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R Mierau

Publications and source records attributed to R Mierau.

At least 19 recordsLinked to original sources
PubMed2006

[Scleroderma associated autoantibodies - clinical and diagnostic relevance].

In systemic sclerosis (SSc) and its variants, autoantibodies are the best known immunological aberration. In more than 95% of the patients, antinuclear antibodies or other autoantibodies can be detected. In about 90% of SSc patients with antinuclear antibodies, scleroderma associated autoantibodies highly specific for systemic sclerosis are found. These autoantibodies usually exclude each other in individual patients, and they are detectable early, persisting during the course of the disease. SSc patients characterized by scleroderma associated autoantibodies belong to disease subsets which are relatively homogeneous in clinical, genetic and prognostic terms. Besides these diagnostically relevant autoantibodies, numerous additional ones have also been described. These are neither SSc specific nor mutually exclusive, and their antigens have only been partially characterized. Some, however, are thought to be relevant to the as yet unanswered question of whether autoantibodies are directly involved in SSc pathogenesis.

Antibodies, Antinuclear↗
PubMed2002

[New aspects in autoantibody diagnosis in collagen diseases].

Distinct, especially non-organ specific autoantibodies are closely associated with connective tissue diseases and in many cases are vital elements of the laboratory diagnostics of these disorders. Their inclusion into the common classification criteria is quite heterogeneous. None of the autoantibodies is 100% specific for a certain disease, and diagnostic specificity is usually reduced when application of the test is broadened and when more sensitive methods are used. In individual patients with scleroderma and/or myositis related diseases, typical autoantibodies usually exclude each other; however, there are characteristical exceptions from that rule. Evidence is accumulating that autoantibodies are detectable early during disease course and often even in preclinical stages. Variations of antibody levels during disease course are different in different systems and in some cases have been shown to correlate with disease activity. Negative results in sensitive screening assays are often essential to exclude a connective tissue disease. Although it has certain drawbacks and is being disputed, the indirect immunofluorescence assay with HEp-2 cells still serves as a standard first step in connective tissue disease-related antibody detection. In case of positive results in this assay, further steps should be performed carefully, considering the signs and symptoms of the suspected disease as well as the immunofluorescence pattern, and being aware of the peculiarities and limitations of the assay methods used.

Antibody Specificity↗
PubMed2002

Coexistence of antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis.

BACKGROUND: Antibodies targeting DNA topoisomerase I (ATA) or centromere proteins (ACA) are associated with clinical subsets of patients with systemic sclerosis (SSc). The occurrence of those autoantibodies is considered to be mutually exclusive. OBJECTIVE: To describe the clinical and immunogenetic data of three patients who are co-expressing both antibodies, and then review previous publications. METHODS: Both antibodies were detected by different methods, including indirect immunofluorescence technique, enzyme linked immunosorbent assay, immunodiffusion, and immunoblot. Patients were HLA typed by serological and molecular genetic methods. Data were extracted from published reports for comparison. The search for published studies was through Medline and other database research programmes. RESULTS: During routine laboratory diagnostics over several years three patients with scleroderma and coincidence of ATA and ACA were identified: patient 1 with diffuse SSc, Raynaud's phenomenon, puffy fingers and fingertip necrosis, contractures, and calcinosis; patient 2 with diffuse SSc, Raynaud's phenomenon, oedema of the hands, and interstitial calcinosis of hands, knees, and shoulders, and pulmonary fibrosis; patient 3 with scleroderma of hands, forearms, and face, Raynaud's phenomenon, puffy fingers, finger contractures, fingertip necrosis, and calcinosis. All three patients studied were carriers of HLA alleles known to be associated with these autoantibodies. In serial measurements the concentrations of the two antibodies showed independent or even reverse fluctuations. Screening of 100 patients with ACA for ATA and vice versa disclosed no further patients with coincidence of these antibodies. Twenty eight cases of ACA/ATA coexistence in 5423 patients (0.52%) with SSc or SSc associated symptoms were found in an analysis of published studies. CONCLUSION: The expression of ATA and ACA is not totally mutually exclusive, but coincidence is rare (<1% of patients with SSc). Patients with both autoantibodies often have diffuse scleroderma and show immunogenetic features of both antibody defined subsets of SSc.

