26.4% patients of group A and B respectively. Endoscopic assessment showed superficial lesions in 36.5% and 18.7% while endoscopic ulcer in 2.4% and 1.1% patients of groups A and B respectively. Thus in patients receiving chronic NSAID therapy, simultaneous administration of sucralfate reduces the incidence of superficial gastric lesions but has no significant effect on symptoms or ulcer formation.
8776373 Reversible cutaneous lymphoma occurring during methotrexate therapy. 1996 Jul A B-cell lymphoma, restricted to the skin, developed in a 58-year-old man receiving methotrexate for non-rheumatoid peripheral arthritis, with the simultaneous occurrence of a cytolytic hepatitis and carcinoma of the lung. Two weeks after methotrexate was stopped, both the skin tumour and the hepatitis disappeared spontaneously, with no recurrence during a 12-month follow-up period. Immunoglobulin gene rearrangement was shown by polymerase chain reaction (PCR) but in situ hybridization failed to reveal neoplastic cells positive for Epstein-Barr virus (EBV).
7938045 Synthetic autoantigens of immunoglobulins and T-cell receptors: their recognition in aging 1994 Nov Immunoglobulins and their close relatives, the antigen-specific T-cell receptors, are recognition proteins that express structures which readily serve as self-immunogens. Healthy humans can produce antibodies against variable region-defined recognition structures termed idiotypes, as well as against constant region structures, and the levels of these can increase markedly in autoimmune disease; e.g., rheumatoid factors are autoantibodies directed against a conformational determinant of the gamma heavy chain. More recent analyses employing synthetic peptide technologies and construction of recombinant T-cell receptors document that autoantibodies directed against both variable and constant region markers of the alpha/beta T-cell receptor occur in healthy individuals. Alterations in levels of antibody, usage of IgM or IgG isotypes, and specificity for particular peptide-defined regions vary with natural physiological processes (aging, pregnancy), with artificial allografting, with retroviral infection, and with the inception and progression of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus). Two of the major autoimmunogeneic regions of the Tcr alpha/beta are "constitutive" markers inasmuch as all individuals tested produce antibodies against these regions. The most frequently observed autoantibodies are against Tcr V beta CDR1 and Fr3 markers. It is hypothesized that these are normally involved in immunoregulation. Autoantibodies usually are not detected against CDR2 region determinants, or the "private idiotypes" defined by the CDR3 region, or the highly conserved FR4 segment specified by the joining gene segment. However, autoantibodies against the CDR2 of the Tcr alpha chain occur in some SLE patients, and healthy pregnant women produce antibodies against the common peptide determinant expressed by the joining gene and the beginning of the C alpha or C beta domain. Although the precise role of the naturally occurring autoantibodies in immunoregulation remains to be determined, modification of the course of autoimmune diseases in experimental rodent models (experimental allergic encephalomyelitis) has been successfully carried out by immunization with synthetic peptides corresponding to the CDR2 and Fr3/CDR3 segments, and immunization of humans with synthetic V beta CDR2 segments may prove helpful in multiple sclerosis. Moreover, infusion of intravenous immunoglobulins has been successful in the treatment of many autoimmune diseases, including examples where levels of T cells bearing particular V beta gene subsets were elevated. The recent knowledge gained from T-cell receptor structural analysis and antigenic modeling holds promise for determining the roles of particular variable domain structures in antigen recognition MHC-restriction and immunoregulation, and in the development of synthetic and recombinant reagents for modulation of autoimmune and infectious diseases.
8972954 Cheilo-candidosis in an adult. 1996 Nov 9 A rare case of candidal infection of the lips is presented. Predisposing factors appeared to be intra-oral candidal carriage, actinic lip damage and Sjögren's syndrome. Systemic antifungal therapy with fluconazole resolved the initial infection and a subsequent recurrence.
7515377 Heterogeneity of human anti-Golgi auto-antibodies: reactivity with components from 35 to 2 1994 Apr The Golgi auto-antigens recognized by five human autoimmune sera were characterized with anti-Golgi auto-antibodies. The five sera showed strong anti-Golgi reactivity, together with weak anti-nuclear reactivity, as assessed by indirect immunofluorescence using the human HEp2 epithelial cell line. The Golgi auto-antigens recognized by the autoimmune sera were identified by immunoprecipitation and immunoblotting of post-nuclear supernatants. These sera reacted with at least 14 components of molecular mass (M(r)) 35-260 kDa; three components were detected only by immunoprecipitation, six components detected only by immunoblotting and five components appear to be detected by both techniques. We have previously shown that a patient with Sjögren's syndrome has auto-antibodies specific for a 230 kDa Golgi auto-antigens; a bacterial fusion protein containing auto-epitope(s) of this Golgi auto-antigen is not recognized by the other four autoimmune sera. Taken together, this study shows that the five anti-Golgi autoimmune sera recognize distinct sets of auto-antigens which include both conformational and/or sequential epitopes.