Adult↗
PubMed2001

A population of autoantibodies against a centromere-associated protein A major epitope motif cross-reacts with related cryptic epitopes on other nuclear autoantigens and on the Epstein-Barr nuclear antigen 1.

Autoimmune diseases arise from a host's immune response against self-antigens. The triggering events ultimately resulting in such a break of tolerance are largely unknown. It is also not known why certain molecular structures become autoantigenic. The hypothesis has long been proposed that autoimmune diseases arise from molecular mimicry followed by an epitope spreading mechanism. Recently we have shown that the anti-centromere-associated protein A (CENP-A) immune response is directed against an autoantigenic motif, G/A-P-R/S-R-R, that occurs three times in the N-terminal amino acids of CENP-A. In the present study we used mutational analyses with immobilized oligopeptide arrays to identify the amino acids in this motif that are responsible for antibody binding. In particular, we found that surprisingly mimotopes of this motif are present in a vast number of autoantigens and in the Epstein-Barr nuclear antigen 1. With affinity-purified antibodies we show that the antibodies against this motif are polyclonal and cross-react with several autoantigens. However, in these autoantigens this motif often represents a cryptic epitope explaining the obvious conflict between our results and the known high specificity of autoantibodies. The presence of such an ubiquitous structure on autoantigens suggests a novel peptide-driven mechanism for the evolution of autoantibodies.

Amino Acid Motifs↗
PubMed2000

Fine-specificity of the anti-CENP-A B-cell autoimmune response.

The major targets recognized by anti-centromere autoantibodies are the three centromere-associated proteins (CENPs) A, B, and C, with apparent molecular masses of 19, 80, and 140 kDa, respectively. Previously a major epitope region on the 19-kDa CENP-A antigen was identified by synthesis of a soluble synthetic 15-mer peptide (amino acids 3-17) to be used in enzyme-linked immunosorbent assay and western blot competition assays. However, no systematic experimental scanning for epitope regions on the CENP-A autoantigen has yet been performed. In this study we scanned the complete CENP-A amino acid sequence for epitopes using 19 previously characterized autoimmune-sera. Overlapping peptides 15 amino acids in length and offset by three amino acids were synthesized on activated membranes, covering the whole CENP-A autoantigen. Probing of the membranes with various anti-centromere sera showed that all epitopes are clustered in the N-terminal 45 amino acids. For fine-mapping of this autoreactive region the N-terminus of CENP-A (amino acids 1-45) was scanned again by probing overlapping 15-mer, 12-mer, 10-mer, 8-mer, 7-mer, 6-mer, and 5-mer peptides, all offset by one amino acid, with anti-centromere sera. In this way we localized two epitope core regions within the N-terminal 45 amino acids, one covering amino acids 2-17, recognized by 17 sera, and the other covering amino acids 22-38, recognized by 18 sera. One serum did not react with CENP-A at all. Several sera seem to recognize overlapping individual epitopes within these two epitope core regions. All sera, however, recognize a sequence motif G/A-P-R/S-R-R.

Adult↗
PubMed2000

Clinical and serological aspects of patients with anti-Jo-1 antibodies--an evolving spectrum of disease manifestations.

The aim of this study was to compare ELISA, immunodiffusion and immunoblot for the detection of anti-Jo-1 antibodies, and to investigate the association of the results with clinical manifestations. In two medical centres for rheumatology and one for pulmonology, all patients with suspected connective tissue disease were screened over a 5-year period for anti-Jo-1 antibodies by ELISA. Positive sera were controlled in another laboratory by immunodiffusion. If immunodiffusion was negative, sera were controlled again by ELISA. ELISA-positive immunodiffusion-negative sera were tested by immunoblotting. The patients were characterised clinically, and their clinical signs and symptoms were compared with those of 257 patients with anti-Jo-1 antibodies published in 15 case series and 30 case reports. Twenty-five patients had a positive ELISA test. Fifteen sera were positive by ELISA and immunodiffusion (group 1). Three sera showed high titres in both ELISA tests with negative immunodiffusion and immunoblot (group 2). Seven sera showed low titres in both ELISA tests. The results were negative in the other tests (group 3). Patients in groups 1 and 2 could be classified as Jo-1 syndrome patients. Of these 18 patients, 15 had arthritis, 14 had myositis and 14 had interstitial lung disease. Only four patients had myositis at disease onset. We describe four unusual patients with Jo-1 syndrome in detail: 1. Long history of seronegative rheumatoid arthritis; 2. Sjögren's syndrome with Ro- and La-antibodies; 3. Scleroderma and bronchial carcinoma with centromere antibodies; 4. Corticoid-sensitive psychosis. Patients with suspected connective tissue disease may be screened for anti-Jo-1 antibodies by ELISA. It detects some patients that are missed by immunodiffusion. Especially lower ELISA titres should be controlled by another method because of the low specificity of the test. The clinical picture is variable. Most patients have features other than myositis at disease onset.

Adult↗
PubMed1996

Strong association of dermatomyositis-specific Mi-2 autoantibodies with a tryptophan at position 9 of the HLA-DR beta chain.

OBJECTIVE: To characterize the clinical and immunogenetic features of patients with Mi-2 autoantibodies. METHODS: Eighteen adult white patients with Mi-2 antibodies were clinically characterized and compared with 41 Mi-2-negative dermatomyositis (DM) patients. HLA class I and class II typing for DRB alleles was done by microcytotoxicity assay and for DQA and DQB alleles by polymerase chain reaction-based oligotyping. RESULTS: Seventeen of the 18 Mi-2-positive patients had DM. Symptoms of scleroderma, lung involvement, and arthritis were less common in this group than in the Mi-2-negative DM patients; the V-sign rash and nailfold involvement were found more frequently. Mi-2 antibodies were strongly associated with HLA-DR7 (88% versus 24% in healthy controls), HLA-DQA1*0201 (86% versus 23%), and DR7 "homozygosity" (31% versus 0%). A tryptophan residue at position 9 of the HLA-DR beta chain was present in all Mi-2-positive patients (100% versus 62%; homozygous in 81% versus 15%). CONCLUSION: Our results reemphasize the specificity of Mi-2 antibodies for DM, and extend previous reports that Mi-2 antibody production is associated with certain HLA class II antigens. We propose beta 9-Trp as a candidate epitope on the HLA-DR beta chain as a prerequisite for this type of autoimmune response.

Adenosine Triphosphatases↗
PubMed1995

Clinical relevance and HLA association of autoantibodies against the nucleolus organizer region (NOR-90).

OBJECTIVE: NOR-90 autoantibodies directed against the nucleolus organizer region (NOR) have been described as rare scleroderma associated antibodies. We studied the clinical features of patients with NOR-90 antibodies as well as their HLA phenotype. METHODS: NOR-90 antibodies were detected by indirect immunofluorescence assay using HEp-2 cells, by chromosome spreads as a substrate and in addition by Western blot analysis with HeLa-S3 nucleolar extract. HLA antigens of the NOR-90 antibody positive patients were typed with the standard NIH complement dependent microcytotoxicity test. RESULTS: Nine sera selected by means of the indirect immunofluorescence revealed a typical double band pattern of about 90 kDa identical with the pattern of 2 NOR-90 reference sera by Western blot analysis. Only one patient positive for NOR-90 antibodies suffered from systemic sclerosis (limited cutaneous scleroderma). The other patients with NOR-90 antibodies showed no signs of systemic sclerosis. All patients with NOR-90 antibodies were women and 8 of 9 patients (89 versus 13% of healthy controls, Pcorr < 0.001) were positive for the HLA-DR1 allele. CONCLUSION: In contrast to the first report on NOR-90 antibodies we demonstrated no association of these antibodies with systemic sclerosis; however, we found strong evidence for an immunogenetic background of NOR-90 antibody formation.

Adult↗
PubMed1994

Persistence of a rheumatoid factor (RF)-producing B cell clone with a somatically mutated Ig kappa chain in a patient with rheumatoid arthritis.

The V kappa IV gene encoding the light chain of an IgA has been shown to have undergone 31 somatic mutations compared with the single existing V kappa IV germ-line gene. We now show the persistence of the rearranged and mutated DNA coding for this RF over a period of 5 years in the peripheral blood lymphocytes (PBL) of the patient with rheumatoid arthritis (RA). The sequence of the RF has been conserved to identity over this period. These results raise the possibility that the particular antigenic stimulus leading to RF production in this RA patient is active over a long period of time.

Arthritis, Rheumatoid↗
PubMed1992

A human monoclonal IgA rheumatoid factor using the VkIV light chain gene.

A human hybridoma stably secreting IgA rheumatoid factor (RF) was produced by cell hybridization with peripheral blood lymphocytes of a patient with rheumatoid arthritis. The RF was of the IgA1 isotype with kappa-light chains and was useful for standardization or specificity controls in class-specific RF assays. RF activity was detected only when the IgA molecular were in a polymeric state, and could be measured by enzyme linked immunosorbent assay as well as in conventional agglutination based tests. The RF had the modified Ga fine specificity described previously for several RFs and for protein A. The immunoglobulin V genes used were isolated and sequenced. The light chain was encoded by the VkIV gene rearranged to Jk2; compared to the published VkIV germ line gene there was 90% nucleotide homology. The heavy chain gene used belonged to the VHI family and was rearranged to JH4. Comparisons with published sequences revealed 90% homology with the recently characterized VH gene expressed by RF-TS3, a rheumatoid synovia RF hybridoma.

Aged↗
PubMed1992

A somatically mutated V kappa IV gene encoding a human rheumatoid factor light chain.

The light chain of an IgA kappa rheumatoid factor (RF) produced by a hybridoma derived from a patient with rheumatoid arthritis (RA) has been shown to belong to the V kappa IV family. This RF light chain has 31 nucleotide differences compared with the single V kappa IV germline gene reported for the human genome. The patient's V kappa IV germline gene was sequenced, using the polymerase chain reaction (PCR), and shown to be identical to that previously reported. This demonstrates that the RF light chain is the product of a somatically mutated gene. A comparison with other known V kappa IV sequences shows that the RF light chain has more replacement mutations than most of the known V kappa IV light chains.

Amino Acid Sequence↗
PubMed1990

Immunogenetic associations of scleroderma-related antinuclear antibodies.

Patients selected for the presence of scleroderma-related antibodies (anti-DNA-topoisomerase I [anti-topo I; n = 43], anticentromere antibody [ACA; n = 63], or anti-Pm-Scl [n = 12]) were studied for class I and class II major histocompatibility complex antigens, as well as for Gm and Km allotypes. Anti-topo I was associated with HLA-DR5 (70% of patients versus 30.6% of controls; Pcorr = 0.0018, relative risk [RR] = 5.3). All patients with anti-Pm-Scl were positive for HLA-DR3 (versus 23.5% of controls; Pcorr less than 0.001); 6 of these patients were DR3/4 heterozygous (50% versus 3.5% of controls; Pcorr less than 0.001, RR = 27.3). Patients with ACA were frequently positive for HLA-DR1, DR4, or DRw8, with 73.7% demonstrating at least 1 of these alleles (versus 41.2% of controls; Pcorr = 0.0152, RR = 4.0). This group of ACA-positive patients who had DR1, DR4, and/or DRw8 consisted mainly of a subgroup of patients with rheumatoid arthritis. We conclude that different class II major histocompatibility complex antigens influence the formation of anti-topo I and anti-Pm-Scl. Important clinical differences between these patient groups and the immunogenetic heterogeneity support the notion of different antibody-defined scleroderma subsets.

Antibodies, Antinuclear↗
PubMed1988

Immunoglobulin allotype Gm(1,2;21) in ankylosing spondylitis with peripheral arthritis.

Frequencies of immunoglobulin G (Gm) allotypes were determined in 240 patients with ankylosing spondylitis (AS). The uncommon phenotype Gm(1,2;21) was increased in frequency in 55 patients with AS and peripheral arthritis (14.5% v 3.5% of healthy blood donors; p less than 0.05). In 16 patients with arthritis only of wrist/hand or ankle/forefoot, or both, the Gm(1,2;21) frequency was even higher (31.3%; p less than 0.0005). Patients with AS negative for the HLA antigen B27 (n = 28) differed from the B27 positive patients (n = 205) with regard to the frequency of the Gm(1,2,3;5,21) phenotype (39.3% v 9.3%; p less than 0.0005). These findings support the notion of genetic heterogeneity among patients with AS.

Adult↗